Physiol Rev
84: 489 –539, 2004; 10.1152/physrev.00030.2003.
Control of Aldosterone Secretion: A Model
for Convergence in Cellular Signaling Pathways
ANDRÁS SPÄT AND LÁSZLÓ HUNYADY
Department of Physiology and Laboratory of Cellular and Molecular Physiology, Semmelweis University and
Hungarian Academy of Sciences, Budapest, Hungary
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I. Introduction: Multiple Control of Aldosterone Secretion—Multiplicity of Signal Transduction
Pathways in the Glomerulosa Cell
II. Calcium Signal Generation in Glomerulosa Cells
A. Receptor-mediated Ca2⫹ release
B. Ca2⫹ transport through the plasma membrane
C. Diacylglycerol-PKC and lipoxygenase pathways
D. Vasopressin: a transiently acting paracrine agonist
III. Effect of Cytoplasmic Calcium on Mitochondrial Function
IV. Cross-Talk Between Calcium and cAMP-Activated Pathways
A. Ca2⫹ influx evoked by ACTH
B. Ca2⫹-induced formation of cAMP
V. Regulation at the Level of Plasma Membrane Receptors
A. Mechanisms for regulation of GPCRs
B. Regulation of adrenal angiotensin receptors in vivo
C. Desensitization of glomerulosa cells
D. Intracellular trafficking of angiotensin receptors
E. Receptor downregulation
VI. Long-Term Effects of Angiotensin II
A. Activation of growth responses by ANG II in the glomerulosa cell
B. Role of receptor and nonreceptor tyrosine kinases
C. ANG II-induced activation of MAPKs
VII. The Final Action: Role of Calcium in the Control of Steroid Production
A. Cholesterol transport
B. Increased reduction of pyridine nucleotides in mitochondria
C. Induction of aldosterone synthase
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Spät, András, and László Hunyady. Control of Aldosterone Secretion: A Model for Convergence in Cellular
Signaling Pathways. Physiol Rev 84: 489 –539, 2004; 10.1152/physrev.00030.2003.—Aldosterone secretion by glomerulosa cells is stimulated by angiotensin II (ANG II), extracellular K⫹, corticotrophin, and several paracrine factors.
Electrophysiological, fluorimetric, and molecular biological techniques have significantly clarified the molecular
action of these stimuli. The steroidogenic effect of corticotrophin is mediated by adenylyl cyclase, whereas
potassium activates voltage-operated Ca2⫹ channels. ANG II, bound to AT1 receptors, acts through the inositol
1,4,5-trisphosphate (IP3)-Ca2⫹/calmodulin system. All three types of IP3 receptors are coexpressed, rendering a
complex control of Ca2⫹ release possible. Ca2⫹ release is followed by both capacitative and voltage-activated Ca2⫹
influx. ANG II inhibits the background K⫹ channel TASK and Na⫹-K⫹-ATPase, and the ensuing depolarization
activates T-type (Cav3.2) Ca2⫹ channels. Activation of protein kinase C by diacylglcerol (DAG) inhibits aldosterone
production, whereas the arachidonate released from DAG in ANG II-stimulated cells is converted by lipoxygenase
to 12-hydroxyeicosatetraenoic acid, which may also induce Ca2⫹ signaling. Feedback effects and cross-talk of
signal-transducing pathways sensitize glomerulosa cells to low-intensity stimuli, such as physiological elevations of
[K⫹] (ⱕ1 mM), ANG II, and ACTH. Ca2⫹ signaling is also modified by cell swelling, as well as receptor desensitization, resensitization, and downregulation. Long-term regulation of glomerulosa cells involves cell growth and
proliferation and induction of steroidogenic enzymes. Ca2⫹, receptor, and nonreceptor tyrosine kinases and
mitogen-activated kinases participate in these processes. Ca2⫹- and cAMP-dependent phosphorylation induce the
transfer of the steroid precursor cholesterol from the cytoplasm to the inner mitochondrial membrane. Ca2⫹
signaling, transferred into the mitochondria, stimulates the reduction of pyridine nucleotides.
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I. INTRODUCTION: MULTIPLE CONTROL OF
ALDOSTERONE SECRETION—MULTIPLICITY
OF SIGNAL TRANSDUCTION PATHWAYS IN
THE GLOMERULOSA CELL
TABLE
1. Stimuli of aldosterone production in vitro
Stimuli of Aldosterone Production
Acetylcholine (293)
Angiotensin II (198)
ATP (274)
Bradykinin (469)
Cholecystokinin (336)
Corticotrophin (ACTH) (278)
␤-Endorphine (529)
Enkephalins (239)
Endothelin (195)
Epidermal growth factor (282)
12-Hydroxyeicosatetraenoic acid (378)
Kⴙ (368)
Melanocyte stimulating hormone (530)
Neuropeptide Y (239)
Neurotensin (239)
Norepinephrine (134)
Parathormone (264)
Prolactin (279)
Prostaglandins (517)
Serotonin (370)
Substance P (393)
Vasoactive intestinal polypeptide (394)
Vasopressin (22)
Factors of documented physiological significance are printed in
bold.
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2. Inhibitors of aldosterone production in vitro
Inhibitors of Aldosterone Production
Atrial natriuretic hormone (85)
Calcitonin gene-related peptide (373)
Dopamine (353)
Nitric oxide (380)
Platelet-derived growth factor (381)
Somatostatin (4)
Transforming growth factor-␤ (208)
Unsaturated fatty acids (155)
Factors of documented physiological significance are printed in
bold.
uretic hormone (ANP). In fact, most or all increases in
aldosterone secretion may be attributable to increased
activity of the renin-angiotensin system and/or increased
plasma level of K⫹. When sodium or fluid loss is severe,
ACTH is also secreted and synergizes with ANG II or K⫹
in stimulating glomerulosa cells. ANP secretion is increased in response to sodium and/or water loading, and
it in turn inhibits aldosterone secretion. The roles of other
factors (shown in Tables 1 and 2) in the physiological
control of aldosterone secretion may not be essential.
Signal transduction in the adrenal cortex has been
studied for almost half a century. The role of cAMP in the
stimulation of steroid production by pituitary trophic hormones was one of the earliest discoveries in this field,
leading to the concept of second messengers (232). The
formation and mode of action of cAMP have been described in several reviews. Our review focuses on the
mechanism and role of Ca2⫹ signaling, paying special
attention to the interaction of Ca2⫹ signaling with other
signal-transducing mechanisms. The Ca2⫹ dependence of
the secretory process was described by Douglas and Rubin four decades ago (142), and it is now well established
that Ca2⫹ acts by inducing the exocytosis of secretory
vesicles. This principle is not applicable for steroid-producing cells, which lack secretory vesicles and are devoid
of an exocytotic mechanism. The steroid precursor cholesterol is stored in lipid droplets, and the rate of hormone
secretion depends on the rate of hormone synthesis. However, the activation of hormone synthesis is Ca2⫹ dependent, and the regulatory mechanism involves both Ca2⫹mediated and Ca2⫹-permitted processes.
Following the pioneering observation of Hokin and
Hokin (241) of acetylcholine-induced increase in phospholipid turnover of pancreatic and brain cortical slices in
1955, systematic studies on the role of Ca2⫹ in agonistinduced biological response were initiated in 1975 by
Michell’s hallmark paper (355). After surveying data on
the mode of action of several hormones and neurotransmitters, he hypothesized that Ca2⫹-dependent agonists
activate phospholipase C and induce the hydrolysis of
phosphatidylinositol and that this breakdown triggers, in
turn, the influx of Ca2⫹ from the extracellular fluid. It was
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The steroid hormone aldosterone, secreted by the
glomerulosa cells of the adrenal cortex, controls sodium
and potassium balance and also influences acid-base homeostasis of the vertebrate organism. Its major physiological targets are the epithelial cells, of which the most
important are located in the distal nephron. It augments
Na⫹ reabsorption as well as K⫹ and H⫹ excretion.
Through changes in sodium balance, it influences the
extracellular space and blood pressure. In addition to its
epithelial actions, aldosterone influences the function of
the cardiovascular system by acting on the heart, vessels,
and central nervous system. Aldosterone secretion is increased during acute or chronic sodium depletion or fluid
loss, erect postural position, dietary potassium loading,
and tissue damage leading to hyperkalemia. In view of its
essential role in maintaining extracellular fluid and
thereby circulation, it is not surprising that its secretion is
controlled by several factors. The list of hormonal and
paracrine factors reported to exert a stimulatory effect on
aldosterone production in vitro is quite long (Table 1),
and the number of proposed inhibitory factors is also
remarkable (Table 2). However, under physiological conditions the control of secretion is probably confined to the
stimulatory factors corticotrophin (ACTH), angiotensin II
(ANG II), and K⫹ and the inhibitory factor atrial natri-
TABLE
CONTROL OF ALDOSTERONE SECRETION
II. CALCIUM SIGNAL GENERATION
IN GLOMERULOSA CELLS
The two most important physiological stimuli of aldosterone secretion, ANG II and extracellular K⫹ (reviewed in Ref. 570), exert their effects through generating
cytoplasmic Ca2⫹ signal. The octapeptide ANG II is
formed from the plasma protein angiotensinogen by the
sequential action of two proteases, renin and angiotensinconverting enzyme. Under resting conditions its plasma
concentration in humans and rats is between 10 and 60
pM (309, 492). ANG II level rises above 100 pM in response to administration of furosemide or dietary sodium
depletion, whereas it may attain several hundred picomoles per liter following hemorrhage or water deprivation (337, 492). Plasma levels between 1 and 2 nM were
measured under severe pathological conditions (e.g., malignant hypertension) (337).
Renin expression and ANG II production also occur
in adrenal glomerulosa cells (371, 372). Within the adrenal
cortex, immunolabeling for renin and prorenin is not
limited to the steroid-producing cells of the zona glomerulosa but is also present in chromaffin cells, which occur
singly or in groups throughout the whole cortex (45, 594).
In this latter cell type the expression of angiotensinogen
mRNA and the presence of ANG II in chromaffin granules
were also shown (594), suggesting a paracrine action of
ANG II released from vicinal chromaffin cells. The adrenal
expression of renin mRNA is activated by the recognized
Physiol Rev • VOL
physiological stimuli of aldosterone secretion, namely,
ANG II (593), ACTH (576), and K⫹ (102, 281, 576). Transcription of the (pro)renin gene is also enhanced in dietary sodium depletion (566). In transgenic rats termed
TGR(mREN2)27, the murine ren-2 renin gene, originally
detected in the submaxillary gland, is expressed predominantly in the adrenal cortex. Although plasma renin and
ANG II concentrations are low in these animals, aldosterone secretion is high, indicating that intra-adrenal production of renin can effectively stimulate the glomerulosa
cells by stimulating local ANG II production (419). Sodium restriction also increases adrenal renin activity and
mRNA in such transgenic rats (480). The observation that
the AT1-type ANG II receptor antagonist DuP 753 attenuates K⫹-stimulated and ACTH-stimulated aldosterone production (209) suggests that the intra-adrenal renin-angiotensin system functions as a local amplifier of systemic
stimuli. Renin, in addition to acting as a soluble enzyme,
has been found to bind to a 350-amino acid membrane
protein. This binding results not only in increased catalytic activity, but also in the activation of mitogen-activated protein kinases (MAPKs) within the respective cell
(385). No data are yet available as to whether this binding
protein is expressed in the adrenal cortex. Additional
studies are required to assess the tissue concentration of
ANG II within the glomerulosa zone. Such data would be
essential for the evaluation of the physiological relevance
of experimental results obtained with exogenous ANG II.
ANG II-stimulated aldosterone production by incubated rat glomerulosa cells exhibits a biphasic dose-response curve. Steroidogenesis is stimulated in the physiological concentration range of 10⫺11 M, maximal effect is
attained at ⬃10⫺9 M, above which level hormone output is
reduced (97, 230, 323). In superfusion system ANG II
increases aldosterone production of isolated cells by two
orders of magnitude (24, 447).
Aldosterone secretion in vivo (76) and production in
vitro (74, 180, 238, 563) are stimulated by increases in K⫹
concentration as small as a few tenths of millimolar.
Maximal hormone production is attained by [K⫹] around
8 –10 mM both in capsular (glomerulosa) tissue (225, 368)
and cell suspension experiments (323, 432), whereas decreased hormone production can be observed at [K⫹]
between 10 and 20 mM (33, 442). The falling phase of the
K⫹-aldosterone dose-response curve is due to the rapid
decay of aldosterone output, which follows in time the
steep onset of the response (28).
ANG II is a classical Ca2⫹-mobilizing ligand: it induces Ca2⫹ release from IP3-sensitive intracellular stores,
and this release is followed by Ca2⫹ influx from the
extracellular space. The mode of action of K⫹ is quite
different, because its primary site of action is a voltageoperated Ca2⫹ channel. Nevertheless, how the exceptional sensitivity of glomerulosa cell to K⫹ is achieved is
a question still only partially elucidated. In the forthcom-
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only later discovered that also the phosphatidylinositol
derivative phosphatidylinositol 4,5-bisphosphate is
cleaved (356). Subsequently, it was firmly established that
the primary consequence of this breakdown is the formation of inositol 1,4,5-trisphosphate (IP3), a water-soluble
second messenger which primarily induces Ca2⫹ release
from intracellular stores, rather than Ca2⫹ influx from the
extracellular space (53, 437, 522).
Adrenal glomerulosa cells are a cell type in which
Ca2⫹ and cAMP are equally significant in stimulationsecretion coupling. The effect of ACTH is mediated by
cAMP, that of ANG II by Ca2⫹ and diacylglycerol (DAG),
and that of K⫹ by Ca2⫹. ANP acts by antagonizing Ca2⫹
signaling. The basic framework of the IP3-Ca2⫹-DAG system in adrenal glomerulosa cells was characterized in the
1980s and reviewed subsequently (32, 189, 503, 509).
Therefore, classical data on the phosphoinositide-Ca2⫹DAG system will only be reviewed concisely here. We will
primarily deal with the control of Ca2⫹-releasing and influx mechanisms, the interaction of various signaling
pathways, the long-term effects of Ca2⫹-mobilizing agonists, and the mechanism terminating Ca2⫹ signaling. Finally, we summarize current views on the basis of Ca2⫹induced steroid secretion.
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ing sections we first describe the primary actions of the
two agonists and later deal with additional actions that
ensure the fine-tuning of regulation.
A. Receptor-Mediated Ca2ⴙ Release
frequency of Ca2⫹ oscillations is reduced by nifedipine,
suggesting that voltage-activated Ca2⫹ channels have a
supporting role during the process (479). Several models
have been proposed for the mechanism of Ca2⫹ oscillation in other cell types (for review, see Refs. 178, 490), but
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Glomerulosa cells do not constitute a homogeneous
population. Expression of aldosterone synthase is confined to the two or three outer cell layers of the rat zona
glomerulosa (221, 396, 418). The function of glomerulosa
cells not expressing aldosterone synthase is not clear;
moreover, presently no method is available for correlating
aldosterone production and Ca2⫹ response at the singlecell level. Individual cells also differ in their response to
different stimuli. Although the majority of the cells generate a Ca2⫹ signal in response to both K⫹ and ANG II,
only a smaller percentage of the cells respond to vasopressin (AVP) (447) and still less to ACTH (551). Immunocell blot assay data suggest that 20 –25% of the glomerulosa cells release ANG II (103).
This cellular heterogeneity is also reflected by the
variable Ca2⫹ response of single cells to ANG II and K⫹
(119) (Fig. 1). However, some general characteristics of
the response may be observed. Similar to other Ca2⫹mobilizing agonists (47, 545), ANG II evokes an oscillating
signal at physiological concentrations (usually below 300
pM). The hormone concentration affects the frequency
rather than the amplitude of the single spikes. Gradual
confluence of the spikes occurs at higher concentrations
of the peptide, and the Ca2⫹ response becomes sustained
in the nanomolar angiotensin II range (rat, Refs. 447– 449,
466; bovine cells, Refs. 107, 269, 479). Also, the onset of
the response exhibits a concentration-dependent delay
(447, 466). Oscillatory Ca2⫹ signals show a gradual decrease in spiking frequency and/or amplitude after a few
minutes (269, 433), which results in a gradually decreasing Ca2⫹ signal in cell suspension, where the response of
100,000 or more cells is averaged. (The underlying mechanism may also account for the declining [Ca2⫹] during
the sustained phase of the Ca2⫹ signal in single cells
exposed to higher concentration of ANG II.) Ca2⫹ spiking
is maintained in the absence of extracellular Ca2⫹ for at
least 20 min, indicating that oscillating Ca2⫹ release occurs from the IP3-sensitive intracellular store (479). The
FIG. 1. Effect of angiotensin II (ANG II) applied at a physiological
concentration of 150 or 300 pM (37°C) on cytoplasmic and mitochondrial [Ca2⫹]. Cytoplasmic [Ca2⫹] was monitored with Fura Red (red),
and changes in mitochondrial [Ca2⫹] were followed with rhod 2 (blue)
by confocal microscopy in MitoTracker Green-preloaded single glomerulosa cells. The y-axis shows the fluorescence ratio of (Fo-F)/Fo for
Fura Red and (F-Fo)/Fo for rhod 2, where F is the actual fluorescence
intensity and Fo is the averaged fluorescence intesity of the control
period. Note the heterogeneity of the Ca2⫹ response of individual cells.
(Recordings courtesy of A. Spät.)
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CONTROL OF ALDOSTERONE SECRETION
assays are characterized by a slope factor significantly
lower than 1. These curves were originally explained by
the presence of high- and low-affinity AT1 receptor-binding sites. Depending on the experimental conditions in rat
and bovine glomerulosa cells, the high-affinity sites have
dissociation constant (Kd) values around or below 1 nM,
whereas the affinity of the low-affinity site is ⬃1 order of
magnitude lower (73, 133). Both uncoupling of the receptor from G proteins, by nonhydrolyzable GTP analogs (see
references in Ref. 132) and desensitization of the receptor, markedly reduces the number of high-affinity sites
(see sect. VC). Although the two-state model is now generally considered to be an oversimplification of the receptor activation process (257), the effects of G protein coupling and/or receptor phosphorylation on binding affinity
are considered to be general features of many G proteincoupled receptors (GPCRs).
1. ANG II receptors
2. G proteins
ANG II is the major physiological regulator of aldosterone secretion, cell growth, and proliferation of glomerulosa cells. The effects of ANG II in glomerulosa cells
and other target tissues are mediated by binding to heptahelical, G protein-coupled receptors. Two different
binding sites of ANG II, termed AT1 and AT2, were identified in the rat adrenal cortex, and the AT1 receptor was
found to be the predominant isoform (17, 140, 579),
whereas the bovine cortex contains almost exclusively
AT1 receptors (17). Immunocytochemical localization of
the receptors in the adult rat confirmed that glomerulosa
cells contain AT1 receptors, whereas AT2 is expressed in
the medulla (177, 501). Nonpeptide receptor antagonists
have demonstrated that AT1 receptors mediate the ANG
II-induced enhanced formation of IP3 and depolarization
(217), inhibition of adenylyl cyclase (17), stimulation of
aldosterone production (17, 217), and the growth-promoting effect of ANG II in glomerulosa cells (see sect. VIA).
However, AT2 receptors appear to activate protein phosphatases, the nitric oxide-cGMP system, and phospholipase A2 (390). AT2 receptors inhibit cell growth and
stimulate apoptosis, and the expression of this receptor is
increased during fetal growth and tissue regeneration
(132, 360). In contrast to other cloned mammalian AT1
receptors, rat and mouse AT1 receptors exist as two
distinct subtypes, termed AT1A and AT1B. They are 95%
identical in their amino acid sequences and have very
similar ligand binding and activation properties, but differ
in tissue distribution and transcriptional regulation. Although most ANG II target tissues express predominantly
AT1A receptor mRNA, in the adrenal and the pituitary
glands the AT1B message is the major subtype (132, 192).
In contrast to pituitary cells, in rat and murine adrenal
cells the mRNA of AT1A receptors can also be detected
(144, 192).
Competition curves of ANG II in radioligand-binding
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Catt and co-workers (194) described the inhibition of
the binding of ANG II by guanine nucleotides as early as
1974. The underlying mechanism of this phenomenon was
elucidated by the discovery of heterotrimeric G proteins 6
years later (464). Of the different heterotrimeric G proteins in glomerulosa cells, Gi, the inhibitory G protein of
adenylyl cyclase, was the first to be identified on the basis
of pertussis toxin-induced ADP-ribosylation of a 41-kDa
protein (162). Immunoblotting revealed Gi (and the related Go) in bovine glomerulosa cells (344). These observations were in harmony with the previous finding that
ANG II reduces, rather than enhances, ACTH-induced and
serotonin-induced cAMP production in rat glomerulosa
cells (43, 230, 463) and adenylyl cyclase activity of membrane preparations (587). Gi seems to couple the activated ANG II receptor with T-type voltage-activated Ca2⫹
channels in bovine and L-type Ca2⫹ channels in both rat
and bovine glomerulosa cells (see sect. IIB).
The primary effect of calcium-mobilizing agonists,
such as ANG II, is the hydrolysis of phosphoinositides by
a phosphoinositide-specific phospholipase C (PLC). Although ␤␥-subunits derived from Gi/o may activate the
␤2-isoform of PLC (454), inhibition of Gi by pertussis toxin
failed to influence the ANG II-induced and AVP-induced
activation of phosphoinositide metabolism (36, 162, 204,
296) or aldosterone production (230). Therefore, it may be
assumed that the ␤2-isoform of PLC is not expressed in
the glomerulosa cell; however, nonhydrolyzable GTP analogs increased the formation or potentiated the ANG
II-induced formation of IP3 by permeabilized glomerulosa
cells and glomerulosa membrane preparations (36, 162,
473). These observations indicated the involvement of
another G protein in the action of ANG II. It was demonstrated in 1992 that the two pertussis toxin-insensitive G
proteins, Gq and G11 (the Gq family of heterotrimeric G
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none of these has been thoroughly tested for steroidsecreting cells.
When cytoplasmic Ca2⫹ concentration ([Ca2⫹]c) is
examined in cell suspension, i.e., a statistical average of
several hundred thousand cells is monitored, the Ca2⫹
signal induced by low concentration of ANG II is characterized by a slow increase followed by a gradual decrease,
whereas that induced by supraphysiological concentration consists of an initial peak followed by a smaller
plateau (24, 255, 301). If extracellular Ca2⫹ is chelated in
a superfusion system after the onset of ANG II-induced
aldosterone production, hormone output falls below resting levels (503). This phenomenon indicates that the
maintenance of [Ca2⫹]c at a suprabasal level is essential
for maintaining hypersecretion of aldosterone (269, 300,
435, 449).
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3. Phosphoinositide metabolism and formation
of inositol phosphates
Enhancement of phosphoinositide turnover by ANG
II, but not by the two other physiological stimuli of the
glomerulosa cell, K⫹ and ACTH, was described two decades ago (153, 245, 580). The effect of ANG II did not
require extracellular Ca2⫹ (246), indicating that reduction
of the radioactively labeled phosphatidylinositol pool was
not secondary to ANG II-induced Ca2⫹ influx.
It was R. H. Michel who first presented data showing
that agonist stimulation resulted in a rapid, phosphodiesterase-catalyzed breakdown of phosphatidylinositol,
phosphatidylinositol 4-phosphate, and phosphatidylinositol 4,5-bisphosphate (PIP2) that did not appear to be a
response to changes in [Ca2⫹]c (356). Subsequent work by
Berridge, Irvine, Schulz, and co-workers (52, 522) definitely confirmed in 1983 that Ca2⫹-mobilizing agonists
induce the breakdown of PIP2, resulting in the formation
of the water-soluble, Ca2⫹-releasing second messenger
IP3 and DAG. Shortly after this landmark discovery, the
ANG II-induced rapid breakdown of PIP2 (161, 172, 289)
and the ensuing formation of IP3 (18, 161, 188, 473) were
observed in bovine and rat glomerulosa cells.
Whereas the ACTH-induced cAMP response does not
evoke the formation of IP3 (161, 172), vasopressin (22,
204, 589), endothelin (588), and acethylcholine (293), all
acting in a paracrine mode within the adrenal gland,
enhance the formation of IP3. The hydrolyzing enzyme,
the phosphoinositide-specific PLC, is activated not only
by hormonal or neurotransmitter stimuli (through Gq),
but also by Ca2⫹ (158, 366). The K⫹-induced moderate
breakdown of PIP2 (218) is compatible with such a Ca2⫹
action.
Although ANG II- (18, 161) and AVP-induced increases in IP3 (204) peak within 10 –15 s and decrease
thereafter, a second phase of enhanced PIP2 breakdown
may last as long as stimulation is persisting. In the presence of lithium, an inhibitor of inositol polyphosphate
1-phosphatase and of inositol monophosphatase, labeled
inositol phosphates, exhibit continuous accumulation, indicating the sustained activation of PLC (161, 289). In
contrast to the initial formation of IP3 (246, 473), the
sustained phase of ANG II-stimulated IP3 formation is
dependent on Ca2⫹ influx (248, 590). This observation
may be accounted for by the Ca2⫹ requirement of PLC
activity (158, 375) and is consistent with the Ca2⫹ requirement of the sustained (but not the initial) phase of ANG
II-stimulated aldosterone production (503).
The sustained phase of stimulation with ANG II is
characterized not only by increased formation of inositol
phosphates but also by a change in the ratio of different
inositol phosphate fractions. Dephosphorylation by
5-phosphomonoesterase is the prevailing metabolic route
of IP3 in resting cells and is also a significant pathway in
ANG II-stimulated cells (18). Another metabolic route is
the sequential phosphorylation of IP3 to inositol 1,3,4,5tetrakisphosphate (IP4) by IP3 3-kinase (262) and dephosphorylation to its biologically inactive product, inositol
1,3,4-trisphosphate. Ca2⫹ signaling may activate IP3 -kinase (59), leading to increased formation of IP4 and inositol 1,3,4-trisphosphate, as also observed in bovine glomerulosa cells (18, 23, 475). In the course of sustained
stimulation, inositol 1,3,4-trisphosphate is consecutively
converted into inositol 1,3,4,6-tetrakisphosphate (23, 250),
inositol 1,3,4,5,6-pentakisphosphate, and inositol 1,4,5,6-
FIG. 2. Site of action of heterotrimeric G proteins
in the glomerulosa cell. Mcr2, melanocortin type 2
receptor. The red arrows indicate stimulatory actions,
and the green arrows indicate inhibitory actions. (Inhibition of adenylyl cyclase by Gi may not be effective
in bovine cells; see sect. IVB.)
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proteins), mediate the effects of ANG II and AVP on PLC
(210). Few data are available on Gq in adrenocortical
cells. It was found that the Gq/G11 protein is associated
with the cytoskeleton and that this association is essential
for the translocation of cytosolic G protein to the plasma
membrane (121). As shown with the application of a
specific antibody, ␣q/␣11 mediates the inhibitory effect of
ANG II on Ca2⫹-dependent K⫹ (BK) channels (408).
The third heterotrimeric G protein participating in
the control of steroid-producing cell types is Gs, the stimulator of adenylyl cyclase. The presence of ␣s, the guanyl
nucleotide binding subunit of Gs, in glomerulosa cells was
demonstrated by Western blot analysis. This also showed
that a 1-min exposure to ACTH induced a large but transient translocation of ␣s from the cytoskeleton to the
plasma membrane (122).
The site of action of heterotrimeric G proteins in the
glomerulosa cell is summarized in Figure 2.
CONTROL OF ALDOSTERONE SECRETION
4. Ca2⫹ release by IP3
Before the availability of Ca2⫹-sensitive fluorescent
dyes, Ca2⫹ release from an intracellular particle into the
cytoplasm in response to hormones and neurotransmitters was revealed by the application of isotope flux techniques. Similar to the effect of acetylcholine on the salivary gland (387), ANG II was found to enhance Ca2⫹
efflux from rat glomerulosa cells, irrespective of the presence of extracellular Ca2⫹ (27). These observations indicated that these agonists induce intracellular Ca2⫹ release
and that their primary action does not require Ca2⫹ influx.
Moreover, in ANG II-stimulated glomerulosa cells the applied isotope flux technique revealed a nonmitochondrial
origin of the released Ca2⫹ (27). IP3-induced Ca2⫹ release
from a nonmitochondrial intracellular store was first demonstrated in permeabilized pancreatic acinar cells, in 1983
(522). This observation was soon confirmed in permeabilized bovine glomerulosa cells (289) and in insulinoma
microsomes (436). High-affinity IP3-binding sites were described in 1986 by Spät and coworkers in permeabilized
peritoneal polymorphonuclears and hepatocytes (507)
and liver microsomes (510). The concentration dependence of binding and Ca2⫹ release were comparable,
showing that the binding sites represented biologically
active receptors. Whereas Scatchard analysis revealed
both high-affinity and low-affinity binding compartments
in liver microsomes (426, 510), only a single (high-affinity)
compartment of binding sites was observed in adrenocortical microsomes (37, 94, 201, 403). It is possible that the
lack of low-affinity binding sites in the adrenal cortex was
caused by Ca2⫹-induced conversion of low-affinity to
high-affinity binding sites (367, 427).
In glomerulosa cells, in harmony with other cell
types, the Kd of IP3 binding to the (high-affinity) receptor
(10⫺9 M) is about two orders of magnitude lower than the
EC50 of IP3-induced Ca2⫹ release (201). This discrepancy
may be accounted for by the different experimental conditions (temperature and absence or presence of Mg-ATP)
Physiol Rev • VOL
of binding and transport studies. The redox state of thiol
groups also influences the binding of the ligand (203). It
has also been proposed that Ca2⫹ release by IP3 in other
cell types depends on the occupancy of low-affinity binding sites (426). It is possible that the IP3 concentration in
confined regions of stimulated cells might attain 10⫺6 to
10⫺5 M, which may induce maximal Ca2⫹ release also
from low-affinity receptors (reviewed in Ref. 546).
Fractionation of liver homogenates (510) as well as
electron microscopic studies on cerebellar Purkinje cells
(486) confirmed the localization of the IP3 receptor in the
endoplasmic reticulum (ER). That IP3 acted on the ER
was supported later by several studies, among others on
adrenocortical membrane fractions (94, 201, 403). Comparison of the effect of IP3 and thapsigargin on glomerulosa cells indicated that only a subpopulation of ER vesicles can be regarded as IP3 sensitive (159, 465). These
data were in harmony with the results of subfractionation
studies on liver that suggested that the receptor may not
be evenly distributed in the whole reticulum but concentrated in specialized vesicles, marked with the calciumbinding protein calreticulin (166). In intact exocrine cells
(421) and neurons (51), the ER appeared to be a continuous membrane system that has a number of regional
specializations. Provided that also in intact glomerulosa
cells ER is luminally continuous, IP3 receptors may cluster in confined regions that could appear as a separate
population of vesicles after homogenization.
IP3 receptors have been identified in the plasma
membrane of T lymphocytes (304). However, these receptors probably differ from the ER receptor, since activation
of such nonselective cation channels in the plasma membrane would cause depolarization; that is not the case. IP3
receptors in the plasma membrane were also reported in
adrenocortical cells (474). Observations on adrenocortical cells (202) and liver homogenates (166, 471) strongly
suggest that IP3 receptor detected in the plasma membrane fraction is localized in ER vesicles, loosely attached
to the plasma membrane by cytoskeletal elements. Additional IP3 binding sites, described in the nuclear envelope and in the Golgi apparatus, as well as in secretory vesicles, (presently) have no known relevance in
steroid-producing cells, and therefore we refer to a
recent review (405).
The IP3 receptor type cloned first (IP3R1) contains
2,749 amino acid residues, corresponding to a molecular
mass of 313 kDa. It consists of three functional domains,
the cytosolic NH2-terminal ligand-binding domain, a
COOH-terminal channel-forming domain, and an interconnecting coupling domain. The COOH-terminal 550 amino
acid residues contain six membrane-spanning regions,
which form the ion-conducting pore. The receptor expressed in the brain may differ from that expressed in
peripheral tissues by splice variance: the former containing, and the latter missing, a 40-amino acid segment (SII)
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tetrakisphosphate (25). An alternative pathway of the
pentakisphosphate metabolism, which seems to be significant only after several hours of stimulation, is the formation of two further inositol tetrakisphosphate stereoisomers (1,4,5,6- and 3,4,5,6-P4) (20).
Of these compounds, increased labeling of inositol
1,3,4-trisphosphate and inositol 1,3,4,5-tetrakisphosphate
has been found in rat glomerulosa cells exposed to ANG
II (19, 505) or AVP (204). The formation of an unspecified
pentakisphosphate was also detected, and its labeling was
not influenced by AVP within 30 min (204). The small
number of glomerulosa cells that can be isolated from rat
adrenal (a few hundred thousands per rat) has discouraged further physiologal studies on higher inositol
polyphosphate metabolism in these cells.
495
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Physiol Rev • VOL
tremely important in determining the pattern of Ca2⫹
signaling. The Ca2⫹-dependent enhancement of IP3R activity implies that Ca2⫹-induced Ca2⫹ release (CICR), similar to that occurring through RyRs, may also occur
through the IP3R provided that [Ca2⫹]c is ⬍300 nM (55).
This process may have an essential role in the generation
of cytoplasmic Ca2⫹ oscillations and waves (48). The
dependence of the nadir of the bell-shaped Ca2⫹-dependence curve on [IP3] ensures the coregulation of channel
function by Ca2⫹ and IP3, allowing the generation of
short-lasting Ca2⫹ transients at low levels of IP3, while
maintaining high [Ca2⫹]c during prolonged and intense
stimulation of the cell. Ca2⫹ can directly facilitate IP3induced Ca2⫹ release (at Glu2100 in IP3R1) (56, 224, 365,
405). Calmodulin-dependent kinase II (CaMKII), on the
other hand, phosphorylates the IP3R and potentiates the
Ca2⫹-releasing effect of IP3, thus exerting positive feedback on IP3R function (83, 598). High [Ca2⫹]c may reduce
IP3 binding (510). This inhibition, which may be attributed
to an increase in the Kd of IP3 binding to the receptor
(367), is independent of calmodulin. However, calmodulin
probably exerts tonic inhibition on the IP3R under physiological conditions (357, 389, 405, 406). In contrast to the
bell-shaped Ca2⫹ sensitivity IP3R1, peaking at ⬃300 nM
Ca2⫹, IP3R2 displays a sigmoidal increase in open probability of the release channel up to ⬃1 ␮M, and [Ca2⫹]c
exerts a moderate inhibitory effect only above 1 ␮M (452,
but see Ref. 364). Observations on the Ca2⫹ dependence
of IP3R3 are conflicting, since increasing (212), unaltered
(364), and decreasing open probability at high [Ca2⫹]
were reported (333, 363). The predominant expression of
IP3R1 in the glomerulosa cell is compatible with the observed high affinity of IP3 binding; moreover, the bellshaped Ca2⫹ dependence of IP3-induced Ca2⫹ release is to
be expected.
Simultaneous knock-out of the three types of IP3R in
B lymphocytes abolishes agonist-induced Ca2⫹ signals.
However, signal generation is maintained if any of the
three isoforms can function (523). Nevertheless, when
only a single isoform was expressed, different patterns of
Ca2⫹ signals were observed. IP3R2 was required for sustained Ca2⫹ oscillations, and IP3R1 mediated less regular
Ca2⫹ oscillations, while IP3R3 generated monophasic
Ca2⫹ transients (364).
The threshold and pattern of IP3-induced Ca2⫹ signals are significantly modified by other signal transduction mechanisms. The receptor is phosphorylated in its
coupling domain by protein kinase A (PKA), PKC, and
CaMKII. The number, and even the site, of the phosphorylation consensus sites varies in the different receptor
types (for review, see Refs. 405, 546). In the nonneural
[SII(⫺)] splice variant of IP3R1, that is predominantly
expressed in glomerulosa cells (165), low cAMP concentrations preferentially phosphorylate Ser1589 and therefore potentiate IP3-induced Ca2⫹ release (80, 215). Sub-
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in the coupling domain. IP3 receptors and ryanodine receptors (RyR) share 40% amino acid sequence identity in
their COOH-terminal, pore-forming domains and show
some sequence identity in the NH2-terminal, cytosolic
ligand binding domains (for review, see Refs. 55, 542).
Following the cloning and characterization of IP3R1, two
further types (IP3R2 and IP3R3) have been identified. The
central nervous system contains almost exclusively IP3R1
[SII(⫹) splice variant], while several peripheral cell types
express more than one type of IP3R (reviewed in Refs. 55,
405, 542). Simultaneous with the observation of the coexpression of more than one type of IP3R in peripheral
tissue, including the whole adrenal (containing both cortex and medulla) (384), we reported that rat glomerulosa
cells express the mRNAs of all three types of IP3R (165).
About four times more IP3R1 mRNA was expressed than
IP3R2 mRNA, and the SI segment was present in nearly
50% of the IP3R1 receptors. Somewhat less than 5% of the
total IP3R was expressed as type 3. Interestingly, sodium
restriction for 1 wk, a strong stimulus of aldosterone
secretion by glomerulosa cells, failed to influence the
ratio of expression of the different receptor types or
spliced variants (165).
The receptor affinity for IP3 has a rank order of
IP3R2 ⬎ IP3R1 ⬎ IP3R3 (364, 384). However, the membrane environment may modify the properties of the receptor (425). Different receptor types may exhibit different downregulation or rates of receptor degradation (498,
585). The receptor has a tetrameric structure of ⬃1.2 kDa
(for review, see Refs. 55, 174), and different receptor
isoforms may constitute heterotetramers (272). Since the
three receptor types differ in their affinity for IP3 as well
as in their sensitivity to controlling factors (see below),
the diverse composition of these heterotetrameric receptors may provide more versatile control of IP3 receptor
function.
Physiological concentrations of Ca2⫹-mobilizing agonists usually evoke oscillatory Ca2⫹ signals (see sect. IIA).
Although no uniformly valid model for different cell types
has yet been presented, oscillations are obviously evoked
by positive and negative feedback control of [Ca2⫹]c by
Ca2⫹ itself. Ca2⫹ variously activates different isoforms of
PLC, protein kinase C (PKC), plasmalemmal Ca2⫹ATPase, adenylyl cyclase, and cAMP phosphodiesterase,
and cell type-specific expression of these isoforms contributes to the complexity of Ca2⫹ signal generation. Nevertheless, the major factor responsible for Ca2⫹ oscillations is probably the dual effect of Ca2⫹ on IP3R itself.
Elevation of [Ca2⫹]c within the lower physiological range
(up to ⬃300 nM) increases, and further elevation, still in
the physiological range, decreases the sensitivity of IP3R1
to IP3 (260). Gradual elevation of [IP3] from 20 nM to 180
␮M shifts the peak of the Ca2⫹-dependence curve of
channel open probability from 100 nM to ⬃1 ␮M (275).
The biphasic effect of Ca2⫹ on channel activity is ex-
CONTROL OF ALDOSTERONE SECRETION
Physiol Rev • VOL
for data showing that ANG II is capable of increasing the
formation of IP3 in these cells (468, 581) but fails to evoke
Ca2⫹ signals (77, 584) or increased production of corticosterone (581).
5. Actions of higher inositol phosphates
and polyphosphoinositides
There is a notable contrast between the number of
identified highly phosphorylated inositol phosphates and
our knowledge of their role. There are sporadic observations on the effect of a given compound in a special cell
type, but confirmation of these observations in other cell
types is usually missing. The most studied compound is
the first metabolite of IP3, inositol 1,3,4,5-tetrakisphosphate. It potentiated the Ca2⫹-releasing effect of IP3 in
neuroblastoma (193) and L1210 lymphoma cells (126) as
well as in pituitary microsomes (512). It was also found to
synergize with IP3 in inducing Ca2⫹ influx in sea urchin
eggs (263) and in exocrine acinar cells (420). It was also
proposed that capacitative Ca2⫹ influx is triggered by the
interaction of IP3Rs in the ER vesicle and the vicinal,
plasmalemmal IP4 receptors (261). Adrenocortical microsomes also contain high-affinity binding sites for IP4
(168), but their function has not been examined. Antisecretagogue (555) and hemodynamic effects of other
inositol tetra- and pentakisphosphate analogs (556) have
no relevance for our subject. Data on the modulation of
chromatin-remodeling complexes by inositol polyphosphates (494) are not yet available for adrenocortical cells.
It was recognized only in recent years that PIP2, in
addition to being the precursor of the second messengers
IP3 and DAG, controls the function of several membraneassociated proteins. However, phosphoinositides also
regulate protein targets through direct binding to specific
phosphoinositide-binding domains (266). These domains
include pleckstrin homology (PH) domains, Fab1P,
YOTB, Vps27p, EEA1 (FYVE) domains, Phox homology
(PX) domains and epsin NH2-terminal homology (ENTH)
domains, and other less well-defined lipid-binding structures.
The PH domain is a conserved region of 100 –120
amino acids that was first identified in pleckstrin but also
present in many other proteins. PH domains have a central role in the formation of molecular complexes involved in signaling and trafficking of receptors. These
domains can be categorized into four groups, which preferentially bind phosphatidylinositol 3,4,5-P3 [PI(3,4,5)P3]
(e.g., Bruton tyrosine kinase), PI(4,5)P2 (e.g., PLC␦1,
pleckstrin-N, spectrin), or PI(3,4)P2 (e.g., Akt/PKB) or
show no clear ligand specificity (e.g., dynamin) (see references in Ref. 266). The affinity of such domains for
specific phosphoinositide ligands was sufficient to monitor ANG II-induced changes in membrane lipid composition using GFP-tagged PH domains (558,561), and the lipid
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stantial phosphorylation of the IP3R with PKC, as well as
augmentation of IP3 potency in stimulating 45Ca release,
were detected after pharmacological inhibition of the
Ca2⫹/calmodulin-dependent phosphatase calcineurin,
known to be anchored to IP3R (83). Phosphorylation of
IP3R by PKC and dephosphorylation by calcineurin were
reported also in bovine glomerulosa cells (430). The potentiation by PKC of IP3 action at low [Ca2⫹]c and the
calcineurin-mediated inhibition of IP3 action at higher
[Ca2⫹]c may contribute to the bell-shaped Ca2⫹-sensitive
response to IP3. However, in bovine glomerulosa cells a
persistent high-conductance state was observed in the
phosphorylated state of the release channel, suggesting
that PKC-induced phosphorylation causes cessation of
ANG II-induced Ca2⫹ oscillations (430). Tyrosine phosphorylation and cGMP-dependent phosphorylation of
IP3R were detected in stimulated T lymphocytes and vascular smooth muscle cells, respectively (reviewed in Ref.
405), but no data are available for glomerulosa cells.
ATP exerts a concentration-dependent effect on the
function of IP3R. Applied at micromolar concentrations, it
enhances the binding of IP3 (508, but see Ref. 583) and
potentiates the open probability of the IP3-gated Ca2⫹
channel (for review, see Refs. 55, 405). IP3R1, the dominant receptor isoform in glomerulosa cells, exhibits
greater affinity for ATP and greater ATP sensitivity of
IP3-induced Ca2⫹ release than IP3R3 (331, 332). Competitive inhibition of the binding of IP3 was observed with
supramicromolar concentrations of ATP in several cell
types (391, 512, 582), including adrenocortical cells (94,
474). This competition may be an additional and significant factor in the 10⫺7 M EC50 of IP3-induced Ca2⫹ release
(in ATP-containing media), as opposed to the 10⫺9 M Kd
of IP3 binding. The question may be raised: how can the
potentiating effect of low, and the inhibitory effect of high
concentration of ATP on IP3-induced Ca2⫹ release be
reconciled? We assume that following Ca2⫹ release the
activated Ca2⫹-ATPase would reduce ATP concentration
around the ER. The ensuing disinhibition of IP3R would
facilitate the generation of Ca2⫹ signal.
When describing the control of the different types of
IP3R, emphasis was placed on that of IP3R1, which is
predominantly expressed in glomerulosa cells. IP3R3 constitutes a minor fraction within the IP3R pool (165), and
its significance has yet to be studied. In this respect the
Trp binding site (72) should be kept in mind, since it may
be essential for capacitative Ca2⫹ influx (see sect. IIB).
Significant expression of IP3R in rat adrenal fasciculata-reticularis cells (secreting the glucocorticoid corticosterone) could not be detected. The IP3R mRNA content
was ⬍0.5 molecules/fasciculata cell, while it was ⬃300
copies/glomerulosa cell (524). Since the rat fasciculata
cell would be unique among nucleated cells in lacking
IP3R, this unexpected result certainly requires confirmation by other laboratories. Even so, it seems to account
497
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ANDRÁS SPÄT AND LÁSZLÓ HUNYADY
B. Ca2ⴙ Transport Through the Plasma Membrane
ANG II-induced Ca2⫹ influx was one of the most
contradictory subjects of aldosterone research. Species
differences, inappropriately applied experimental techniques, and application of ANG II at concentrations one or
two orders of magnitude higher than required for maximal
aldosterone production have all delayed the recognition
of the physiological role and mechanism of ANG II action.
Several early studies, applying the 45Ca flux technique, failed to detect increased Ca2⫹ influx in response
to ANG II. This failure may be due to neglecting the
significance of measuring the initial rate of isotope uptake. Yet, this technique could reveal the ANG II-induced
reduction of the exchangeable Ca2⫹ pool in bovine (107,
154, 289) and rat glomerulosa cells (27). The loss of cell
Ca2⫹ is due to increased efflux of Ca2⫹, also detectable in
Physiol Rev • VOL
a Ca2⫹-free medium (27, 157, 176, 301, 584). This Ca2⫹
efflux is due to the extrusion of Ca2⫹, released from the
IP3-sensitive store, by the Ca2⫹-activated plasmalemmal
Ca2⫹-ATPase. The subsequently verified increase of Ca2⫹
influx in ANG II-stimulated cells is not in contradiction
with the sustained efflux; together they perform continuous Ca2⫹ cycling across the plasma membrane. Although
a high concentration of ANG II was applied in all the
aforementioned studies, in a single report on the effect of
ANG II at low concentration no significant change in the
exchangeable Ca2⫹ pool could be revealed (107).
The frequently observed dependence of the ANG IIinduced sustained Ca2⫹ signal on extracellular Ca2⫹ (89,
301, 467) has been regarded as evidence in favor of ANG
II-induced Ca2⫹ influx. The successful demonstration of
ANG II-induced increase in the initial influx rate of 45Ca
confirmed this interpretation in rat (95, 503) as well as
bovine glomerulosa cells (159, 290, 301).
Calcium influx immediately following Ca2⫹ release is
brought about by the depletion of IP3-sensitive calcium
stores and, subsequently, the slowly developing depolarization activates voltage-operated Ca2⫹ influx. Ca2⫹ is
extruded from the cytoplasm by means of the plasmalemmal and ER Ca2⫹ pumps. In addition, Na⫹/Ca2⫹ exchange may modify [Ca2⫹]c.
1. Membrane potential and Ca2⫹ transport
A major factor controlling Ca2⫹ transport through
the plasma membrane is the membrane potential (Em).
Together with the concentration gradient it determines
the driving force of Ca2⫹ transport and also regulates the
activity of a set of Ca2⫹ channels. Considering that the
two major physiological stimuli of aldosterone secretion,
K⫹ and ANG II, depolarize the glomerulosa cell, we first
discuss the control of Em in these cells. Em depends on
the distribution of diffusible ions and their selective conductance accross the membrane. The Na⫹-K⫹ and Ca2⫹
pumps are responsible for the uneven distribution of the
major cations. The greater the contribution of opened K⫹
channels to the total conductance of the cell membrane,
the more the membrane potential approaches the equilibrium potential of K⫹ (EK), which is in the range of 70 –90
mV (inside negative) in excitable cells. Accordingly, a
reduction of (the absolute value of) EK following elevation of extracellular [K⫹] ([K⫹]o), decrease of intracellular
[K⫹], inhibition of Na⫹-K⫹-ATPase, or closure of K⫹ channels will depolarize the cell. This depolarization may, in
turn, activate voltage-operated channels.
[K⫹]o under resting conditions in the rat is 3.5– 4 mM
(75, 513). At such K⫹ levels Em may exceed ⫺80 mV, as
measured with microelectrodes (445) or by patch-clamp
technique (321, 324, 563). This highly negative Em is due
to a dominant K⫹ conductance (gK), as confirmed by the
perforated patch technique, which avoids the rundown of
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binding of the PH domain of dynamin is required for
␤-arrestin-dependent AT1 receptor endocytosis (see references in sect. VD). However, the latter effect cannot be
explained by the role of the PH domain in the targeting of
dynamin, since the lipid binding is not required for the
proper targeting of dynamin to clathrin-coated structures
(531). Therefore, the interaction with phosphoinositides
can regulate the function or the submicroscopical orientation of PH domain-containing proteins.
FYVE domains bind PI(3)P and are present in proteins involved in the processing of endosomal vesicles
(e.g., EEA1) and regulation of actin cytoskeleton (e.g.,
Fgd1). Inhibition of phosphatidylinositol (PI) 3-kinase has
a marked effect on the trafficking of AT1 receptors expressed in HEK 293 cells by interfering with the proper
localization of FYVE domain-containing endosomal proteins (249). PX domains, which also bind 3-phosphoinositides, were first identified in two cytosolic components of NADPH oxidase (p47phox and p40phox), but they
also occur in a variety of other proteins associated with
signaling (e.g., class II PI 3-kinase, phospholipase D) and
membrane trafficking (e.g., sorting nexins). Finally, the
ENTH domain, which was first identified in epsin, is
present in proteins that participate in endocytosis via
clathrin-coated pits, and the intact phosphoinositide binding of this domain was shown to be required for clathrinmediated endocytosis (see references in Ref. 266).
In addition to these well-defined protein folds, the
lipid binding domains of plasmalemmal Ca2⫹ pumps, the
Na⫹/Ca2⫹ exchanger, Na⫹/H⫹ exchangers, the RyR (for
review, see Ref. 237) and the background K⫹ channel
TASK (see sect. IIB) may also be relevant to the adrenocortical actions of ANG II. The role of lipid rafts in the
plasma membrane in the colocalization of the receptor of
the Ca2⫹-mobilizing hormone, PIP2, Gq/11 and PLC, as well
as the transport proteins, is currently being elucidated.
CONTROL OF ALDOSTERONE SECRETION
Physiol Rev • VOL
rone secretion, inhibition of Na⫹-K⫹-ATPase contributes
to the depolarization and Ca2⫹ signal generation in glomerulosa cells.
In addition to Na⫹-K⫹-ATPase, K⫹ conductance is of
great significance in setting Em. Patch-clamp studies revealed inwardly rectifying, outwardly (delayed) rectifying, Ca2⫹-activated as well as background K⫹ current in
glomerulosa cells. The ion channel through which the
current is conducted has been identified in only a few
cases. Of major concern is the estimation of the physiological significance of the observed currents/channels.
Only ion channels that are active in the range of the
resting membrane potential may play a role in its fine
setting. Members of the superfamily of inwardly rectifying
K⫹ channels (386, 481) display a large inward current at
potentials negative to EK (occurring only under laboratory conditions) and a small and gradually diminishing
outward current as Em is shifted from EK to more positive
values. It is this latter K⫹ efflux by which Em approaches
the more negative EK. Inwardly rectifying K⫹ current,
with characteristics of Kir 2, has been observed in the
membrane patch of rat and bovine glomerulosa cells
(564). Kir 2 passes through the ubiquitous IRK channels
and, in contrast to other families of inwardly rectifying
channels, does not require G protein for activation and is
insensitive to the ADP/ATP ratio. Nonetheless, the physiological significance of Kir 2 in glomerulosa cells has
been questioned by the lack of inward rectification in
macroscopic current under whole cell configuration
(79, 321).
The previously mysterious background (or leak) K⫹
current, which, by definition, is also capable of permeating K⫹ in the range of resting Em, would also be capable
of generating highly negative Em. Such a current was
described in glomerulosa cells by Lotshaw in 1997 (322).
Since that time the respective channel has been identified
and termed TASK, an acronym for TWIK (tandem of P
domains in a weak inward rectifying K⫹ channel)-like,
acid-sensitive K⫹ channel (148). The expression of this
two-pore domain K⫹ channel in rat glomerulosa cell has
been demonstrated by Enyedi and co-workers in our laboratory (129). The zona glomerulosa exhibits the highest
density of TASK mRNA among all tissues hitherto examined. In Xenopus oocytes injected with glomerulosa
mRNA, the expressed K⫹ current had a pharmacology
comparable with that of the authentic TASK current
(129). More recently, the mRNA of the subsequently described TASK-3 (284, 451) was also found in rat glomerulosa cells (128). Interestingly, the glomerulosa cell is exclusive among several examined cell types in expressing
TASK-3. TASK-1 and TASK-3 are coexpressed (the latter
in larger amount) and form heterodimers. A fine-tuning of
channel control may be achieved by the formation of
heterodimers by the two subtypes (127).
Several K⫹ currents or channels, active in depolar-
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susceptible ionic currents. The linear relationship between log [K⫹]o and Em had a slope of 53.7 mV/10-fold
change in [K⫹] (323) that almost attains the value predicted by the Nernst equation for a membrane with K⫹
conductance only (58 mV/decade). These findings are
consistent with the lack of Na⫹ channel expression in the
glomerulosa cell.
The primary step in the energy-dependent generation
of membrane potential is the build-up of a transmembrane
K⫹ concentration gradient by the Na⫹-K⫹-ATPase (“sodium pump”). Furthermore, the exchange of three cytoplasmic Na⫹ for two extracellular K⫹ also contributes to
the generation of intracellular electronegativity (“pump
potential”). Reducing the activity of the sodium pump
dissipates the K⫹ gradient and results in depolarization. It
was revealed a quarter of a century ago that ANG II
decreased rather than increased the potassium content of
rat glomerulosa cells (329, 526), suggesting that ANG II
inhibits the pump. Although ANG II had no significant
effect on ouabain-sensitive or potassium-stimulated
ATPase activity in adrenal capsular membranes (139,
175), damage of the signal-transducing pathway in such
membrane preparations cannot be ruled out. In fact, as
shown in our laboratory (213), the uptake of 86Rb, a
surrogate for K⫹, is abolished by ouabain, the conventional inhibitor of the Na⫹-K⫹ pump. Half-maximal inhibition was attained at 80 ␮M, indicating that of the two
forms of Na⫹-K⫹-ATPase present in rat tissues, the
␣-isoenzyme is the predominant form in the rat glomerulosa cell. The isotope uptake is dependent on cytoplasmic
[Na⫹], and it attains half-maximal rate at 10 mM, corresponding again to the ␣-isoenzyme form. Maximal uptake
rate is reached at ⬃25 mM Na⫹, which corresponds to the
measured physiological level of cytoplasmic Na⫹ (557)
and decreases again above 50 mM. The transport activity
is 4 and 20 times higher than that in fasciculata cells and
hepatocytes, respectively. ANG II reduces the ouabainsensitive 86Rb uptake, i.e., the activity of Na⫹-K⫹-ATPase,
and the observed IC50 of ANG II (300 pM) suggests that
the inhibitory effect of the peptide has physiological relevance.
ANG II exerts its inhibitory effect on Na⫹-K⫹-ATPase
through AT1 receptors (213). A recent observation suggests that ANG II inhibits the pump through activating a
tyrosine phosphatase (596), whereas activation of the
pump by Ca2⫹ through CaMKII (597) may serve as negative feedback during intense stimulation with ANG II.
When ouabain is applied at submillimolar concentrations,
the drug induces a continuous increase in [Ca2⫹]c without
any detectable lag time, and this increase can be abolished with nifedipine (213). At similar concentrations the
drug also stimulates the production of aldosterone, again
requiring extracellular Ca2⫹ and activable voltage-operated Ca2⫹ channels (213, 488, 527, 595). These data suggest that during ANG II-induced stimulation of aldoste-
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ANDRÁS SPÄT AND LÁSZLÓ HUNYADY
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ionophore valinomycin significantly reduced ANG II-stimulated aldosterone production (495).
Subsequently, in the patch-clamp era, ANG II was
found to inhibit each type of the hitherto described K⫹
channels. However, only inhibition of channels active at
resting Em may be responsible for triggering depolarization. Of the two channel types meeting this requirement in
glomerulosa cell, Kir 2 displayed reduced single-channel
activity in membrane patches exposed to ANG II (276).
However, as previously mentioned, this current has not
yet been found in whole cells. The background K⫹ current, corresponding to the later described TASK, was
inhibited by physiological concentrations of ANG II in rat
glomerulosa cells. At the moderately elevated physiological concentration of 10⫺10 M, ANG II reduced the leak
membrane conductance (measured between ⫺127 and
⫺87 mV) by 50% and shifted Em by ⬃6 mV to positive
direction. The extent of depolarization was 18 and 32 mV
on average at 10⫺9 and 10⫺8 M ANG II, respectively (323).
A stable level of current inhibition required ⬃10 min at
concentrations below 100 pM ANG II and at least 5 min at
higher concentrations (321).
ANG II also inhibits the TASK channels responsible
for background K⫹ current. ANG II added to isolated
glomerulosa cells or to oocytes injected with glomerulosa
mRNA inhibited the K⫹ current. ANG II also inhibited the
TASK current in oocytes, coexpressing TASK and the
AT1a angiotensin II receptor. These observations provided
firm evidence that TASK exerts a significant role in the
generation of the strongly negative resting membrane
potential in glomerulosa cells and that ANG II may depolarize the cell by inhibiting these channels (129). Although
the inhibition of TASK-3 current by ANG II is smaller than
that of TASK-1 current (128), it still may have physiological significance, especially in view of the modified characteristics of the TASK-1/TASK-3 heterodimers (127). Maneuvers applied to activate phospholipase C, Gq, and protein kinase C, or to increase the concentration of
cytoplasmic Ca2⫹ and IP3, led to the conclusion that the
action of ANG II (or other Ca2⫹-mobilizing hormones) is
mediated by the breakdown of PIP2 in the plasma membrane (130).
ANG II inhibits the delayed rectifier K⫹ current (79,
276). The Ca2⫹-dependent maxi K⫹ channels are also
inhibited by ANG II, and in this case the effect is mediated
by a pertussis toxin-insensitive G protein (408). Considering that depolarization induced by ANG II levels occurring in vivo is probably not sufficient for the activation of
these channel types, their role in the physiological action
of ANG II awaits confirmation.
Activation of nonselective cation channels also results in depolarization. Such a channel, with a nearly
linear slope conductance between ⫺80 and 0 mV under
quasi-physiological ionic conditions, has been described
by Lotshaw and Li (324). The channel was also permeable
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ized cells only, have also been described in the glomerulosa cell. Noninactivating delayed rectifier K⫹ current
(inducing K⫹ efflux from depolarized cells) was described
in rat, bovine, and human glomerulosa cells (79, 407, 409,
564). This current probably corresponds to KvLQT1, the
slow component of the delayed outward K⫹ current (IKs)
in the heart. It is conducted by the channel KCNQ1, the
regulatory subunit of which (KCNE1) has been detected
in glomerulosa cells (13). In view of the voltage dependence of their activation, the delayed rectifier channels
may not modify the resting Em, but their activation could
limit the extent of depolarization by allowing the efflux of
K⫹. In harmony with this prediction, knock-out of the
KCNE1 gene resulted in enhanced responsiveness of the
plasma aldosterone concentration to K⫹ loading (13).
Transient outward (A-type) K⫹ current was observed
in rat, bovine, and human glomerulosa cells (407, 409,
564). Ca2⫹-dependent maxi-K⫹ (BK) channels were also
described in the rat (321, 408, 564). In view of the voltage
dependence of their activation, the A-type and the BK
channels may not modify the resting Em. On the other
hand, ANG II, probably acting through Gq/11, inhibits the
Ca2⫹-dependent K⫹ channel (408), an action that could
augment the depolarization triggered by some other
mechanism. ANP, probably acting via cGMP, increases K⫹
conductance by facilitating the function of BK channels
(191). The ensuing hyperpolarization may represent one
of the means by which the peptide antagonizes the secretagogue action of Ca2⫹-mobilizing hormones.
Any agent that decreases K⫹ conductance evokes the
shift of Em from the strongly negative EK towards the
positive equilibrium potential of Na⫹ and Ca2⫹. The first
evidence that ANG II induces membrane depolarization
was obtained with intracellular microelectrode recording
of cat adrenocortical slices as early as the 1970s (383).
Later studies provided evidence that a significant component of this depolarization is caused by the reduction of
gK. In microelectrode studies a biphasic Em response to
ANG II was observed in rat glomerulosa cells (446). A
brief hyperpolarization was followed by a long-lasting
depolarization, characterized by a large decrease in cell
conductance. The reversal potential of the response suggested that Em followed changes in gK. Subsequent 86Rb
flux measurements confirmed that ANG II inhibits gK in
rat glomerulosa cells (217). The primary site of action of
ANG II is the AT1 receptor, and its effect is mimicked
neither by ionomycin-induced elevation of [Ca2⫹]c nor by
pharmacological activation of PKC, suggesting that inhibition of K⫹ conductance by ANG II is a membranedelimited process. An initial increase, followed by a prolonged decrease in gK, was observed by means of 86Rb
flux studies also in bovine glomerulosa cells. [Surprisingly, the decrease in gK was found to be Ca2⫹ dependent
(320).] The significance of the ANG II-induced decrease in
K⫹ conductance is shown by the observation that the K⫹
CONTROL OF ALDOSTERONE SECRETION
rat glomerulosa cells. K⫹ currents were inhibited with
CsCl-containing pipette solution and 10 mM Ba2⫹ and 10
mM tetraethylammonium in the extracellular bath. With
the application of nearly symmetrical Cl⫺ concentration,
the current at ⫺100 mV was less than ⫺20 pA. Membrane
resistance in the voltage range of ⫺100 and ⫺120 mV
reached 7 G⍀ on average, indicating the absence of any
significant channel activity. Also, the current displayed
ohmic change only during a slow ramp depolarization
from ⫺100 to ⫺60 mV. However, in a significant fraction
of the cells, the slow activation of a tiny inward current
could be observed at strongly negative voltages. This was
significantly accentuated by reducing extracellular pH
from 7.4 to 6.9, attaining ⫺3.5 pA/pF on average at ⫺100
mV. Both the kinetic and pharmacological characteristics
of this inwardly rectifying current suggest that it passes
through ClC-2 Cl⫺ channels (J. K. Makara and A. Spät,
unpublished observations). The role of this current in the
glomerulosa cells remains to be elucidated.
2. Capacitative influx
The concept of capacitative Ca2⫹ influx, also termed
store-operated or calcium release-activated Ca2⫹ influx,
was introduced by Putney and co-workers in 1989 (534,
535). They proposed that agonist-induced Ca2⫹ uptake
from the extracellular fluid is evoked by the depletion of
IP3-sensitive intracellular calcium stores. Store depletion
can be experimentally elicited by pharmacological inhibition of the SERCA-type Ca2⫹-ATPase (e.g., with thapsigargin). Since that time, capacitative Ca2⫹ uptake has
been demonstrated as a general and major Ca2⫹ uptake
mechanism in nonexcitable cells and may also be present
in excitable cells. The current flowing through capacitative Ca2⫹ entry channels was first characterized in mast
cells and has been termed calcium-release activated Ca2⫹
⫹
⫹
FIG. 3. The participation of the Na -K -ATPase
and ion channels in hormonally induced resetting of
membrane potential (Em). Nonspecif., nonspecific
cation channel; delayed rect. K⫹, delayed rectifier K⫹
channel; big K, Ca2⫹-activated maxi (BK) K⫹ channel.
The red arrows indicate stimulatory actions, and the
green arrows indicate inhibitory hormonal actions.
Physiol Rev • VOL
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to Ca2⫹, exhibiting a PCa/PNa of 4 (with 110 mM Ca2⫹ on
the extracellular side). It would be worthwhile to examine
the relation of this current with the dihydropyridine
(DHP)-insensitive background Ca2⫹ currents observed in
glomerulosa cells by applying the cell-attached mode of
the patch-clamp technique, but with pipette solutions
lacking monovalent cations (149). In cell-attached
patches ANG II (1 nM) increased the opening probability
of the nonselective cation channel, rendering cation influx
and depolarization possible in the intact cell. In fact, using
the nystatin-perforated patch technique, depolarization
began in ⬃2 min and was characterized by a large increase in input resistance, indicating the decrease in gK.
However, transient depolarizations of variable amplitude
were superimposed on the slow depolarization, and membrane conductance during these voltage transients exhibited large increases. Considering that Ca2⫹ was omitted
from the pipette solution, the increased conductance indicated the activation of nonselective cation channels.
Summarizing, these channels may contribute to signal
generation by ANG II by two means: cation influx contributes to the voltage-dependent activation of Ca2⫹ channels; moreover, Ca2⫹ influx per se may participate in Ca2⫹
signaling. (For further studies of channel structure, see
Ref. 325.)
The participation of the Na⫹-K⫹-ATPase and ion
channels in hormonally induced resetting of Em is summarized in Figure 3.
Because changes in Cl⫺ conductance are involved in
the depolarization or repolarization of various cell types,
their function in glomerulosa cells is also summarized.
Apart from a Ras-dependent chloride current activated by
ACTH (105), we are not aware of any report on Cl⫺
current in the glomerulosa cell. No significant Cl⫺ current
was detected in early microelectrode studies (445). We
examined Cl⫺ currents with the patch-clamp technique in
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Expression of antisense trp4 cDNA reduced both the
endogenous capacitative current and the amount of Trp4
protein, indicating the role of this protein species in the
formation of store-operated Ca2⫹ channels in bovine adrenocortical cells (424). The Trp-binding site was described in the cytosolic NH2 terminus of IP3R3 (72).
Therefore, the expression of IP3R3 in glomerulosa cells
(165) may have a special role in controlling Ca2⫹ influx in
glomerulosa cells.
The role of capacitative Ca2⫹ influx in the action of
ANG II has been supported by several observations. In
bovine adrenocortical microsomes, the thapsigargin-releasable Ca2⫹ pool was larger than the IP3-sensitive pool
(159). Consistent with this observation, in rat glomerulosa
cells ANG II did not induce any further elevation of
[Ca2⫹]c after exposure to thapsigargin, whereas a second
rise in [Ca2⫹]c could be obtained if the agonists were
applied in the reverse order (159). These observations
indicate that the IP3-sensitive Ca2⫹ pool constitutes a
subcompartment within a larger, thapsigargin-sensitive
compartment. In bovine cells the oscillatory Ca2⫹ signal
induced by ANG II at physiological (100 pM) concentration was maintained for at least 20 min in a Ca2⫹-free
medium, but was rapidly extinguished by adding thapsigargin. Nifedipine reduced the frequency of oscillations
by only ⬃30% in the Ca2⫹-restored state; moreover, it had
no effect on the plateau level of the Ca2⫹ signal induced
by a high dose of ANG II (479). The Ca2⫹ signal, as
measured 5 min after adding ANG II, was little affected by
blocking T-type Ca2⫹ and L-type Ca2⫹ current but was
eliminated by thapsigargin (81). The relatively high expression of a capacitative Ca2⫹ channel homologous to
Drosophila Trp channels in bovine (whole) adrenal (423)
is also in agreement with the biological relevance of capacitative Ca2⫹ influx in this organ, although the respective cell type has not yet been specified (423).
The sustainment of capacitative Ca2⫹ influx obviously requires continuous depletion of the IP3-sensitive
calcium store, which seems to be due to the continuous
production of IP3. Although the postinitial level of IP3 is
small, it is suprabasal (161), and this moderately elevated
level may be sufficient for the continuous flow of Ca2⫹ out
of the ER vesicles. If Li⫹ or a high concentration of
wortmannin were added to the incubation medium to
prevent the replenishment of the PIP2 pool, the sustained
formation of IP3 (18) and the sustained phase of the Ca2⫹
signal (376) were inhibited in bovine glomerulosa cells.
Lithium ions also severely compromised the sustained
phase of the aldosterone response to ANG II (but not to
ACTH) in rat cells (21). The requirement for maintained
activation of PLC, and the ensuing formation of IP3, is
compatible with the essential role of capacitative Ca2⫹
influx in sustaining ANG II-induced aldosterone production.
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current (ICRAC) (243). It is highly Ca2⫹ selective, inwardly
rectifying, and although its very low unitary conductance
is compatible with a carrier mechanism; noise analysis
indicates that ICRAC passes through a channel. There are,
however, several types of store-operated currents, different from ICRAC, in cells that exhibit store-operated Ca2⫹
influx (404).
Three major hypotheses have been proposed to explain the activation of capacitative Ca2⫹ influx by store
depletion. One of these hypotheses assumes that a small
diffusible cytosolic factor links the IP3-sensitive calcium
store with the plasmalemmal channel. Another model
attributes channel activation to the insertion of channelcontaining vesicles into the plasma membrane. The third,
and currently most accepted, hypothesis suggests a Ca2⫹dependent protein-protein interaction between the release and influx channels. The multitude of models may
indicate that there is no uniform mechanism responsible
for channel gating in different cell types. Since no specific
data are available for the mechanism in glomerulosa cell,
we refer to general reviews on this topic (49, 64, 404, 440,
565). The structure and gating mechanism of the channel
responsible for Ca2⫹ entry remain to be clarified. Mammalian homologs of Trp proteins (termed after Drosophila transient receptor potential), products of at least
seven genes, are presumed to constitute the channel. The
channel contains four subunits, and the great number of
possible heterotetramers may explain the variable function of these channels in different cell types. In fact, the
channels may display selective or nonselective Ca2⫹ conductance after activation of PLC. Store depletion evoked
by thapsigargin opens some but not all Trp channels
(reviewed in Ref. 361).
In 1989 we observed that, in contrast to K⫹-induced
2⫹
Ca influx, ANG II-induced early Ca2⫹ influx was not
sensitive to the DHP Ca2⫹ channel inhibitor nifedipine.
This observation led us to postulate that the two agonists
activate different Ca2⫹ entry mechanisms (504). A similar
observation was subsequently reported in bovine glomerulosa cells (302). Further results have unambiguously
demonstrated the significance of DHP-insensitive capacitative Ca2⫹ influx in ANG II-induced Ca2⫹ uptake. In rat
glomerulosa cells, thapsigargin dose-dependently increases [Ca2⫹]c and aldosterone production (219). The
Ca2⫹ signal is DHP insensitive and transient only in Ca2⫹free medium. Readdition of Ca2⫹ induces a steeper and
higher rise in [Ca2⫹]c than that observed in thapsigarginuntreated cells (465), indicating that influx rate depends
on the state of the calcium store rather than on [Ca2⫹]c.
Similar results were obtained in bovine glomerulosa cells.
Thapsigargin dose-dependently increases [Ca2⫹]c (159)
and stimulates aldosterone production (81).
Both mRNA and protein of Trp 4 are abundantly
expressed in the bovine adrenal cortex, where the only
other transcript found at a considerable level was Trp1.
CONTROL OF ALDOSTERONE SECRETION
3. Voltage-activated Ca2⫹ currents and Ca2⫹ channels
Physiol Rev • VOL
(409). L-type current has also been described in rat (150,
323, 562), bovine (113, 343, 344), and human cells (409).
N-type current was observed only in Long-Evans rats
(150); no report on its expression in any other rat strain or
other species has been published.
Patch-clamp studies usually employ Ba2⫹ as the
charge carrier to avoid Ca2⫹-dependent inactivation of
L-type channels, and few data have been obtained using
Ca2⫹ as charge carrier. The low-threshold, T-type current
was characterized in the presence of 2.5 mM Ca2⫹ in rat
and bovine glomerulosa cells by Quinn et al. (444). Following the elimination of K⫹ currents, the activation
threshold was between ⫺80 and ⫺70 mV, peak current
occurred near ⫺30 mV, and half-maximal steady-state
inactivation was attained at ⫺73 mV. In our studies (563),
performed with 2 mM Ca2⫹, the average activation threshold of T-type current was ⫺71 mV. The threshold of L-type
current was determined with a very slow voltage ramp
depolarization from ⫺100 to ⫹40 mV and also with ramp
depolarization following inactivating T-type channels at
⫺60 mV. The average threshold of L-current was ⫺57 mV,
applying either protocol.
Voltage-activated Ca2⫹ channels have heteromultimeric structures, and the electrophysiological characteristics of their ionic current are primarily determined by
the pore-forming ␣1-subunit. This subunit consists of four
homologous repeats (I–IV) of six membrane-spanning
segments (termed SI–SVI). Every third amino acid residue
in segments IV is lysine or arginine. Changes in the electrical field induce motion of these positively charged segments, which therefore serve as voltage sensors. The
intramembrane loops between SV and SVI line the channel pore, and four glutamate residues in this pore domain
are responsible for the selective Ca2⫹ permeability (352,
359, 414, 537, 540).
Molecular biological studies have identified the poreforming ␣1-subunits of the low- and high-voltage-activated
channels. Three isoforms of T-type ␣1-subunits are
known, indicated as Cav3.1, 3.2, and 3.3 (␣1G, ␣1H, and ␣1I,
respectively). Their intracellular loops and COOH termini
exhibit significant differences in amino acid sequence,
which provide opportunity for their selective pharmacological inhibition (307, 412). Half-maximal activation in
the presence of 2 mM Ca2⫹ was observed for the three
subtypes at ⫺29, ⫺31, and ⫺25 mV, respectively. The
steady-state inactivation of ␣1I occurs at higher potentials.
␣1G activates and inactivates more rapidly. Their deactivation is relatively slow and is fastest for ␣1I. All have a
tiny single-channel conductance, and ␣1H is the most sensitive to Ni2⫹ (286, 311, 413).
Substantial expression of the mRNA transcript for
the ␣1H subunit was found in the rat and bovine zona
glomerulosa by in situ hybridization. (A much weaker
expression was detected also in bovine zona fasciculata.)
An extremely low level of ␣1G mRNA was found, and ␣1I
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Angiotensin II induces capacitative Ca2⫹ influx and
depolarization, which, in turn, reduce both the Ca2⫹ concentration gradient and electrical gradient, the driving
forces of Ca2⫹ flux from the extracellular space into the
cytoplasm. However, depolarization also results in the
activation of voltage-operated Ca2⫹ channels, and the
ensuing increase in Ca2⫹ conductance may compensate
for the reduced driving force. In this way, voltage-activated Ca2⫹ channels subserve the maintenance of Ca2⫹
influx.
The various members of the superfamily of voltageactivated Ca2⫹ channels give rise to Ca2⫹ currents of
diverse electrophysiological and pharmacological properties. Voltage-activated Ca2⫹ currents are conventionally
classified as low-voltage (or low-threshold) and high-voltage (or high-threshold) currents. In view of the voltageactivated Ca2⫹ currents that participate in the control of
aldosterone secretion, this discussion will be confined to
the low-voltage, T-type current and the high-voltage, Ltype current. Calcium channels may exist in three distinct
states, identified as the closed, activated, and inactivated
states. The latter refers to a depolarization-induced state
from which the opened state cannot be directly attained.
T-type current is activated at more negative potentials
than L-type current. In the presence of 10 mM Ca2⫹, the
activation range of T-type channels is positive to ⫺70 mV,
and that of L-type channels is positive to ⫺10 mV. T-type
current reaches maximum amplitude and is inactivated at
more negative potential than L-type current. T-current
inactivates more rapidly, but deactivates (closes) and reactivates (reprimes) more slowly than L-type current. Ttype channels exhibit comparable permeability for Ca2⫹
and Ba2⫹, whereas Ba2⫹ conductance through L-type
channels exceeds that of Ca2⫹ conductance. The T-type
channel has a unitary conductance of ⬃8 pS versus the 25
pS of an L-type channel (when the charge carrier is 100
mM Ba2⫹). T-type current is generally more sensitive to
blockade by Ni2⫹, amiloride, and mibefradil, and less
sensitive to blocking by Cd2⫹ and nifedipine than L-type
current. In contrast to L-current, T-current is not enhanced by the DHP agonist BAY K 8644 (for further
details, see Refs. 41, 341, 352, 518, 552).
The first electrophysiological study on voltage-operated Ca2⫹ currents in rat glomerulosa cells was published
in 1987 (445) and demonstrated that depolarizing current
pulses elicited a regenerative response. The ionic mechanism underlying the regenerative response was voltageoperated Ca2⫹ current. Following these pioneering studies, three types of voltage-activated Ca2⫹ currents, T-, Land N-type currents, have been identified by application
of the patch-clamp technique to glomerulosa cells. T-type
current has been observed in rat (150, 342, 562), bovine
(113, 118, 259, 323, 343), and human glomerulosa cells
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ANDRÁS SPÄT AND LÁSZLÓ HUNYADY
Physiol Rev • VOL
are inhibited by Go or Gi via their released ␤␥-subunits
(235, 285). Also, Ras-related small G protein that binds
CaM inhibits the L-type current (42).
4. Action of ANG II on voltage-activated Ca2⫹ channels
Aldosterone production stimulated with ANG II or
K⫹ is inhibited by the Ca2⫹ channel inhibitors verapamil
(26, 305, 488) and nifedipine (3, 504). The frequently observed dependence of the ANG II-induced sustained Ca2⫹
signal on extracellular Ca2⫹ (89, 301, 467) has been regarded as evidence in favor of ANG II-induced Ca2⫹ influx. In fact, data on the augmented initial influx rate of
45
Ca after adding ANG II confirmed this interpretation in
rat (95, 503) and bovine cells (159, 290, 301). Several,
although not all, of the studies examining the effect of
channel drugs on ANG II-induced Ca2⫹ signal also supported the stimulation of voltage-activated Ca2⫹ influx by
ANG II. The DHP antagonist nifedipine usually moderately reduced the Ca2⫹ signal in bovine (7, 89) and in rat
cells (77, 255, 516), whereas BAY K 8644, an L-type specific agonist, enhanced ANG II-induced Ca2⫹ signal in rat
(but not bovine) glomerulosa cells (229, 255). However, it
should be noted that ANG II was applied at pharmacological concentration in all these experiments, giving no
information on channel activity under physiological
conditions. Moreover, the description of changes in
[Ca2⫹]c gives only an indirect indication of changes in
unidirectional ion transport and the corresponding
channel activity.
We observed in 1991 that the nifedipine-sensitive
Ca2⫹ signal induced by 18 mM K⫹ is inhibited by physiological concentrations of ANG II in the rat glomerulosa
cell (24). As later discussed, at this concentration of K⫹
the Ca2⫹ signal is evoked dominantly by L-type channels.
Subsequent patch-clamp studies provided evidence that
L-type Ca2⫹ current is in fact inhibited by ANG II (323).
When applied at a pharmacological concentration (10
nM), ANG II also inhibited the K⫹-induced Ca2⫹ signal or
current in bovine cells (107, 344). [In contrast to these
observations, ANG II was found to enhance L-type Ca2⫹
current in the Y1 adrenocortical tumor cell line (236), and
AVP was also reported to augment L-type current in rat
glomerulosa cells (196).]
The inhibition of L-type current in the face of enhanced Ca2⫹ influx indicates that ANG II stimulates Ca2⫹
influx through T-type channels only. Furthermore, the
comparable concentration dependence of inhibition of
T-type current and ANG II-induced aldosterone production by mibefradil, a more-or-less specific inhibitor of
T-channels, provides evidence in favor of the essential
role of T-type channels in eliciting Ca2⫹ influx in the ANG
II-stimulated rat glomerulosa cell (323). The same conclusion could be drawn from the report that mibefradil,
applied at a concentration that inhibits T-type but not
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was virtually absent. In accordance with these data, the
IC50 of Ni2⫹ for inhibition of T-type Ca2⫹ current in these
cells was 6 ␮M (489), corresponding to the Ni2⫹ sensitivity of the ␣1H subunit (7 ␮M) (413). ␣1H is also expressed
in the H295R human glomerulosa cell line, and, unexpectedly, exposure to aldosterone for 24 h increases the expression of the channel protein as well as the density of
T-type current (317). It is noteworthy that only the activity
of the H isoform of the T-type Ca2⫹ channel is enhanced
by Ca2⫹, through phosphorylation by CaMKII (586).
The diverse nature of L-type channels was suggested
long ago by the different excitation-contraction coupling
in skeletal muscle and cardiac muscle. In both cell types,
activation of L-type Ca2⫹ channels results in Ca2⫹ release
from the sarcoplasmic reticulum through ryanodine receptors. However, in skeletal muscle cells the L-channels
(DHP receptors) in the t-tubule membrane activate type 1
RyRs through protein-protein interaction, whereas in cardiac muscle it is Ca2⫹ influx through L-channels that
evokes Ca2⫹-induced Ca2⫹ release through type 2 RyRs.
In addition to the structural differences in RyRs, this
differential coupling is attributed to the molecular differences in the two types of L-type channels. In fact, molecular biological studies on different cell types have identified three, rather than two, isoforms of the pore-forming
␣1-subunit of L-type channels. The ␣1-subunit of the skeletal (S), cardiac (C), and neuroendocrine (D) isoforms of
L-type channel are termed Cav1.1, Cav1.2, and Cav1.3,
respectively (415).
RT-PCR analysis of single rat glomerulosa cells, free
of other cell types, detected mRNA of Cav1.2 and Cav1.3
(␣1C and ␣1D, respectively) (242). The dominant expression of Cav1.3 probably results in a depolarization shift of
the activation threshold and reduced rate of Ca2⫹-dependent inactivation (298, 601). The expression of Cav1.2 and
Cav1.3 was also observed in human H295R cells (317).
Voltage-operated Ca2⫹ channels contain several isoforms of additional (␣2-␦-, ␤-, and ␥-subunits), which modify the current characteristics and pharmacology of the
␣1-subunit as well as its expression at the plasma membrane (137, 271, 414, 560). We are not aware of studies on
these additional subunits in the glomerulosa cell.
Several laboratories have observed that cAMP,
through the activation of PKA, induces marked increases
in L-type current, whereas data on the effect of PKC on
T-type and L-type currents are conflicting (reviewed in
Refs. 93, 352). cGMP opposes the current-enhancing effect of cAMP (268). CaMKII phosphorylates ␣s and thus
enhances L-type current (348). Enhancement of T-type
current by CaMKII was first observed in bovine glomerulosa cells (34). Heterotrimeric G proteins, in addition to
regulating second messenger systems, may also regulate
ionic channels acting via a membrane-delimited pathway.
L-type current is enhanced by the ␣-subunit of Gs (352,
575), and the neuronal N-type and P/Q-type Ca2⫹ currents
CONTROL OF ALDOSTERONE SECRETION
because L-type channels are inhibited by a Gi-mediated
mechanism in cells exposed to ANG II. The neurotransmitter dopamine, which may be released from local varicose axon terminals around glomerulosa cells (571), also
inhibits T-type Ca2⫹ channel (143, 400) and thus inhibits
aldosterone secretion (2).
As summarized in Figure 4, ANG II enhances Ca2⫹
influx through T-type channels. Depolarization as well as
a negative shift in the voltage dependence of channel
activation are the factors inducing enhanced Ca2⫹ influx,
the latter shift being evoked by activation of a pertussis
toxin-sensitive G protein, probably belonging to the Gi/o
family. It is presently not clear whether the relative participation of these factors in current amplification depends on species or experimental conditions. ANG II, at
the same time, may inhibit L-type current, probably also
through the activation of Gi/o. This inhibition may protect
the cell from Ca2⫹ overload.
5. DHP-sensitive Ca2⫹ channels and IP3-induced
Ca2⫹ release
In rat glomerulosa cells, the L-type channel-specific
DHP agonist BAY K 8644 enhances ANG II-induced Ca2⫹
response and aldosterone production (229, 255). This suggests that even if ANG II-induced Ca2⫹ influx takes place
via T-channels, some L-channels also contribute to Ca2⫹
signaling. This presumption, however, is in sharp contradiction to the previously described inhibition of L-type
channels by ANG II. On the other hand, the actions of
channel agonist and antagonists suggest an interaction
between L-type channels and subplasmalemmal IP3 receptors. Such a model (516) has been based on the following
experimental observations.
ANG II-induced depolarization and Ca2⫹ influx do
not become detectable until after the initial peak of Ca2⫹
2⫹
FIG. 4. Generation of Ca
signal in angiotensin II-stimulated glomerulosa cells. SOC, store-op2⫹
erated Ca channel. The red arrows indicate stimulatory actions, and the green arrows indicate inhibitory actions. Metabolic transformation and
transport processes are shown by black arrows.
No data are available for TASK channels in bovine
glomerulosa cells. Gi-mediated activation of T-type
Ca2⫹ channels was found only in bovine cells. The
role of Na⫹-K⫹-ATPase is shown in Fig. 3.
Physiol Rev • VOL
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L-type Ca2⫹ channels, reduced the [Ca2⫹]c response to
ANG II in bovine cells (476). The inhibition of Ca2⫹ current and ANG II-induced aldosterone production by tetrandine, an herbal alkaloid, at concentrations that inhibit
T-type channels but do not yet affect L-type channels
(478), also supports the significance of T-type current in
ANG II-stimulated bovine cells.
ANG II appears to enhance T-type current in rat and
bovine glomerulosa cells by different mechanisms. ANG II
failed to affect the function of T-type channels in Lotshaw’s experiments on rat glomerulosa cells (323), leading to the conclusion that ANG II activates the low-voltage-operated Ca2⫹ channel exclusively by depolarizing
the plasma membrane. The enhancement of T-channel
activity, reported in bovine cells by Barrett’s group, was
explained with a hyperpolarizing shift in the voltage dependence of channel activation (97). This shift requires
intracellular GTP, suggesting that the channel-activating
action of ANG II is mediated by a G protein (349). Although the Ca2⫹ signal activates calmodulin-dependent
kinase II, and this activation may also shift the voltagecurrent function to more negative values (34, 327), the
ANG II-induced shift is basically due to activation of Gi/o
(97, 326). This model is in agreement with previous reports on the pertussis toxin sensitivity of ANG II-induced
Ca2⫹ influx (236, 296, 344). Activation of pertussis toxinsensitive G protein(s) also seem(s) to account for inhibition of L-type current by ANG II (344) or AVP (204).
Atrial natriuretic hormone, a physiological inhibitor
of aldosterone secretion, attenuates agonist-induced Ca2⫹
influx (95, 186). In patch-clamp studies this inhibition was
confined to T-type channels; Ca2⫹ current through L-type
channels was even enhanced (33, 350). The inhibition of
ANG II-induced aldosterone production may be due to the
reduction of T-current, and this effect apparently is not
counteracted by a concomitant enhancement of L-current
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ANDRÁS SPÄT AND LÁSZLÓ HUNYADY
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channels and IP3 receptors is compatible with observations on both smooth and skeletal muscle cells. Ca2⫹
release from IP3-sensitive stores in coronary myocytes,
induced by acetylcholine (but not by supramaximal concentrations of IP3), was potentiated by depolarization
through a mechanism that did not require extracellular
Ca2⫹ (190). Spontaneous membrane depolarizations
(termed slow waves) in visceral smooth muscle also did
not require Ca2⫹ influx, but were dependent on Ca2⫹
release from IP3-sensitive stores. Nevertheless, their frequency increased at more depolarized potentials (559).
The response of peeled skeletal muscle fibers to exogenous IP3 was significantly larger when t tubules were in a
depolarized state (138). Although the authors emphasized
the role of Em in controlling the effect of IP3, it should be
recalled that depolarization changes the conformation of
L-type channels.
Sustained formation of IP3, leading to prolonged IP3induced Ca2⫹ release, is a prerequisite for sustained enhancement of aldosterone production (21). Therefore,
modulation of IP3-dependent Ca2⫹ release by dihydropyridines should influence both Ca2⫹ signal and aldosterone
production throughout the duration of stimulation with
ANG II. Although our model still requires direct evidence,
it presently offers an explanation for the effects of channel-regulating drugs on ANG II-induced Ca2⫹ and aldosterone responses in the face of an inhibited state of L-type
channels.
6. Ca2⫹ influx induced by K⫹
As discussed in section IIB, the glomerulosa cell is
characterized by a dominant K⫹ conductance. The high
density of the background (TASK) K⫹ channel makes it an
excellent sensor for [K⫹]o. K⫹-induced depolarization,
which almost perfectly follows the Nernst equation, activates voltage-operated Ca2⫹ channels. Raising [K⫹]o gradually to 20 mM evokes a gradual increase of [Ca2⫹]c (432,
444, 445, 450). The K⫹-induced Ca2⫹ signal is nonoscillating and long-lasting (28, 89, 448, 450, 466).
In rat glomerulosa cells, the activation threshold of
T-type Ca2⫹ channels in the presence of 2–2.5 mM Ca2⫹ is
between ⫺70 and ⫺80 mV, and half-maximal steady-state
inactivation occurs at ⫺73 mV (444, 563). At membrane
potentials where T-type channels can be activated and
inactivation is incomplete, as indicated by the intersection of peak current and steady-state inactivation curves
(in function of Em), a small but sustained Ca2⫹ current
(termed window current) should occur. Because window
currents were usually analyzed using a high concentration
of Ca2⫹ or Ba2⫹ as charge carrier, no precise data are
available for physiological conditions. Assuming that window current begins at ⫺80 mV at physiological extracellular [Ca2⫹], T-type channels may participate in eliciting
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signal has occurred. ANG II (10⫺9 or 10⫺8 M)-induced
depolarization begins at ⬃2 min in bovine (88) and after
30 s in rat glomerulosa cells (255). (The applied fluorimetric technique could record the immediate depolarizing
effect of K⫹.) In patch-clamp studies on rat glomerulosa
cells, using the whole cell configuration, 200 nM ANG II
evoked depolarization after an average lag time of 24 s
(408). In patch-clamp experiments using the perforated
patch technique, depolarization induced by 10⫺10 to 10⫺8
M ANG II began later than 1 min (323). These data suggest
that depolarization-triggered voltage-operated Ca2⫹ influx
cannot account for the generation of the initial (approximately first 15 s) Ca2⫹ signal.
In fluorimetic studies, the Mn2⫹-quench technique is
a sensitive method of detecting Ca2⫹ influx. In rat glomerulosa cells, in contrast to the rapid quenching effect of
a physiological elevation of [K⫹], 25 nM ANG II had no
quenching effect within 150 s. Mn2⫹ exerted a rapid
quenching effect only if added several minutes after the
application of ANG II (516). This observation is in accordance with measurements of the initial 45Ca influx rate in
rat (107, 504) and bovine glomerulosa cells (301), stimulated with nanomolar ANG II. Accordingly, these studies
indicate that ANG II-induced Ca2⫹ influx has a lag time of
⬎150 s. Nevertheless, the initial phase of ANG II-induced
Ca2⫹ signal was modified by organic Ca2⫹ channel drugs
in bovine (7, 81, 302), human (63), and rat glomerulosa
cells (229). In our studies on rat glomerulosa cells, nifedipine and the benzothiazepine diltiazem reduced and BAY
K 8644 augmented the amplitude of the ANG II-induced
Ca2⫹ peak (attained at 13–15 s after adding the agonist)
(255, 516). It is important to emphasize that nifedipine
does not inhibit T-type Ca2⫹ current in these cells (562).
The lack of any contribution of enhanced Ca2⫹ influx to
the generation of the initial Ca2⫹ signal was also confirmed by examination of the signal when Ca2⫹ influx was
blocked by 5 mM Ni2⫹. Nifedipine was capable of diminishing the ANG II-induced cytoplasmic Ca2⫹ signal even
under such conditions (516).
These observations suggest that activation of L-type
channels by a G protein (e.g., Gi, cf. Refs. 196, 236, 296,
344) modifies IP3-induced Ca2⫹ release. Because nifedipine did not decrease ANG II-induced formation of IP3
(516), an effect of L-type channels on the function of IP3R
had to be assumed (516). In this respect it should be
recalled that a population of the IP3-sensitive calciumstoring vesicles is cytoskeletally attached to the plasma
membrane (166, 471). Moreover, considering the proteinprotein interaction between type 1 RyRs and L-type Ca2⫹
channels (Cav 1.1) in skeletal muscle, as well as the
significant amino acid identity between the cytoplasmic
NH2-terminal loops of RyR and IP3 receptors (181, 536),
coupling between L-type channels (Cav1.2 and 1.3) and
subplasmalemmal IP3Rs can be hypothesized.
The assumption of an interaction between L-type
CONTROL OF ALDOSTERONE SECRETION
Physiol Rev • VOL
[Ca2⫹]c. This second phase coincides with the detectable
onset of swelling. The postinitial elevation of [Ca2⫹]c may
be prevented by keeping cell volume constant, with application of KCl in a hyperosmotic medium (335). This
observation indicates that increased cell volume sensitizes T-type channels to depolarization. Raising [K⫹]o
from 4 mM to the supraphysiological level of 7 mM also
induces swelling in bovine glomerulosa cells (231). However, the mechanism sensitizing bovine cells to elevated
[K⫹] seems to differ from that observed in rat glomerulosa cells. The Ca2⫹ signal evokes a CaMKII-mediated
shift of the voltage dependence of the activation of T-type
channels (34, 327), more specifically that of the poreforming subunit ␣1H (but not that of ␣1G) (586) to more
negative potential values. Therefore, it appears that increased cell volume exerts a positive feed-forward effect
in rat, and elevated [Ca2⫹]c exerts a positive feedback
effect on the voltage threshold of T-type channels in
bovine glomerulosa cells, and these mechanisms contribute to the generation of Ca2⫹ responses to elevation of
[K⫹].
Summarizing the mechanism of K⫹-induced Ca2⫹ signaling, increased K⫹ in the physiological concentration
range enhances Ca2⫹ influx through T-type channels. This
response may be amplified by K⫹-evoked cell swelling
and/or the developing Ca2⫹ signal itself. At high [K⫹],
which still occurs in vivo, activation of some L-type channels contributes to Ca2⫹ signaling, rendering Ca2⫹ signal
generation and aldosterone secretion DHP sensitive. At
pharmacological K⫹ concentrations, T-type channels are
inactivated and continuous Ca2⫹ influx takes place
through L-type channels. (The role of cAMP in K⫹-elicited
cell response is discussed in section IVB.)
7. Na⫹/Ca2⫹ exchange
The sodium-calcium antiporter, which exchanges
three Na⫹ for one Ca2⫹ and is therefore electrogenic, is an
important regulator of [Ca2⫹]c (for review, see Ref. 496).
In most cell types, at least under resting conditions, it
brings about net Ca2⫹ efflux. Its presence in rat glomerulosa cells was indicated by the Na⫹ dependence of Ca2⫹
transport. The efflux rate of 45Ca was decreased when
extracellular [Na⫹] was reduced, whereas 45Ca influx was
accelerated by ouabain-induced increase in intracellular
[Na⫹] (253). [Ca2⫹]c also depends on extracellular [Na⫹]
in bovine glomerulosa cells (295).
Benzamil derivative inhibitors of the antiporter attenuated the effects of extracellular (295) and cytoplasmic
[Na⫹] (253) on Ca2⫹ uptake and also inhibited ANG IIinduced aldosterone production (253, 557). The drug reduced the initial influx rate of 45Ca and the exchangeable
(60-min) pool size of calcium in control cells and inhibited
the stimulatory effect of 25 nM ANG II, added 10 min
earlier, on 45Ca uptake (504). The driving force for Ca2⫹
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the Ca2⫹ signal during stimulation with physiologically
elevated [K⫹].
The question still remains whether the high voltageactivated L-type channels also contribute to Ca2⫹ influx.
Because Ca2⫹ response to ⬃6.0 mM K⫹ (28, 33, 229) is
enhanced by the L-type specific DHP agonist BAY K 8644,
it may be assumed that a fraction of L-type channels is
already open under moderately depolarized conditions.
Consistent with this possibility are observations on the
effect of mebafradil, which inhibits T-type channels much
more effectively than L-type channels. The effect of mebafradil on K⫹-induced aldosterone production by rat
glomerulosa cells was gradually attenuated as a function
of [K⫹] (i.e., with increasing depolarization), indicating
that above 6 mM [K⫹] a shift occurs from T-type to L-type
channels in the generation of Ca2⫹ influx (323). Rossier et
al. (472) examined the effect of nifedipine and calciseptin
on Ca2⫹ currents, [Ca2⫹]c, and aldosterone production in
bovine glomerulosa cells. Their results support the previous data, indicating that in K⫹-stimulated cells aldosterone production correlates with T-type channel activity.
Barrett et al. (33) examined aldosterone production
by bovine glomerulosa cells over a wide range of [K⫹].
From 3 to 20 mM K⫹ the concentration-response curve
was similar to that described for rat glomerulosa cells, a
biphasic function peaking at 10 mM. However, there was
a second increase in aldosterone production between 20
and 30 mM. The voltage dependence of the aldosterone
production rate and that of the predicted Ca2⫹ influx
through T- and L-type channels were similar, suggesting
that both types of Ca2⫹ channels may support steroid
production. Within the potential range studied (⫺76 to
⫺23 mV) no Ca2⫹ influx would be carried exclusively via
one or the other channel population, but their contribution would depend on Em. The calculations show that at 6
mM K⫹ T-type channel influx would be 90% of maximal,
whereas that of L-type channel influx would attain 10% of
maximal.
Rat glomerulosa cells may respond to an elevation of
[K⫹] as small as 0.5 mM with Ca2⫹ signals (563) and
increased activity of mitochondrial NAD(P)H formation
(432). Raising [K⫹] from 3.6 to 4.6 mM may double aldosterone production (432). Although window current (see
above) may account for the activation of T-type channels
despite the tiny shift of Em, the phenomenon still seems to
be disproportionate and requires more complete elucidation. A possible mechanism for increasing the sensitivity
of glomerulosa cells to K⫹ is an increase in cell volume.
Hyposmosis-induced swelling enhances T-type Ca2⫹ current and, hence, K⫹-induced Ca2⫹ signal (334). The enhanced Ca2⫹ response is not sensitive either to cytochalasin D or colchicine (335). When [K⫹] is raised from 3.6
to 5 mM, a steep initial rise in [Ca2⫹]c is followed by a
slower further rise, and several cells display a second
phase of rapid rise, superimposed on the already elevated
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ANDRÁS SPÄT AND LÁSZLÓ HUNYADY
2⫹
FIG. 5. Activation of Ca
influx by the sodium-calcium antiporter
(NCX) in the angiotensin II-stimulated glomerulosa cells. The red arrows
indicate stimulatory actions, and the green arrows indicate inhibitory
actions. (The pathway shown with dotted lines has been shown in other
cell types only.)
Physiol Rev • VOL
consideration. Extrusion of Ca2⫹ from the cytoplasm by
the plasmalemmal Ca2⫹-ATPase and the Na⫹-Ca2⫹ antiporter is enhanced by the increase in [Ca2⫹]c and is partly
opposed by reduction of the membrane PIP2 pool, which
attenuates the activity of the Ca2⫹ pump. The proposed
inhibition of the antiporter by ANG II could mean a further blunting of Ca2⫹ loss. In view of the potential significance of such a mechanism, direct evidence in favor of
the inhibition of the antiporter by the 12-HETE-p38 MAPK
pathway should be provided by unidirectional radioflux
measurements, at low ANG II concentrations.
8. Ca2⫹-eliminating mechanisms
Mechanisms eliminating Ca2⫹ from the cytoplasm
include the plasma membrane Ca2⫹-ATPase (PMCA), the
sarco/endoplasmatic Ca2⫹-ATPase (SERCA), and the
Na⫹-Ca2⫹ antiporter. The function of the latter has been
discussed in the previous subsection. In view of the current topic, it should be emphasized that PMCA is activated by acidic phospholipids (e.g., PIP2) and CaM (91).
For lack of studies on the glomerulosa cells, in all other
respects we refer to general reviews (e.g., Refs. 200, 330).
C. Diacylglycerol-PKC and Lipoxygenase Pathways
Rasmussen and co-workers (294) proposed that sustained responses to Ca2⫹-mobilizing agonists would be
initiated by Ca2⫹, while protein phosphorylation by PKC
(or PKA) would account for the sustained phase of steroid
production. Their postulation was based mainly on studies on bovine glomerulosa cells, in which stimulation of
PKC with tetradecanoylphorbol acetate (TPA) slightly increased aldosterone production per se and efficiently potentiated the effect of a Ca2⫹ ionophore. The kinetics of
hormone production stimulated by the combined application of TPA and the ionophore were similar to that of ANG
II-induced production (294). In view of the cell-damaging
effect of prolonged elevation of [Ca2⫹]c, this dual system
was considered to have advantages over a simple, Ca2⫹mediated system (32, 289, 292). Occasionally, phosphorylation by PKA would serve a similar purpose (291).
PKC was originally regarded as a Ca2⫹ and phospholipid-dependent protein-phosphorylating enzyme. Today,
the large family of PKCs is known to consist of at least a
dozen isoenzymes with various activation characteristics
and substrate specificities. While the classical forms are
activated by DAG, high [Ca2⫹] may attenuate the DAG
requirement of some isoforms and arachidonate may also
be an efficient activator (135, 170, 388).
DAG is produced simultaneously with IP3 from PIP2
by the action of PLC. In rat glomerulosa cells ANG II
evokes a biphasic increase in DAG production, with an
early peak at 30 s and a later one at 10 min (378). In the
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influx may be the high intracellular [Na⫹] of glomerulosa
cells (131, 557). Depolarization and an increase in cytoplasmic [Na⫹] (557) may further enhance Ca2⫹ influx by
the Na⫹/Ca2⫹ antiporter in cells stimulated with ANG II
(Fig. 5). {PKC activates Na⫹/H⫹ exchange and thus raises
[Na⫹]c in several cell types, and such an effect of PKC has
also been suggested in glomerulosa cells (117).} These
observations indicate the participation of the antiporter in
the calcium metabolism of glomerulosa cells, and also
suggest that it contributes to Ca2⫹ influx during exposure
to ANG II (382). Benzamil derivatives compete with Na⫹
for its binding site. However, since they accumulate inside
the cell where they have to compete with Na⫹ present at
low concentration, they may inhibit Ca2⫹ influx more
efficiently than Ca2⫹ efflux. Therefore, although these
drugs provide a means to reveal the participation of the
antiporter in an examined mechanism, their effect on
Ca2⫹ efflux may be masked by a more pronounced inhibition of Ca2⫹ influx. Thus the data on their effect on Ca2⫹
influx do not exclude the possibility that the Na⫹/Ca2⫹
exchanger mediates net Ca2⫹ efflux.
ANG II, through the activation of lipoxygenase and
the ensuing formation of 12-HETE, activates p38 mitogenactivated protein kinase (MAPK) (382, 519) (see sect. IIC).
The activation of p38 MAPK, in turn, was reported to
inhibit Na⫹/Ca2⫹ exchange and to prolong the sustained
phase of the Ca2⫹ signal (519). However, the fact that
ANG II reduces the exchangeable Ca2⫹ pool (27, 107, 154,
289) in spite of the enhanced Ca2⫹ influx requires further
CONTROL OF ALDOSTERONE SECRETION
Physiol Rev • VOL
compatible with the proposed secretagogue action of
PKC.
In one report the PKC inhibitor Ro31– 8220 reduced
ANG II-stimulated aldosterone production in rat glomerulosa cells (277). On the other hand, in our studies the PKC
antagonist staurosporine potentiated the aldosterone response to K⫹ and enhanced the initial (30-min) phase of
ANG II-induced aldosterone production, but failed to influence the effect of ACTH. The enzyme inhibitor enhanced the initial (30 min) phase of the ANG II-induced
aldosterone production (218).
A more straightforward means of preventing PKC
effects is by depletion of the enzyme. When PKC activity
in both the cytosol and the membrane fraction was reduced below the control level by long-lasting exposure to
TPA, aldosterone production induced by physiological
stimuli (300 pM ANG II or 5.4 mM K⫹) was significantly
enhanced (218). [In K⫹-stimulated cells the activation of
PKC was secondary to a weak activation of PLC by Ca2⫹
(218).] PKC depletion failed to alter ANG II-induced aldosterone production in the experiments of Aguilera and
co-workers (377), who also refuted the involvement of
PKC in the stimulation of aldosterone production by ANG
II.
The contradictions in the PKC literature may be attributed to several factors. Determination of enzyme activity has several pitfalls, including lack of appropriate
substrate specificity as well as limited proteolysis of the
enzyme during homogenization, which leads to a Ca2⫹
and phospholipid-independent kinase activity. TPA or
other DAG analogs may be anchored in the whole cell
membrane rather than at confined domains around the
(probably clustered) ANG II receptors. Therefore, PKC
may translocate to nonspecific sites of the membrane,
resulting in artifacts. In view of the moderate specificity
of kinase C blockers, their inhibitory effects may be inconclusive about the role of PKC. The species-dependent
and cell type-dependent expression of different isoforms
of the enzyme, often exerting opposing effects (135),
should also be kept in mind. In summary, the bulk of
evidence indicates that PKC has an inhibitory, rather than
stimulatory, role in the acute control of aldosterone secretion.
The hydrolysis of phosphoinositides by PLA2 results
in the release of arachidonate, a precursor of eicosanoids.
Since PLA2 is not activated in ANG II-stimulated rat glomerulosa cells (244), any arachidonate released should
originate from DAG. This means that the role of DAG,
formed by the hydrolysis of PIP2, may not be confined to
the activation of PKC, but may also serve as an inducer of
additional signaling pathways. The arachidonate derivatives, prostaglandins E2 and A2, stimulate aldosterone
production (511, 517). Nevertheless, cyclooxygenase inhibitors do not counteract the induction of aldosterone
production by ANG II, K⫹, or ACTH. Therefore, we must
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bovine glomerulosa cell an early peak (at ⬃30 s), detected
if sampling is frequent enough (248, 297), is followed by a
second phase, maintained for several tens of minutes (67,
248, 297). DAG may also derive from phosphatidylcholine
by the combined activity of phospholipase D (PLD) and
phosphatidic acid phosphohydrolase (60). It has been
suggested by Bollag and co-workers (66, 68, 273) that,
during the sustained phase of stimulation with ANG II, the
activation of PLD contributes to the formation of DAG. It
is worth mentioning that in K⫹-stimulated cells, weak
activation of PLC by Ca2⫹, obviously through the formation of DAG, results in the moderate activation of PKC
(218).
In spite of the convincing logic of the dual-control
system, the role of PKC in the control of aldosterone
secretion is highly controversial. The criteria for accepting such a role are the following: 1) translocation of PKC
from the cytosol into the membrane fraction in response
to the respective stimulus; 2) induction of the biological
response with DAG analogs or an active phorbol ester;
and 3) inhibition of the biological response with a specific
inhibitor of the enzyme (e.g., staurosporine) or by means
of depleting the cell of activable PKC (with several hours
of exposure to a high concentration of an active phorbol
ester). We will group the data in the literature according
to these criteria.
ANG II brings about the translocation of PKC from
the cytosol into the particulate fraction in bovine (226,
291, 308) as well as rat glomerulosa cells (377). The
enzyme also translocates to the membrane fraction in
response to high [Ca2⫹]c (171), and ANG II-induced activation of PKC may depend on concomitant Ca2⫹ influx
(288).
At variance with the reports of Rasmussen’s group,
TPA or 1-oleoyl-2-acetylglycerol, a DAG analog, added to
bovine glomerulosa cells failed to increase basal aldosterone production (187). These drugs also inhibited the
effect of ANG II and K⫹ on T-type current, [Ca2⫹]c, and
the aldosterone response (12, 187, 470). TPA augmented
aldosterone production in freshly isolated human adrenocortical cells (305) but failed to do so in the H295R human
adrenocortical cell line (110). In the rat, TPA-stimulated
aldosterone production was observed exclusively in adrenal capsular tissue (569). In contrast, TPA inhibited
basal as well as ANG II-stimulated, K⫹-stimulated, and
ACTH-stimulated hormone production by isolated glomerulosa cells (218). TPA induced the phosphorylation of
the cholesterol carrier protein StAR (see sect. VIIA) in
bovine glomerulosa cells (54, 226) but not in rat cells
(226). TPA, in contrast to ANG II, also failed to increase
the steady-state StAR mRNA level in human (H295R)
glomerulosa cells (110). PKC, at least in the hamster
glomerulosa cell, also depresses the expression of aldosterone synthase (314, 315). Overall, these data are not
509
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ANDRÁS SPÄT AND LÁSZLÓ HUNYADY
D. Vasopressin: A Transiently Acting
Paracrine Agonist
Several neurotransmitters may reach the glomerulosa cells, either from splanchnic nerve endings (528, 571,
572) or from the chromaffin cells, located in medullary
rays within the zona glomerulosa (185). The most studied
Physiol Rev • VOL
FIG. 6. Proposed mechanism of the stimulation of aldosterone
production by ANG II via the lipoxygenase product 12-HETE and p38
MAPK (based on Refs. 84, 199, 382, 519, 520). The red arrows indicate
stimulatory actions, and the green arrows indicate inhibitory actions.
Metabolic routes are shown by black arrows.
Ca2⫹-mobilizing paracrine agonist, vasopressin, binds to
the pressor (V1) type receptor in glomerulosa cells. Activation of the V1 receptor elicits the breakdown of PIP2,
induces Ca2⫹ signaling, and stimulates aldosterone production in rat (22, 205, 589) and human glomerulosa cells
(206).
In rat glomerulosa cells, ANG II and AVP, applied at
concentrations equipotent in terms of the phosphoinositide response, stimulated initial aldosterone production to
the same extent, but only ANG II elicited a sustained
response. AVP does not maintain aldosterone production
at a high level, in spite of activating phosphoinositide
turnover for at least 2 h. The early decay in AVP-induced
aldosterone production is not due to some form of inhibition, since AVP does not attenuate ANG II-stimulated
aldosterone production (160). The Ca2⫹ signals, elicited
by the two agonists, have different kinetics. AVP-induced
oscillations decay within 15 min, while ANG II (evoking a
similar phosphoinositide response) induces sustained
Ca2⫹ oscillations as well as prolonged and significantly
greater aldosterone production (447). In contrast to Gimediated inhibition of L-type Ca2⫹ channels in ANG IIstimulated rat glomerulosa cells (see sect. IIB), AVP was
reported to stimulate pertussis toxin-sensitive (i.e., Gi/omediated) Ca2⫹ influx through such channels (196, 204).
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reject the physiological role of prostaglandins in the control of aldosterone secretion (164). However, the observation showing that the aldosterone-stimulating effect of
arachidonate cannot be blocked by cyclooxygenase inhibitors (164) suggests a role for some other arachidonate
derivative in the control of steroid production (164).
Rat glomerulosa cells metabolized arachidonate to
hydroxyeicosatetraenoic acids (HETEs) by lipoxygenases
and epoxyeicosatrienoic acids (EETs) by a cytochrome
P-450 epoxygenase, but no leukotrienes were detected
(84). A DAG lipase inhibitor, which prevents the release of
arachidonate, blocked ANG II-induced 12-HETE and aldosterone formation. In contrast, a DAG kinase inhibitor,
which prevents the conversion of DAG to phosphatidic
acid, potentiated 12-HETE and aldosterone production
(378). 12-HETE itself induced Ca2⫹ release from intracellular stores as well as Ca2⫹ influx from the extracellular
fluid, whereas lipoxygenase inhibitors inhibited the effect
of ANG II on [Ca2⫹]c and aldosterone production (520).
12-Lipoxygenase products activate p38 MAPK (382),
which, in turn, was reported to reduce Ca2⫹ efflux (519)
(see sect. IIB7). More recent experiments applying molecular biological techniques (199) gave strong support to
these data, and also indicated that activation of p38 MAPK
leads to increased expression of the CYP11B2 gene product, aldosterone synthase (cytochrome P-450aldo). Overall, these data support the assumption that 12-HETE is
required for a full response of the glomerulosa cells to
ANG II. Nevertheless, it does not seem to be sufficient to
evoke maximal aldosterone response, since 12-HETE production in cells overexpressing 12-lipoxygenase was severalfold higher than that in ANG II-exposed cells transfected with empty vector, yet aldosterone production attained comparable (submaximal) levels in the two groups.
The participation of 12-HETE in ANG II-induced aldosterone secretion is shown in Figure 6.
Whether the formation of 12-HETEs should be regarded as a consequence of PIP2 hydrolysis only, or the
release of arachidonate from DAG is activated by a separate mechanism, should be further studied.
In view of the presumably increased formation of
arachidonate, another important issue worth examination
is whether ANG II activates an arachidonic acid-dependent non-store-operated Ca2⫹ channel before the activation of store-operated (capacitative) Ca2⫹ channels, as
recently observed in other cell types (reviewed in Ref. 69).
CONTROL OF ALDOSTERONE SECRETION
AVP exerts a weak inhibition on T-type Ca2⫹ channels
(196). In view of the significance of T-type Ca2⫹ current in
the stimulatory action of ANG II, the AVP-induced inhibition of T-type channels may be a factor responsible for the
transient character of vasopressin action. Activation of
PKC (183) may also result in a gradually developing inhibition of aldosterone secretion.
III. EFFECT OF CYTOPLASMIC CALCIUM
ON MITOCHONDRIAL FUNCTION
Physiol Rev • VOL
ANG II (78, 433, 466) and AVP (466) have also been
reported, but no data on signal reshaping are available.
The question may be raised whether stimuli of physiological intensity, i.e., physiological increases in [Ca2⫹]c,
are also effective in eliciting the mitochondrial response.
Elevating [K⫹] from 3.6 to 4.1 mM slowly induces a small
cytoplasmic Ca2⫹ signal (563) and enhances the formation of NAD(P)H (432). However, this observation was in
conflict with the low affinity of the mitochondrial Ca2⫹
uptake mechanism, which predicts that submicromolar
Ca2⫹ signals would fail to affect net Ca2⫹ uptake by the
mitochondria. Mitochondria contain calcium at millimolar
concentration; however, its major fraction is complexed
with phosphate and ATP or bound to matrix protein.
Under resting conditions the concentration of ionized
calcium in the matrix of glomerulosa cells is comparable
to that in the cytoplasm (428). The mitochondrial outer
membrane is assumed to be permeable to Ca2⫹ (but see
Ref. 125), and the barrier of Ca2⫹ diffusion is the inner
mitochondrial membrane. The transport of Ca2⫹ through
this membrane has been reviewed by Gunter et al. (207).
Briefly, Ca2⫹ uptake via the ruthenium-sensitive Ca2⫹
uniporter is driven by the 150 –180 mV (inside negative)
mitochondrial membrane potential. The half-maximal
transport rate is attained in the range of 10⫺6-10⫺4 M
Ca2⫹, and external Ca2⫹ exerts a positive cooperative
effect with a Hill coefficient of 2. Efflux of Ca2⫹ occurs by
means of a Na⫹-Ca2⫹ and/or a H⫹-Ca2⫹ antiporter, the
former having been detected also in the adrenal cortex
(123, 477). The capacity of the efflux mechanism is low,
and it saturates under conditions when [Ca2⫹]c reaches
⬃0.5 ␮M. At this [Ca2⫹]c the plasmalemmal Ca2⫹ pump
also saturates, and therefore further elevation of [Ca2⫹]c
results in steeply increasing net Ca2⫹ flux into the mitochondria. These data led to the still-prevailing view that
net mitochondrial Ca2⫹ uptake occurs only if [Ca2⫹]c
exceeds the micromolar, but at least the half-micromolar
level. Excessive uptake of Ca2⫹ may activate the mitochondrial permeability transition pore, resulting in the,
often fatal, loss of ions and molecules smaller than 1,600
Da (reviewed, e.g., in Ref. 46). Due to the lack of relevant
data in regard to glomerulosa cells, we do not discuss this
issue in more detail.
The global Ca2⫹ signal, as measured in the cytoplasm, is the average of highly focused, transient, elementary changes of Ca2⫹ (50), limited by the diffusion of Ca2⫹
in the cytoplasm (e.g., Ref. 6). Therefore, the uptake of
Ca2⫹ by, and the ensuing activation of, mitochondria will
depend primarily on the distance between the Ca2⫹
source and the mitochondrion. Since ER vesicles may
form contacts with mitochondria (338, 457), the narrow
space around such contact points could be presumed to
be an optimal site for the activation of mitochondria. The
discovery of rapidly forming but short-lived high-Ca2⫹
microdomains in the perimitochondrial cytoplasm near
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The adrenal cortex and the gonads do not store steroids; they secrete de novo synthesized hormones. Sidechain cleavage of cholesterol and all except one (C-21) of
hydroxylation steps take place in mitochondria which
occupy 25–30% of the cytoplasmic volume in glomerulosa
cells (392). The mitochondrial hydroxylations require
NADPH, which is generated from NAD⫹ by the mitochondrial nicotinamide nucleotide transhydrogenase (222,
240). The role of Ca2⫹ in the control of mitochondrial
function in glomerulosa cells has been a neglected area of
research.
Following the earlier assumption that the role of
mitochondria in intracellular calcium metabolism is confined to situations of calcium overload, it became firmly
established that physiological changes in [Ca2⫹]c also
influence mitochondrial metabolism. The renaissance of
mitochondrial studies (431) began by the observations of
Denton, McCormack, and co-workers (351), who demonstrated in mitochondrial homogenates and suspensions
that Ca2⫹ activates three mitochondrial dehydrogenases:
the pyruvate, isocitrate, and oxoglutarate dehydrogenase.
It was also found in suspended cardiac mitochondria that
physiological fluctuations in their calcium content alters
[Ca2⫹]m in the range that regulates the matrix dehydrogenases (328). We provided evidence for the physiological
significance of the cytoplasmic-mitochondrial Ca2⫹ relationship in intact cells in 1992, observing that in rat glomerulosa cells K⫹ stimulates the formation of mitochondrial pyridine nucleotides, NADH plus NADPH [designated as NAD(P)H] in a Ca2⫹-dependent manner (432).
Activation of voltage-dependent Ca2⫹ channels in sensory
neurons also increased the formation of NAD(P)H (145).
These data suggested the transfer of cytoplasmic Ca2⫹
signal into the mitochondrial matrix, an assumption that
was directly demonstrated in the same year following the
successful targeting of the Ca2⫹-sensitive luminescent
protein aequorin into the mitochondria (461). Since that
time, the mitochondrial Ca2⫹ and/or NAD(P)H response
to cytoplasmic Ca2⫹ signal has been described in several
cell types (reviewed in Refs. 147, 214, 458). Mitochondria,
by buffering the changes in [Ca2⫹]c, often reshape the
Ca2⫹ signal and may also modify the function of IP3R
(146). In glomerulosa cells the mitochondrial response to
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The mitochondrial response to submicromolar increases in [Ca2⫹]c seems to be a hitherto neglected, yet
more-or-less general phenomenon. Our data are in harmony with the results of direct measurements of cytoplasmic-mitochondrial Ca2⫹ relationship in excitable cells
such as chromaffin cells (15) and ventricular myocytes
(602), as well as in the nonexcitable HeLa cells (115) and
osteosarcoma cells (428). Indirect measurements of
[Ca2⫹]m (114, 179, 429) in chromaffin and neural cells also
support the view that submicromolar Ca2⫹ signal can be
transferred into the mitochondrial matrix. {The RBL-2H3
cell line with a response threshold of 2 ␮M [Ca2⫹]c seems
to be an exception; however, in this cell type even the
outer mitochondrial membrane exhibits restricted permeability to Ca2⫹ (125).}
A comparison of data from different laboratories indicates that glomerulosa and luteal cells, the two hitherto
examined steroid-producing cell types, exhibit the greatest mitochondrial sensitivity to cytoplasmic Ca2⫹ signals.
Interestingly, this sensitivity is reflected not only by the
response threshold (below 200 nM [Ca2⫹]c) but also, at
least in the case of glomerulosa cells, by kinetic data.
Similar to other cell types, oscillating Ca2⫹ signals often
evoke an oscillating mitochondrial Ca2⫹ (Fig. 1) and
NAD(P)H response in glomerulosa cells (433, 466). What
makes a difference from several other cell types is that
the sustained cytoplasmic Ca2⫹ signal, induced by K⫹,
elicits sustained mitochondrial Ca2⫹ (514) and NAD(P)H
(432) level. Similarly, elevated [Ca2⫹]c evoked by high
concentrations of ANG II (466), or achieved by cell permeabilization (466), is associated with sustained rises in
the mitochondrial NAD(P)H level. These observations
contrast with the behavior of hepatocytes, in which only
oscillatory Ca2⫹ signals, but not sustained rises in [Ca2⫹]c,
can induce sustained mitochondrial Ca2⫹ and NAD(P)H
responses (216, 433, 462). The special coupling between
[Ca2⫹]c and mitochondrial metabolism in the glomerulosa
cell reflects adaptation to physiological demands. Physiological stimuli of hepatocytes induce oscillating Ca2⫹
signals, whereas glomerulosa cells respond to physiological K⫹ stimuli with a sustained Ca2⫹ signal. HeLa cells
may represent the other extreme of mitochondrial kinetics, since not even trains of repetitive Ca2⫹ oscillations
can maintain elevated [Ca2⫹]m (115). The physiological
significance of the ability to sustain mitochondrial response in the glomerulosa cell is obvious, the adrenocortical responsiveness to sustained exposure to hyperkalemia is essential for vertebral homeostasis, and the sustained enhancement of mitochondrial NADPH formation
may efficiently support the long-term hypersecretion of
aldosterone under such a condition (see sect. VII). The
significance of cell type-specific mitochondrial Ca2⫹ management has been recently demonstrated also in synaptic
transmission (61).
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the IP3-sensitive calcium stores (460) provided an explanation for the large mitochondrial Ca2⫹ signal (216, 459)
evoked by IP3-mediated agonists. In fact, activation (125)
or overexpression (453) of the Ca2⫹-permeable voltagedependent anion channel in the outer mitochondrial
membrane enhances the IP3-induced (but not the thapsigargin-induced) mitochondrial Ca2⫹ signal, indicating the
special role of high-Ca2⫹ microdomains at the ER-mitochondrial contact sites. Similarly, the abrupt increase in
subplasmalemmal [Ca2⫹] during voltage-activated Ca2⫹
influx may be responsible for the activation of mitochondrial metabolism in insulin-producing INS-1 cells (280)
and neurons (429). The observation that in rat glomerulosa cells IP3-induced Ca2⫹ release more effectively induces the formation of mitochondrial NAD(P)H than
Ca2⫹ influx (467) may also be attributed to the IP3-induced formation of perimitochondrial high-Ca2⫹ microdomain. The low affinity of the Ca2⫹ uniporter, and the
formation of high-Ca2⫹ microdomains, led to the general
view that the rapid formation of micromolar [Ca2⫹] in the
perimitochondrial space is essential for the activation of
mitochondria.
In steroid-producing cells, physiological stimuli induce submicromolar Ca2⫹ signals. The activation of mitochondrial dehydrogenases is not, however, confined to
the action of the IP3-induced Ca2⫹ release in glomerulosa
(432, 433, 466) or luteal cells (525), capacitative Ca2⫹
influx also induces mitochondrial response in either cell
type (467, 525). The increase in [Ca2⫹]m and the enhanced
formation of NAD(P)H occur in spite of the obvious absence of high-Ca2⫹ microdomains, since [Ca2⫹]c increases
gradually (giving time for Ca2⫹ diffusion from the plasma
membrane to more remote sites in the cytoplasm) and
does not attain 200 nM (219, 525). Therefore, the transfer
of submicromolar Ca2⫹ signals into the mitochondrial
matrix had to be assumed. We have measured the effect
of buffered [Ca2⫹]c on [Ca2⫹]m with the fluorescent dye
rhod 2 in permeabilized rat glomerulosa cells (428).
[Ca2⫹]m correlated with [Ca2⫹]c in the examined range of
60 –740 nM, and an increase in [Ca2⫹]m could be detected
already on raising [Ca2⫹]c from 60 to only 140 nM. The
mitochondrial response was small but reproducible and
was associated with an increased level of NAD(P)H. In rat
luteal cells [Ca2⫹]m, as measured either with the fluorescent dye rhod 2 or with the mitochondrially targeted
luminescent protein aequorin, showed similar dependence on [Ca2⫹]c (428, 515). Moreover, the increased
formation rate of NAD(P)H during capacitative Ca2⫹ influx has also been documented in this cell type (525). This
unexpected responsiveness is not unique to steroid-producing cell types in which the formed NADPH is a cofactor of steroid hydroxylation. It also occurs in insulinproducing INS-1/EK-3 cells, where increased formation of
NADH, via ATP, induces the specific biological response
of the cell, the exocytosis of insulin (428).
CONTROL OF ALDOSTERONE SECRETION
IV. CROSS-TALK BETWEEN CALCIUM AND
cAMP-ACTIVATED PATHWAYS
A. Ca2ⴙ Influx Evoked by ACTH
2⫹
FIG. 7. Interaction of the Ca -cAMP signaling pathways. The red
arrows indicate stimulatory actions.
Physiol Rev • VOL
(463). In rat glomerulosa cells, serotonin via the 5-HT7
receptor increases both cAMP and Ca2⫹ levels. The primary action of serotonin is on the Gs-mediated activation
of adenylyl cyclase, leading to cAMP formation and a
slowly developing Ca2⫹ signal. T-type Ca2⫹ current was
enhanced both by 8-bromo-cAMP and serotonin, and the
latter effect was reduced by a PKA inhibitor. Serotonin
also induced a slow and sustained high-threshold current,
probably via L-type Ca2⫹ channels (Fig. 7A in Ref. 316).
This activation resembles the L-channel activating action
of ACTH. Although activation of T-type channels by cAMP
is an unprecedented observation, it is noteworthy these
studies were performed in freshly isolated cells, whereas
other laboratories have examined glomerulosa cells cultured for 1–2 days.
B. Ca2ⴙ-Induced Formation of cAMP
Although the messenger role of cAMP has been well
established, the steroidogenic action of ACTH also requires Ca2⫹. In its major target organ, the adrenal zona
fasciculata, chelation of extracellular Ca2⫹ prevents the
corticosterone response to even high doses of ACTH, but
only reduces the response to dibutyryl cAMP. This disparity indicates that the Ca2⫹ requirement in the action of
ACTH is more important for events before the formation
of cAMP (220).
Studies on glomerulosa cells have also demonstrated
the Ca2⫹ dependence of ACTH action. After an initial
increase, the sustained phase of ACTH-stimulated aldosterone secretion by superfused rat glomerulosa cells is
completely abolished in the absence of Ca2⫹ (503). The
question can be raised again whether Ca2⫹ is required for
the formation or the effect of cAMP. Studies with the
organic Ca2⫹ channel inhibitor verapamil (26, 488) indicate that the activation of adenylyl cyclase has a higher
requirement for Ca2⫹ than activation of steroid synthesis
by cAMP. This conclusion was also supported by measurements showing that ACTH-induced cAMP production
is highly Ca2⫹ dependent, and only a very small and
transient increase in cAMP is observed in the absence of
Ca2⫹ (184).
Although extracellular Ca2⫹ is essential for the
binding of ACTH to its receptors (92), Ca2⫹ also exerts
postreceptorial effects. Studies by Taits’ group (258)
revealed that stepwise elevation of K⫹ from 3.6 to 8.9
mM progressively increased cAMP secretion from rat
glomerulosa cells. This response required extracellular
Ca2⫹ and was prevented with nifedipine, indicating that
adenylyl cyclase was stimulated by Ca2⫹ entering
through voltage-operated Ca2⫹ channels (258). In contrast, K⫹ did not induce Ca2⫹ signaling and did not
influence cAMP output in fasciculata cells (5). While
these observations indicated an interaction between
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Although ACTH acts primarily through cAMP, as
originally observed in the adrenal fasciculata zone (232),
it also stimulates Ca2⫹ influx in glomerulosa cells. Both
ACTH and 8-bromo-cAMP induce a sustained Ca2⫹ response after a lag time of ⬃10 min in rat glomerulosa cells
(551). ACTH also elicits a Ca2⫹ signal, with a lag time of
⬃2 min, in human glomerulosa cells (184). Such responses are caused by activation of L-type Ca2⫹ channels
(151, 184). The ability of ␤-adrenergic stimulation to enhance ANG II-induced Ca2⫹ influx and aldosterone secretion in rat adrenal capsules (434) may result from the
same mechanism. The potentiation of ANG II-induced
inositol phosphate formation by 8-bromo-cAMP in bovine
glomerulosa cells (38) is also attributable to increased
Ca2⫹ influx, which, in turn, may stimulate PLC. The
cAMP-induced Ca2⫹ influx may exert positive feedback
on the formation of cAMP itself and could also support
stimulated steroidogenesis (Fig. 7) by the means discussed in section VII. cAMP, via PKA, may also potentiate
IP3-induced Ca2⫹ release (80, 215), an effect that has not
been examined in the glomerulosa cell.
Serotonin, potentially released by neighboring chromaffin or mast cells, also stimulates aldosterone production (370) and enhances ANG II-induced Ca2⫹ influx
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V. REGULATION AT THE LEVEL OF PLASMA
MEMBRANE RECEPTORS
Continuous stimulation of cells with hormones and
other stimulators very rarely evokes a continuous biological response. Although some agonists cause increased
sensitivity, most activate mechanisms that reduce the
biological response of the cell and protect it from excessive stimulation. Desensitization is defined as the tendency of responses to reduce in intensity despite the
continued presence of the stimulus (313). Agonist-induced cellular desensitization may occur at several different levels. In this section, changes in cellular responsiveness that occur at the level of plasma membrane receptors will be discussed. Mechanisms that regulate more
distal elements of the signal transduction pathway have
been discussed previously. After a brief introduction to
the regulation of GPCRs, special attention will be given to
the regulation of angiotensin receptors in adrenocortical
cells.
A. Mechanisms for Regulation of GPCRs
The accepted paradigm of GPCR regulation involves
their homologous and heterologous desensitization, receptor internalization, and downregulation. Desensitization and internalization are rapid phenomena that develop
in minutes, or in some cases seconds, after the stimulation of GPCRs, whereas downregulation is a much slower
decrease in the total cellular receptor pool.
Homologous desensitization of a GPCR involves the
uncoupling of the receptor from its cognate G protein,
after stimulation of the receptor with its agonist. This
process is associated with agonist-induced phosphorylation of the receptor. In most cases, specific GPCR kinases
(GRKs) appear to be responsible for this phosphorylation.
Receptor phosphorylation promotes the binding of ␤-arrestin molecules, rather than the respective G protein, to
the receptor (108, 303). However, in some receptors other
kinases, such as casein kinases or PKA, might serve as
receptor kinase (16, 549, 574). Furthermore, recent studies on metabotropic glutamate receptors suggested that
binding of GRKs to the activated receptor can cause
phosphorylation-independent desensitization (136). After
prolonged stimulation, significant accumulation of desensitized receptors may occur, depending on the kinetics of
receptor internalization and recycling (see sect. VD), but
pharmacological agonist concentrations are often required to detect cellular desensitization induced by this
mechanism. However, the importance of homologous desensitization should not be underestimated since it selectively affects agonist-activated receptors, which undergo
rapid uncoupling from G proteins by this mechanism
limiting the duration of the signal generation after recep-
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the cAMP and Ca2⫹ signaling pathways in glomerulosa
cells, there were also conflicting reports on this proposal. More recently, Tait and Tait (532) provided a
critical review of the literature, considering the methodological problems arising from the various biological
preparations, sample for analysis, and artifacts related
to phosphodiesterase inhibition by isobutyl methylxanthine. Their conclusion was consistent with the original
concept that Ca2⫹, entering the cell in response to K⫹,
activates adenylyl cyclase and cAMP formation that
prolongs the stimulation of steroid production. Considering the slight but reproducible activation of phospholipase C by K⫹ (218), Tait and Tait also proposed that
“the action of increased extracellular K⫹ can potentially involve all known mechanisms for the stimulation
of steroidogenesis in endocrine cells.”
Taits’ observation suggests that a Ca2⫹-dependent
isoform of adenylyl cylase is expressed in rat glomerulosa
cells. Out of the nine well-characterized isoforms of adenylyl cyclase, types 1, 3, and 8 are stimulated by Ca2⫹,
provided that Gs␣ is present. The PKC-activated cyclases
AC2 and AC7 may be also subject to Ca2⫹ control through
Ca2⫹-dependent PKC (10). Type AC3 is expressed in bovine (82) and human glomerulosa cells (120). AC1 could
not be detected (493), and no data are available on the
expression of other Ca2⫹-dependent iosoforms in rat glomerulosa cells.
In rat glomerulosa cells, ANG II reduces, rather than
enhances, cAMP production (43, 587), and inhibition of
PKA by H-89 does not affect ANG II- and AVP-induced
aldosterone production (184). The failure of the Ca2⫹
signal to activate adenylyl cylase may be due to activation
of the inhibitory G protein, Gi, a phenomenon observed in
bovine cells (97, 326, 344).
ANG II also inhibits adenylyl cyclase activity in purified membranes from the bovine zona glomerulosa (339),
yet increases in basal and potentiation of ACTH-induced
adenylyl cyclase activity by ANG II have been observed in
intact cells (39, 82). Pharmacological data suggest that the
enhancement of the cAMP response by ANG II involves
the Ca2⫹-dependent and PKC-dependent phosphatase calcineurin (39). This finding may account for the positive
interaction of ANG II and ACTH.
What is the significance of Ca2⫹-induced or Ca2⫹amplified cAMP production in the glomerulosa cell? As
shown in section IVA, cAMP-dependent phosphorylation
may exert positive feedback on Ca2⫹ influx. Enhancement
of cholesterol transport into mitochondria is discussed in
section VIIA. Activation of cell metabolism by cAMP also
supports increased hormone production, but the details
of this effect are beyond the scope of this review.
The interaction of the cAMP and Ca2⫹ signaling pathways is shown in Figure 7.
CONTROL OF ALDOSTERONE SECRETION
Physiol Rev • VOL
to interact with specific proteins that affect intracellular
sorting (86, 550, 578).
Whereas the term internalization is applied to the
translocation of cell surface receptors into intracellular
compartments with no major change in total receptor
number, downregulation signifies a decrease in the total
cellular receptor pool. This decrease may result from both
increased receptor degradation and reduced receptor synthesis, and usually develops over hours or days. Although
receptor degradation, preceded by agonist-induced endocytosis, appears to be a major mechanism of downregulation, mutations that affect receptor internalization do
not always interfere with the extent of downregulation
(228). This finding indicates the potential importance of
impaired receptor synthesis in the process. Long-term
agonist stimulation frequently reduces receptor transcription, or induces mechanisms that destabilize receptor
mRNA. These mechanisms cause internalization-independent downregulation by decreasing the steady-state level
of the receptor population (reviewed in Ref. 487).
B. Regulation of Adrenal Angiotensin Receptors
In Vivo
AT1 receptors are present in very high density in
glomerulosa cells. Because the biological response correlates with the formation of a defined number of hormonereceptor complexes, consistent with the law of mass action, the higher the number of surface receptors the lower
the agonist concentration required for maximal stimulation. Thus, due to the high receptor density, maximal
steroidogenic response occurs at ANG II concentrations
that only partially saturate the available receptors. The
higher the number of excess (“spare”) receptors, the more
left-shifted is the dose-response curve for the biological
response in comparision to the receptor saturation curve.
The presence of a high receptor reserve explains the
finding that the EC50 of ANG II-induced aldosterone response is about one order of magnitude lower than the Kd
of the receptor in glomerulosa cells (411). This consideration is also valid for in vivo conditions. Because circulating levels of ANG II (see the first paragraph of sect. II)
are well below the Kd of AT1 receptors (see sect. IIA),
physiological elevations of ANG II levels that only partially saturate the receptor can elicit full stimulation of
steroid secretion. Regulation of ANG II receptors in the
zona glomerulosa also frequently affects the magnitude of
the receptor reserve. Upregulation of AT1 receptors creates a larger receptor reserve, enhances the potency of
ANG II to stimulate aldosterone secretion, consequently
increasing the sensitivity of the tissue. However, a reduction of the number of functional surface receptors (e.g.,
by downregulation) decreases receptor reserve and
causes a right-shift in the dose-response curve for steroi-
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tor activation. Thus this mechanism is more important in
desensitizing signaling of the receptor in time than in
desensitizing the hormonal responsiveness of the tissue.
However, if continuous supply of plasma membrane receptors (e.g., via new receptor synthesis or receptor recycling) is not available, prolonged agonist stimulation
may lead to depletion of the nondesensitized plasma
membrane receptor population, and homologous desensitization of the tissue may occur.
Heterologous desensitization is caused by phosphorylation of GPCRs during stimulation of the cell with agonist(s) that target different receptors. This process is
mediated by second messenger-induced stimulation of
protein kinases, such as PKA or PKC. Heterologous desensitization typically occurs at lower hormone concentrations than homologous desensitization, since full activation of the second messenger generation may occur,
when receptor occupancy is still low. Activated second
messenger-regulated kinases can phosphorylate and effectively desensitize both active and inactive receptors, in
which the consensus site for the kinase is present. Because desensitization of a large receptor population may
occur at relatively low hormone concentrations, this
mechanism is an important regulator of the agonist sensitivity of hormone target tissues (reviewed in Ref. 313).
Agonist binding also stimulates internalization of the
receptor from the plasma membrane into intracellular
vesicles. Although clathrin-independent mechanisms
(e.g., via caveolae) have also been reported, endocytosis
via clathrin-coated vesicles is the most well-defined mechanism of internalization of GPCRs. The process is preceded by agonist-induced phosphorylation and ␤-arrestin
binding to the activated receptor. ␤-Arrestin, in addition
to its role in homologous desensitization, serves as an
adapter molecule to connect the receptor to clathrin and
␤2-adaptin, two main components of the clathrin coat
(108, 252, 303). During this mechanism, internalization
follows rather than precedes desensitization because the
internalized receptors are already uncoupled from the G
protein by ␤-arrestins.
Intracellular trafficking of internalized receptors occurs via acidic endosomal compartments, in which the
ligand can dissociate and the receptor can be dephosphorylated by intracellular phosphatases (312). After these
steps the resensitized receptor may recycle to the plasma
membrane. Some internalized receptors also move from
the endosomes to the lysosomes for degradation.
Whereas receptor recycling mediates receptor resensitization after homologous desensitization, lysosomal degradation causes downregulation of the receptor (see below). Some GPCRs, such as the AT1 receptor, are preferentially targeted for recycling, whereas others, such as the
thrombin receptor, are destined for degradation (550).
Such targeting is determined by amino acid sequences,
usually in the cytoplasmic tail of the receptor, that appear
515
516
ANDRÁS SPÄT AND LÁSZLÓ HUNYADY
C. Desensitization of Glomerulosa Cells
Desensitization of the receptor for several hormones,
including ANG II, ACTH, bradykinin, and vasopressin, has
been shown in mammalian glomerulosa cells (106, 167,
Physiol Rev • VOL
183), and similar mechanisms operate in the adrenal
glands of lower vertebrates (70). Early studies showed
that ANG II-induced steroid secretion is subject to homologous and heterologous regulatory mechanisms in glomerulosa (167) and fasciculata cells (411). These experiments demonstrated that ANG II directly reduces adrenal
responsiveness and does not cause upregulation of ANG
II-induced aldosterone responses, even in cells pretreated
with low physiological concentrations of ANG II. In isolated rat glomerulosa cells, superfusion of ANG II for 6 h
reduced the aldosterone responses to ANG II, potassium
ions, and ACTH. This effect was maintained when superfusion with ANG II was performed in the presence of
aminogluthetimide to prevent steroid synthesis, suggesting that the inhibitory effect was caused by factors other
than substrate depletion or a metabolite of steroid synthesis (e.g., free radical). The ANG II-induced heterologous desensitization of the aldosterone response was attributed to inhibition of the late stage of aldosterone
biosynthesis. Preincubation with ANG II evoked homologous desensitization of the ANG II-induced inositol phosphate generation, suggesting that this process involves
mechanisms proximal to signal generation, such as receptor desensitization or downregulation. Phorbol ester
treatment did not elicit such desensitization, suggesting
that it was independent of PKC activation (163).
In other studies on the mechanism of ANG II-induced
desensitization of bovine adrenocortical cells, short-term
(30-min) pretreatment of glomerulosa cells with 10 nM
ANG II caused rapid loss of 125I-ANG II binding. Scatchard
analysis revealed that exposure to ANG II induced the
transformation of high-affinity ANG II binding sites
(Kd ⬃0.2 nM) to a low-affinity state (Kd ⬃2 nM) with no
change in the total number of extracellular binding sites
(73). This homologous desensitization was suggested to
be caused by PKC- and calmodulin kinase-independent
uncoupling of AT1 receptors from G proteins. ANG II
binding to AT2 receptors did not show similar regulation.
In analogy to the ␤2-adrenergic receptor and other GPCRs
(313), the most likely mechanism for ANG II-induced
rapid homologous desensitization of AT1 receptors is
their phosphorylation by receptor kinases, such as GRKs.
Phosphorylation-induced uncoupling of the receptor from
its cognate G protein(s) can explain the observed reduction in receptor affinity, since interaction with G proteins
is believed to stabilize the high-affinity conformation of
the receptor (484). In fact, ANG II rapidly induces phosphorylation of the AT1 receptor in bovine glomerulosa
cells. Such phosphorylation was correlated with the degree of agonist occupancy of the receptor and was not
affected by tyrosine kinase inhibitors. Also, it was stimulated, rather than reduced, by PKC inhibitors (501). These
data suggest that receptor phosphorylation, which possibly causes early homologous desensitization of the receptor and may be responsible for the above-mentioned ef-
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dogenesis. In this situation, desensitization of the tissue
does occur because aldosterone secretion will be reduced
at any given circulating ANG II level.
In most ANG II target tissues, prolonged agonist
activation causes desensitization of its biological response and downregulation of its receptors. However, in
vivo studies in rats have shown that long-term (1- to
2-day) infusion of low doses of ANG II causes upregulation of adrenal ANG II receptors and increases the aldosterone response to ANG II (141, 227). The hormonal
response was similarly enhanced by ANG II infusion in
humans (395). It was also observed several decades ago
that sodium depletion (known to stimulate renin secretion) enhances the aldosterone seceretory response to
ANG II in humans, rats, and dogs (reviewed in Refs. 369,
570). Because low-sodium diet increases AT1A and AT1B
receptor mRNAs in rat adrenal glands, and this increase is
inhibited by an AT1 receptor blocker (144), it is likely that
ANG II induces upregulation of AT1 receptors during
sodium deficiency. Increased receptor binding of ANG II
during sodium depletion and ANG II infusion was originally attributed to a positive feedback effect of ANG II on
its receptors (227). Although molecular biological studies
supported the receptor-inducing effect of ANG II (267),
and this mechanism seems to explain upregulation of
AT1B receptors (573), the effect of sodium depletion is
primarily induced via an ANG II-AT1 receptor-independent mechanism (63, 573). Furthermore, in extra-adrenal
tissues of other species, and even in the zona glomerulosa
of dogs, prolonged low-dose infusion of ANG II reduces
the responsiveness of the target tissue to ANG II (40).
Downregulation of adrenal angiotensin receptors was
also observed in rats following in vivo long-term administration of pharmacological doses of ANG II (416). Because ANG II also exerts extra-adrenal effects and, in the
sodium-depleted rat, changes in potassium balance (75,
541) can also modulate adrenal ANG II responsiveness
(140), the upregulation of adrenal AT1 receptors in sodium deficiency may be predominantly due to an indirect
effect of the hormone. In agreement with this, as detailed
in section VC, studies with isolated glomerulosa and fasciculata cells found no evidence of ANG II-induced upregulation of angiotensin receptors. Overall, these findings suggest that the in vivo upregulation of angiotensin
receptors is an indirect effect of agonist treatment or
requires the presence of cofactors, such as ACTH or other
circulating hormones, which are absent in experiments
with isolated cells.
CONTROL OF ALDOSTERONE SECRETION
D. Intracellular Trafficking
of Angiotensin Receptors
ANG II-induced angiotensin receptor internalization
in glomerulosa cells was first described by Bianchi et al.
(58), who showed in the rat that injected 125I-ANG II first
accumulates on the cell surface, then clusters within
coated pits, is internalized in coated vesicles, and appears
in lysosomes within 20 min. Internalization of radiolabeled ANG II was also reported in cultured bovine adrenocortical cells (124). Immunocytochemical localization
of AT1 receptors using receptor specific antibodies has
also been reported in glomerulosa cells (501, 567). DePhysiol Rev • VOL
tailed analyses of the mechanism of intracellular trafficking of AT1 receptors have been performed in expression
systems using epitope-tagged (233) or green fluorescent
protein (GFP)-labeled (96, 249, 362) receptors. Endocytosis of a GFP-tagged rat AT1A receptor after stimulation
with rhodamine-labeled ANG II is demonstrated in Figure
8. Endocytosis of surface-bound radiolabeled ANG II occurs very rapidly in bovine glomerulosa cells (254, 455),
which express predominantly AT1 receptors (see sect.
IIA). Incubation of adrenocortical cells with ANG II causes
progressive loss of surface angiotensin receptors (402,
411). In fasciculata cells, half-maximal loss of surface
receptors occurred at an ANG II concentration (⬃3 nM)
similar to the Kd (2 nM) of the receptor, which resembles
the dose dependence of homologous desensitization (see
sect. VB). The EC50 of ANG II to stimulate this response
was much higher than that to induce steroidogenesis
(411). ANG II is unable to induce internalization of AT2
receptors in cells that selectively express AT2 receptors
(233, 251, 397, 438). In accordance with these findings, no
internalization of AT2 receptors was detected in bovine
fasciculata cells (402).
Most of the available data suggest that the main
mechanism of agonist-induced endocytosis of AT1 receptors in glomerulosa cells is endocytosis via clathrincoated vesicles. In rat glomerulosa cells, morphological
studies detected internalized angiotensin receptors in
coated pits (58). Disruption of the clathrin coat by potassium depletion or phenylarsine oxide treatment markedly
inhibits AT1 receptor endocytosis in bovine glomerulosa
cells and other ANG II target tissues (252, 254). In COS-7
cells the kinetics of AT1A receptors are somewhat faster
than that of AT1B receptors (256). Internalization of expressed AT1 receptors is independent of G protein coupling (247) and appears to be regulated by agonist-induced phosphorylation of the receptor molecule (251,
502, 543, 544). The receptor kinase that regulates the
internalization process has not been identified, since PKC
inhibitors and/or coexpression of a kinase-deficient GRK
markedly reduced agonist-induced phosphorylation of
AT1 receptors without affecting its internalization kinetics
(30, 31, 398). Nevertheless, ␤-arrestins associate with the
ANG II-stimulated and phosphorylated receptors in tumor
cells expressing AT1 receptors (8, 443, 599). Coexpression
of functionally deficient, mutant ␤-arrestins and dynamins
with the AT1 receptor exerts dominant negative inhibitory
effect on the internalization of the receptor at physiological hormone concentrations (182, 443), and internalization of AT1 receptors is strongly impaired in cells derived
from mice deficient in ␤-arrestins (287). These data provide a mechanism for endocytosis of the AT1 receptor via
clathrin-coated pits, and it is likely that endocytosis of
AT1 receptors in glomerulosa cells is mediated by a similar mechanism. However, at higher ANG II concentrations, when the AT1 receptor population becomes rapidly
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fect of ANG II on the affinity of AT1 receptors, is mediated
by receptor kinase(s).
Although the receptor kinase that mediates this effect in glomerulosa cells has not been identified, studies
with AT1 receptors expressed in tumor cell lines suggest
that GRKs have an important role in the ANG II-induced
rapid phosphorylation of AT1 receptors. Coexpression of
a kinase-deficient GRK2 exerted dominant negative inhibitory effect on ANG II-induced receptor phosphorylation
in HEK293 (399) and COS7 cells (398). Oppermann et al.
(399) also observed that in HEK 293 cells the kinasedeficient GRK2 prevented homologous desensitization of
the AT1A receptor, whereas inhibition of PKC failed to
affect this process (399). Nevertheless, studies in other
cell types question the general role of GRK2 in homologous desensitization of AT1 receptors. In COS7 cells, inhibition of receptor phosphorylation by coexpression of a
kinase-deficient GRK2 did not affect the desensitization of
the receptor (398). Also, a study in CHO cells suggested
that homologous desensitization of AT1A receptors is mediated by a heparin-sensitive kinase that is different from
GRKs (538). In the latter cell line, desensitization of AT1B
receptors is mediated by PKC (539). These data indicate
that the identification of the receptor kinase responsible
for this process in glomerulosa cells requires additional
studies. Nevertheless, it is likely that ␤-arrestin binding to
the phosphorylated receptor has an important role in the
uncoupling of the receptor molecule from the G protein,
since it has been firmly established that ANG II induces
association of these molecules with the cytoplasmic tail
of AT1 receptors (8, 173, 443).
Much less is known about the desensitization of AT2
receptors. It has been reported that no homologous desensitization of AT2 receptors occurs in bovine adrenocortical cells, but heterologous desensitization of AT2
receptors caused by stimulation of AT1 receptors has
been reported (402). The latter effect was mimicked by
activation of PKC, which is consistent with the PKCmediated stimulation of AT2 receptor phosphorylation
observed in transfected COS-7 cells (397).
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ANDRÁS SPÄT AND LÁSZLÓ HUNYADY
saturated with the agonist, this mechanism apparently
becomes saturated and a ␤-arrestin- and dynamin-independent mechanism becomes predominant (182, 600). Although caveolae have been suggested as another possible
mechanism for AT1 receptor endocytosis (265), this requires further studies, since endocytosis via caveolae is
also dynamin dependent (234). The exact mechanism of
␤-arrestin- and dynamin-independent endocytosis of AT1
receptors and its importance in adrenal cells has yet to be
elucidated.
Studies in HEK 293 cells using fluorescent markers
have demonstrated that early endosomes, recycling endosomes, and multivesicular bodies related to late endosomes participate in the intracellular trafficking of internalized AT1 receptors (249, 491). Acidification of the endosomal compartments is required for efficient recycling
of adrenocortical and expressed AT1 receptors to the cell
surface (124, 233, 411, 455). Acidification causes agonist
dissociation from many GPCRs, including angiotensin receptors, and the resulting conformational change is believed to promote the dissociation of ␤-arrestins from
internalized receptors and dephosphorylation of the receptor molecule (312). The rapid ANG II-induced loss of
plasmalemmal AT1 receptors in adrenocortical cells
treated with monensin, an inhibitor of vesicular acidificaPhysiol Rev • VOL
tion, suggests that recycling of the receptor to the plasma
membrane is a highly efficient process (411).
It was initially assumed that receptor internalization
mediates agonist-induced desensitization of the cells by
reducing the number of surface receptors. However, at
physiological hormone concentrations many activated
GPCRs, including AT1 receptors, use ␤-arrestins as adaptor proteins to connect with clathrin-coated structures
(182, 303). Because ␤-arrestins also uncouple the receptors from their G proteins, the internalized receptors are
already desensitized. Thus endocytosis of AT1 receptors,
similar to that of other GPCRs, could serve to maintain
signal generation, since it leads to intracellular dephosphorylation, resensitization, and recycling of receptors
(312). This mechanism may explain the previously reported importance of receptor internalization for the sustained phase of ANG II-induced inositol phosphate and
Ca2⫹ signal generation in bovine glomerulosa cells (254).
Some of the internalized AT1 receptors are also targeted
to lysosomes for degradation, and during prolonged ANG
II stimulation this process could eventually cause degradation of ANG II and downregulation of the AT1 receptors
in bovine adrenocortical cells (124, 411). It has also been
proposed that endocytosis of AT1 receptors is required for
ANG II-induced PKC translocation (568). There is no ev-
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FIG. 8. Endocytosis of rhodamine-ANG II
(red) in HEK 293 cells stably expressing a
GFP-tagged rat AT1A receptor (green). Confocal images of the distribution of the receptors
after stimulation for 1 min (top panels) or 30
min (bottom panels) with rhodamine-ANG II
at 37°C. The internalized receptors colocalize
with rhodamine-ANG II in peripheral early endosomes and juxtanuclear recycling endosomes as described previously (249). (Images
courtesy of L. Hunyady and T. Balla.)
CONTROL OF ALDOSTERONE SECRETION
idence in adrenal cells for a role of ␤-arrestins and/or
receptor internalization in ANG II-induced MAPK activation (see also sect. VIC). Intracellular accumulation of
ANG II also prolongs the half-life of the peptide, which is
rapidly degraded in the circulation, and may be utilized
for paracrine and autocrine actions, or could exert intracellular actions by stimulating cytoplasmic or nuclear
angiotensin receptors. However, in adrenocortical cells
the importance of these mechanisms has not been established. This topic was reviewed in more detail previously
(252).
E. Receptor Downregulation
Physiol Rev • VOL
tion of the AT1 receptor has a role in its targeting to
lysosomes, but recent studies indicated that elimination
of the lysine residues that serve as potential ubiquitylation
sites causes increased accumulation of labeled ANG II in
CHO cells expressing AT1A receptors (358). This finding
raises the possibility that ubiquitylation has a role in the
regulation of intracellular targeting of the receptor.
A recent study has questioned the importance of
short-term AT1 receptor desensitization and long-term
receptor downregulation in ANG II-induced regulation of
glomerulosa cells, because desensitization of the steroidogenic action of ANG II required 24-h preincubation with
a pharmacological concentration (1 ␮M) of ANG II,
whereas 10 nM ANG II had no effect on the steroidogenic
response (456). However, the steroidogenic response was
analyzed using only maximally effective concentrations of
ANG II, which may not reveal changes in cellular responsiveness in cells with excess receptors. In fact, earlier
studies showed that ANG II pretreatment had a much
larger effect on ANG II-induced steroidogenesis in rat and
bovine glomerulosa cells (167, 411). Also, rapid desensitization of second messenger production was observed
after ANG II treatment in AT1 receptor-transfected cells
(399, 539). Thus the available data indicate that ANG
II-induced desensitization or reduction of plasma membrane AT1 receptors causes desensitization of adrenocortical cells.
VI. LONG-TERM EFFECTS OF ANGIOTENSIN II
Long-term effects of ANG II at the cellular level include regulation of cell growth, proliferation, differentiation and apoptosis, induction of steroidogenic enzymes,
modulation of cell migration, and extracellular matrix
deposition. These effects are mediated by complex and
highly cell-specific signaling pathways, involving G proteins, receptor and nonreceptor tyrosine kinases, MAPKs,
and cytokine-like signaling pathways (132). In this paper
we focus on mechanisms that have been reported to be
present in aldosterone-producing cells, and we refer to
recent reviews for mechanisms identified in other ANG II
target cells (132, 152, 483).
A. Activation of Growth Responses by ANG II
in the Glomerulosa Cell
Rat glomerulosa cells respond to sodium deficiency
with hypertrophy and hyperplasia and undergo regression
in animals on a high-sodium diet. These changes are
dependent on the level of circulating ANG II, which has
proven to be a major determinant of trophic changes in
the zona glomerulosa (see references in Refs. 132, 372).
These studies provided the first evidence that ANG II
stimulates cell growth and/or proliferation in its target
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Downregulation of receptors is defined as a decrease
of total number of receptors (313), which typically requires agonist exposure for at least 1 h and may involve
modulation of the rate of receptor synthesis or degradation. Long-term incubation of adrenocortical cells with
high concentrations of ANG II has been suggested to
cause downregulation of angiotensin receptors (402, 411).
However, since the available studies determined surface
binding of the receptor, and the decrease during the first
3 h was caused by internalization of surface receptors, it
is unclear whether true downregulation of total cellular
binding sites occurred during this period. More prolonged
(more than 3 h) stimulation with pharmacological concentration of ANG II reduces the level of AT1 receptor
mRNA (402, 456). This decrease in mRNA levels is caused
by inhibition of transcription, without significant change
in the half-life of the mRNA (402). Interestingly, in the
same study stimulation of AT1 receptors also reduced the
binding sites and the mRNA of AT2 receptors, but this
effect was mediated by a decrease in AT2 receptor mRNA
stability. AT1 receptor-mediated regulation of AT2 receptors was also observed in expression systems, where it
has been shown to cause PKC-mediated phosphorylation
of AT2 receptors (397).
Downregulation of AT1 receptors may also be caused
by increased receptor degradation, which is preceded by
internalization of the receptor into endosomal compartments. It has been shown in bovine adrenocortical cells
that after internalization, cellular processing of the hormone-receptor complex leads to degradation of the ligand. The acidic pH of endosomal compartments, which
facilitates hormone dissociation, is also essential for ligand degradation (124). Studies in HEK 293 cells have
suggested that most internalized AT1 receptors recycle to
the plasma membrane, whereas the hormone dissociates
in acidic compartments and enters lysosomes for degradation (233). However, it is likely that a small fraction of
receptors undergoes lysosomal degradation, and after
prolonged incubation with ANG II, this leads to increased
receptor loss. It is presently unclear whether ubiquityla-
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ANDRÁS SPÄT AND LÁSZLÓ HUNYADY
B. Role of Receptor and Nonreceptor
Tyrosine Kinases
In rat glomerulosa cells, parallel roles of tyrosine
kinase and PKC activation in ANG II-mediated stimulation
of DNA synthesis and cell proliferation have been reported and are independent of PLA2, cyclooxygenase, and
lipoxygenase activation (345). Endothelins, acting via the
ETA endothelin receptor, also stimulate proliferation of
glomerulosa cells by activating tyrosine kinases and PKC
(347). Endothelins, ghrelin, and proadrenomedullin-derived peptides exert proliferative actions on glomerulosa
cells by stimulating tyrosine kinase-dependent activation
of the p42/p44 MAPK pathway (9, 44, 346). The specific
tyrosine kinases and their mode of action during ANG
II-induced proliferation of adrenal glomerulosa cells have
not yet been identified. It has also been proposed that
ANG II promotes capacitative calcium entry and aldosterone biosynthesis in these cells via tyrosine kinases (11,
65, 277). Furthermore, tyrosine kinases have long-term
effects on the synthesis of steroidogenic enzymes, and in
the H295R cell line Src tyrosine kinase was reported to
have a role in maintaining the glomerulosa-like phenotype
(499).
In smooth muscle and other target cells, ANG II also
promotes cell migration and induces changes in cell shape
and volume by activating focal adhesion kinase. It stimulates the closely related tyrosine kinase, Pyk2, which is an
important link between ANG II-mediated Ca2⫹ signal generation and the growth factor-regulated signaling pathways (152, 211). ANG II can also activate the Jak family of
tyrosine kinases, which mediate the actions of cytokinetype receptors on transcription via phosphorylation of
STAT (signal transducers and activators of transcription)
proteins (57, 340). However, additional studies are required to demonstrate the roles of these mechanisms in
adrenal glomerulosa cells.
Transactivation of receptor tyrosine kinases, such as
the epidermal growth factor receptor and platelet-derived
growth factor receptor or Axl, has been proposed to have
a major role in ANG II-induced proliferation of vascular
smooth muscle and other target cells (152, 482) (Fig. 9).
EGF receptors are present in glomerulosa cells, as evidenced by the stimulatory effect of EGF on the aldoste-
FIG. 9. Mechanism of ERK1/2 activation
in glomerulosa cells. The thickness of the arrows reflects the quantitative importance of
the pathways in glomerulosa cells, as described in text. R, receptor.
Physiol Rev • VOL
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tissues, a phenomenon which has since been shown in
many other cell types, including vascular smooth muscle
cells, cardiac myocytes and fibroblasts, and renal mesangial cells (132). Pharmacological studies have revealed
that the growth-promoting actions of ANG II are mediated
by the AT1 receptor and that ANG II binding to AT2
receptors has an opposing effect in many tissues (390).
The growth-promoting effects of ANG II are exerted
directly by the hormone, because the stimulation observed in vivo can be demonstrated in isolated glomerulosa cells. However, lipoxygenase-mediated formation of
arachidonic acid metabolites (see sect. IIC) has been suggested as a contributing factor in this process (379). In rat
(345) and bovine (547) glomerulosa cells, ANG II stimulates cell growth and increases thymidine incorporation
and cell proliferation. Activation of PKC, tyrosine kinases,
and MAPKs, leading to increased expression of several
early genes, including c-fos, c-jun, and c-myc, is believed
to play a central role in these processes (29, 109).
CONTROL OF ALDOSTERONE SECRETION
rone production of porcine glomerulosa cells (282), but
the relevance of EGF receptor transactivation to the proliferative action of ANG II has not been elucidated in
these cells.
C. ANG II-Induced Activation of MAPKs
Physiol Rev • VOL
sents a PKC-independent pathway, whereas the major
pathway of ERK activation is mediated by PKC via an
unidentified target downstream to raf-1 kinase, possibly
MEK (548). More detailed studies on the mechanism of
ANG II-induced raf-1 kinase activation have demonstrated
that the PKC-independent stimulation of this kinase is
mediated partly by pertussis toxin-sensitive Gi/o proteins
and phosphatidylinositol 3-kinase (500). The proposed
mechanisms of MAPK activation in the glomerulosa cell
are shown in Figure 9.
In H295R cells, high concentrations of ANG II induced prolonged stimulation of ERK and JNK (SAPK)
activity with a maximal response at 5 and 30 min, respectively (577). However, the effect of ANG II on JNK activation in these cells is controversial (199, 577). ANG II
also caused ras and ERK-dependent increases in cyclin
D1 promoter activity as well as enhanced cyclin D1 mRNA
levels and cyclin D1 protein levels, and promoted cell
cycle progression (577). c-Fos and c-Jun have a role in the
stimulation of the cyclin D1 promoter activity, and the
induction of JNK activity by ANG II may also contribute to
the enhanced transactivation by c-Jun. Since the induction of cyclin D1 serine/threonine kinase activity promotes cell cycle progression and cellular proliferation,
these effects participate in the mitogenic action of ANG II
in aldosterone-producing cells.
ANG II also stimulates the transcription of the aldosterone synthase (CYP11B2) gene, and the details of this
process are described in section VIIC.
VII. THE FINAL ACTION: ROLE OF
CALCIUM IN THE CONTROL OF
STEROID PRODUCTION
Neurons and skeletal muscle cells may exhibit Ca2⫹
signals that far exceed 10⫺5 M in well-confined microdomains. Such a large Ca2⫹ signal may be required for the
extremely rapid biological response, often occurring
within milliseconds. The release of steroid hormones
takes place by a much slower rate by diffusion across the
plasma membrane. There are no data indicating the generation of such Ca2⫹ hotspots in steroid-producing cells,
in which they are not required. Nevertheless, even without such hotspots, in this review ample evidence has been
presented in favor of the messenger role of Ca2⫹ in the
control of steroidogenesis by the glomerulosa cell; Ca2⫹
ionophores stimulate aldosterone production, secretagogue stimuli evoke a cytoplasmic Ca2⫹ signal, and prevention of this Ca2⫹ signal abolishes the hormonal response. There is an excellent correlation between K⫹induced Ca2⫹ signal and aldosterone production (28, 89,
432); moreover, aldosterone stimulation by the cAMPmediated agonist ACTH is also Ca2⫹ dependent (see
sect. IVB).
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MAPKs are serine/threonine kinases that have a central role in the regulation of gene expression by plasma
membrane receptors. Receptor tyrosine kinases and
GPCRs can stimulate phosphorylation cascades leading
to concomitant phosphorylation of MAPKs on adjacent
threonine and tyrosine residues. Activated MAPKs translocate to the nucleus and regulate transcription factors
and gene expression, resulting in cell-specific long-term
cellular responses such as cell growth, apoptosis, and
differentiation (270). The functional outcome of MAPK
activation is dependent on the availability of downstream
substrates.
Mammalian subtypes of MAPKs are grouped into six
major subfamilies, such as ERK1/2 (also known as p42/
p44 MAPKs), c-Jun NH2-terminal protein kinases (JNKs,
or stress-activated protein kinases, SAPKs), p38 MAPKs,
ERK6, ERK3, and ERK5 (or Big MAPK). Typically, receptor-mediated activation of ERK1/2 regulates cell growth
and differentiation. JNKs and p38 MAPKs are activated by
cellular stress and inflammatory cytokines, which regulate cellular processes leading to inhibition of cell proliferation and induction of apoptosis, whereas ERK5 has
been proposed as a redox-sensitive MAPK (1). The ability
of ANG II to activate ERK1/2, JNK, p38 MAPK and ERK5
is consistent with its growth-promoting, cytokine-like,
and redox-sensitive actions (132).
In glomerulosa and H295R cells, ANG II-induced activation of the ERK, JNK, and the p38 MAPK pathways has
been reported (199, 354, 548, 577). Activation of the ERK
pathway is believed to be the major mediator of the effect
of ANG II on the proliferation of these cells (Fig. 9). As in
other cell types, ANG II causes tyrosine kinase-dependent
activation of the Ras small G protein in bovine and rat
glomerulosa cells, leading to stimulation of Raf-1, a MAPK
kinase kinase, which phosphorylates MEK, a MAPK kinase, and to phosphorylation and activation of ERKs (354,
548). However, in contrast to other target cells (152), ANG
II-stimulated ERK activation in bovine glomerulosa cells
was not mediated by the increase in [Ca2⫹]c, although
Ca2⫹ played a permissive role in this process (548). The
major mechanism leading to ERK activation was pertussis
toxin insensitive, although a small contribution from pertussis toxin-sensitive Gi/o proteins could not be excluded.
Although PKC depletion significantly reduced ANG IIinduced ERK activation in these cells, ras- and raf-1 kinase-mediated ERK activation was independent of PKC.
This difference suggests that ras/raf-1 activation repre-
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ANDRÁS SPÄT AND LÁSZLÓ HUNYADY
A. Cholesterol Transport
Steroid-secreting cells do not store hormones; the
rate of hormone secretion depends on the de novo synthesis of the cell-specific steroid. The precursor of steroid
hormones is cholesterol, which may be synthesized intracellularly from acetyl CoA. However, increased hormone
secretion requires its uptake from plasma lipoproteins.
Glomerulosa cells utilize both low-density lipoprotein
(LDL) and high-density lipoprotein (HDL) as a source of
cholesterol (374), and ANG II stimulates the uptake of
HDL-cholesterol. This effect of ANG II is due to enhanced
expression of scavenger receptor class B type 1 (SR-B1)
(98). Cholesterol is stored in esterified form in cytoplasmic lipid droplets and released in response to hormonal
activation of cholesterol ester hydrolase. ANG II activates
the enzyme via the MAPK extracellular signal-regulated
kinase (ERK 1/2)-mediated phosphorylation (87).
The rate-limiting step in steroidogenesis is the conversion of the precursor compound cholesterol to pregnenolone. This step, which results in the removal of a
six-carbon unit from cholesterol by the cholesterol sidechain-cleaving enzyme, cytochrome P-450scc (the gene
product of CYP11A1), takes place at the matrix side of
the inner mitochondrial membrane. The transport of cholesterol from the cytoplasmic lipid droplets to the mitochondria requires an intact cytoskeleton and is facilitated
by specific proteins. While the sterol carrier protein-2
Physiol Rev • VOL
(SCP2) (554) may transport cholesterol to the outer mitochondrial membrane, the limiting step of steroid synthesis is the rate of cholesterol transfer from the outer to
the inner mitochondrial membrane through the aqueous
phase of the intermembrane space. This transfer is dependent on a “cycloheximide-sensitive, highly labile protein,”
the level of which is raised by ACTH via cAMP-dependent
phosphorylation (for reviews, see Refs. 497, 521). Ca2⫹
also activates the transport of cholesterol into mitochondria and its subsequent side-chain cleavage (223, 299).
Elevation of [Ca2⫹]c by either ANG II or via cell permeation results in increased cholesterol content in the inner
mitochondrial membrane, and especially in the contact
sites between the outer and inner mitochondrial membrane. This effect of Ca2⫹ is also sensitive to cycloheximide (100, 101).
Although the previously described “steroidogenesis
activating polypeptide” (SAP) (410) has characteristics
similar to those of the “labile protein,” the 37-kDa protein
(p37) termed steroidogenic acute regulating (StAR) protein (169) currently meets the requirements for being
identical with the labile protein. StAR is expressed in all
steroid-secreting cell types, and its mutation is the cause
of congenital lipoid adrenal hyperplasia, an autosomal
recessive disorder characterized by impaired synthesis of
adrenal and gonadal steroid hormones (318). The half-life
of StAR is 3–5 min, which corresponds to that of the labile
protein. After its transport into the mitochondrial matrix,
its mitochondrial leader sequence is cleaved off to yield
the stable 30-kDa intramitrochondrial StAR (p30). StAR
mRNA and protein are induced via a cAMP-mediated
mechanism that causes the enhancement of StAR transcription and/or mRNA stability. ACTH, acting via PKA,
phosphorylates and activates both the putative “labile
protein” and StAR. Phosphorylation of StAR itself may not
be required for mitochondrial import, but phosphorylation is directly linked to the steroidogenic response of the
cell to stimulation (521). The crystal structure of its lipid
transfer domain suggests that StAR acts by shuttling cholesterol molecules one at a time through the intermembrane space of the mitochondrion (553). However, the
experimental data on its site of action are controversial.
Some observations suggest that phosphorylated StAR
(pp37) exerts its action at the outer mitochondrial membrane and that its further transport into the matrix and
conversion to pp30 are irrelevant to cholesterol transport
(71). Other observations suggest that phosphorylation of
newly synthetized StAR p37, as well as its mitochondrial
import and processing to pp30, are essential for enhanced
steroidogenesis (14).
Expression and phosphorylation of StAR in glomerulosa cells are enhanced by ACTH as well as by Ca2⫹mediated stimuli such as ANG II and K⫹ (54, 101, 111, 156,
226). Elevated [Ca2⫹]c, induced by the Ca2⫹ channel agonist BAY K 8644 (111) or by application of a Ca2⫹ iono-
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The amplitude of the Ca2⫹ signal is an essential, but
not the only, factor controlling Ca2⫹-induced steroid responses. Coapplication of ANG II or thapsigargin, on the
one hand, and K⫹, on the other, stimulates aldosterone
production at a rate that far exceeds that attained by
simple additive effects. To stimulate aldosterone production with K⫹ alone, [Ca2⫹]c has to attain a much higher
value than that measured in the cells stimulated with two
agonists simultaneously (81, 219). This observation led us
to postulate (509) that it is not only the size, but also the
subcellular localization of the Ca2⫹ signal that determines
the rate of aldosterone production. It should be recalled
in this regard that Ca2⫹ released from IP3-sensitive stores
is more efficient in activating mitochondrial dehydrogenases than that entering from the extracellular space
(467). Also, Ca2⫹ entering through voltage-activated Ca2⫹
channels into the subplasmalemmal space may be more
efficient in activating adenylyl cyclase (5, 258).
Ca2⫹ exerts a feedback effect on the initial steps of
various signal-transducing pathways, but its major action
is on the stimulation of steroidogenesis. Its best-elucidated effect is the stimulation of cholesterol transport
into the mitochondria, the process that determines the
rate of hormone secretion during acute stimulation in
each steroid-producing cell type.
CONTROL OF ALDOSTERONE SECRETION
phore (101), also induced StAR expression. The transcriptional effect of ANG II involves the activation of MAPK
ERK 1/2, which represses DAX-1 (401), a transcription
factor known to repress the StAR protein (306). Atrial
natriuretic hormone, a physiological antagonist of aldosterone secretion, in addition to increasing K⫹ conductance and inhibiting T-type Ca2⫹ channels (see sect. IIB),
also inhibits the transcription of the StAR gene (99).
Accordingly, ANF prevents the mitochondrial import of
StAR protein and the accumulation of cholesterol in mitochondrial contact sites (99, 156).
Whereas the action of CaM and CaMKII in supporting
aldosterone production is confined to the transport of
cholesterol to the inner mitochondrial membrane (422),
the cytoplasmic Ca2⫹ signal is transferred into the mitochondrial matrix (see sect. III), and intramitochondrial
Ca2⫹ contributes to the stimulation of hormone production. In cycloheximide-treated adrenocortical mitochondria (which are depleted of the cholesterol-transporting
labile protein), the conversion of cholesterol (present in
the inner mitochondrial membrane) to pregnenolone is
stimulated by Ca2⫹. This effect is completely inhibited by
ruthenium red, an inhibitor of mitochondrial Ca2⫹ uptake
(299). In electropermeabilized bovine glomerulosa cells,
the Ca2⫹-induced aldosterone response in the presence of
NADP⫹ is also blocked by ruthenium red (90). The mitochondrial Na⫹/Ca2⫹ exchanger extrudes Ca2⫹ from the
mitochondria, and its inhibition also augments Ca2⫹-induced steroid production (78). These observations indicate that Ca2⫹ has an intramitochondrial site of action,
and this could suggest that the underlying mechanism of
this action is the activation of cholesterol transport again.
However, intramitochondrial Ca2⫹ does not affect the
function of StAR transiently located in the outer mitochondrial membrane (71), and no data are available to
support a role of intramitochondrial Ca2⫹ in the transport
of cholesterol.
Intramitochondrial NADP⫹ is reduced by transhydrogenation at the expense of NADH. All of the major mitochondrial steps of aldosterone biosynthesis, namely, the
side-chain cleavage of cholesterol (yielding pregnenolone), the hydroxylation of 11-deoxycorticosterone
to corticosterone, and the conversion of the latter compound to aldosterone, require NADPH. Tricarboxylic acid
cycle intermediates support not only the reduction of
pyridine nucleotides (439) but also steroid hydroxylation
in (mixed) adrenocortical cells (310, 319, 417), including
glomerulosa cells (197). Inhibition of the electron transport chain at site 1 by rotenone stimulates the side-chain
cleavage of cholesterol, indicating an effect of the accuPhysiol Rev • VOL
mulated NADPH (222). Both NAD(P)H level and aldosterone production rate exhibit a biphasic response to K⫹,
with a maximum at 8.4 mM K⫹ (432). Increased aldosterone production is associated with increased utilization of
NADPH, as shown by the finding that the reoxidation of
NADPH, formed in response to K⫹, is delayed by the
addition of aminoglutethimide, which inhibits the conversion of cholesterol to pregnenolone (466). Although stimulation of mitochondrial metabolism by Ca2⫹ may not be
essential for supporting submaximal formation of pregnenolone (441), the bulk of the evidence supports the
significance of enhanced NADPH formation during stimulation of hormone secretion.
Utilizing NADH for increased formation of ATP is,
obviously, essential during cell stimulation with Ca2⫹mobilizing agonists. ATP is required for protein phosphorylation by different protein kinases. Furthermore, Ca2⫹
signaling alters not only the Ca2⫹ content of the cytoplasm and intracellular Ca2⫹ stores, but also induces
secondary alterations in sodium, potassium, and proton
balance. The restoration of intracellular ionic composition by PMCA and SERCA as well as Na⫹-K⫹-ATPase may
cause a rapidly developing and prolonged energy demand.
2⫹
2⫹
FIG. 10. Steroidogenic actions of Ca . The direct actions of Ca
are shown by red arrows, and the black arrows indicate metabolic
transformations and transport processes. StAR, steroidogenic acute regulatory protein; CYP11B2, aldosterone synthase.
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B. Increased Reduction of Pyridine Nucleotides
in Mitochondria
523
524
ANDRÁS SPÄT AND LÁSZLÓ HUNYADY
C. Induction of Aldosterone Synthase
We thank Dr. Kevin J. Catt for critical reading of this
manuscript and for his valuable comments. The linguistic revision by Matthew Suff (Central European University, Budapest)
is greatly appreciated.
This review honors the late Professor Sylvia A. S. Tait and
Physiol Rev • VOL
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Long-term stimulation of the adrenal cortex results in
cell proliferation (see sect. VIA) and increased synthesis of
steroidogenic enzymes. With regard to aldosterone secretion, the increased expression of the enzyme system converting deoxycorticosterone to aldosterone has special
significance. In humans and rodents, this conversion is
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synthase (CYP11B2, also termed cytochrome P-450aldo or
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time of Ca2⫹-induced expression of aldosterone synthase
in H295R cells is ⬍6 h, as examined by real-time RT-PCR
(W. E. Rainey, personal communication). This lag time
accounts for the observation of increased activity of the
late stage of aldosterone biosynthesis (conversion of corticosterone to aldosterone) in the chronically, but not in
the acutely, sodium-depleted rat (506).
Both CYP11B2, encoding aldosterone synthase in
glomerulosa cells, and CYP11B1, encoding 11␤-hydroxylase in fasciculata cells, contain a cAMP-response element
(CRE) in its promoter region. CaMKI and CaMKIV can
phosphorylate the activating transcription factor ATF-1
and CRE-binding protein (CREB) that bind to CREs, but
this binding is not sufficient to support CYP11B2 expression. CYP11B2 contains at least two additional cis-acting
regulatory elements (Ad-5 and NBRE-1) that are not
present in CYP11B1. The ability of these elements to bind
two members of the NGFIB family of orphan nuclear
receptors, NGFIB and NURR1, suggests that these proteins enhance the expression of CYP11B2 (35). The role
of CaMKs in the activation of these factors is still to be
elucidated.
PKC, which under acute conditions inhibits rather
than stimulates aldosterone production (see sect. IIC),
depresses the expression of CYP11B2, as observed in the
hamster glomerulosa cell (314, 315).
The sites of steroidogenic Ca2⫹ action are shown
summarized in Figure 10.
her husband Professor James F. Tait on the occasion of the 50th
anniversary of the discovery of aldosterone.
Experimental work performed in the authors’ laboratories
has been supported by the National Science Foundation
(OTKA), the Hungarian Academy of Sciences, the (Hungarian)
Council for Medical Science (ETT), the Wellcome Trust, and the
European Union.
Address for reprint requests and other correspondence: A.
Spät, Dept. of Physiology, Semmelweis University, Faculty of
Medicine, PO Box 259, H-1444 Budapest, Hungary (E-mail:
[email protected]).
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