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Endocrine Reviews 28(7):726 –741
Copyright © 2007 by The Endocrine Society
doi: 10.1210/er.2007-0022
Extranuclear Steroid Receptors: Nature and Actions
Stephen R. Hammes and Ellis R. Levin
Division of Endocrinology and the Departments of Medicine and Pharmacology (S.R.H.), University of Texas Southwestern
Medical Center, Dallas, Texas 75390; Division of Endocrinology (E.R.L.), Veterans Affairs Medical Center, Long Beach,
Long Beach, California 90822; and Departments of Medicine, Biochemistry, and Pharmacology (E.R.L.), University of
California, Irvine, Irvine, California 92697
membrane localization and function, as well as the nature of
interactions with G proteins and other signaling molecules in
confined areas of the membrane, have led to a fuller understanding of how steroid receptors effect rapid actions. Increasingly, the relevance of rapid signaling for the in vivo
functions of steroid hormones has been established. Examples
include steroid effects on reproductive organ development
and function, cardiovascular responsiveness, and cancer biology. However, although great strides have been made, much
remains to be understood concerning the integration of extranuclear and nuclear receptor functions to organ biology. In
this review, we highlight the significant progress that has
been made in these areas. (Endocrine Reviews 28: 726 –741,
2007)
Rapid effects of steroid hormones result from the actions of
specific receptors localized most often to the plasma membrane. Fast-acting membrane-initiated steroid signaling
(MISS)1 leads to the modification of existing proteins and cell
behaviors. Rapid steroid-triggered signaling through calcium, amine release, and kinase activation also impacts the
regulation of gene expression by steroids, sometimes requiring integration with nuclear steroid receptor function. In this
and other ways, the integration of all steroid actions in the cell
coordinates outcomes such as cell fate, proliferation, differentiation, and migration. The nature of the receptors is of
intense interest, and significant data suggest that extranuclear and nuclear steroid receptor pools are the same proteins. Insights regarding the structural determinants for
I. Historical Background
VII. Thyroid Hormone Receptors
A. Functions
B. Classical thyroid receptors
VIII. Vitamin D Receptors
IX. Summary
II. Estrogen Receptors
A. Introduction
B. Nature of membrane estrogen receptors
C. Functions of membrane estrogen receptors
D. Outcomes of extranuclear estrogen signaling
III. Progesterone Receptors
A. Introduction
B. Nature of membrane progesterone receptors
IV. Androgen Receptors
A. Function and importance
V. Glucocorticoid Receptors
A. Function and importance
VI. Mineralocorticoid Receptors
A. Function and importance
I. Historical Background
H
ANS SELYE FIRST reported in the early 1950s that
glucocorticoids and catecholamines regulate the
rapid adaptation to stress (1). In 1967, Clara Szego and June
Davis (2) reported that iv administration of physiological
amounts of 17-␤-estradiol (E2) to ovariectomized rats resulted in a 100% increase in uterine cAMP levels after 15 sec.
This observation suggested that steroid hormones rapidly
signal, and it was subsequently supported by studies demonstrating rapid calcium responses to E2 in endometrial cells
(3). Shortly thereafter, specific, high-affinity binding sites for
estrogen were described at the surface of endometrial cells
(4). These studies effectively launched the field of rapid steroid responses, eventually extending to many members of
the steroid receptor superfamily (5).
First Published Online October 4, 2007
Abbreviations: AR, Androgen receptor; CREB, cAMP-response element binding protein; E2, 17-␤-estradiol; EC, endothelial cell; EGF, epidermal growth factor; EGFR, EGF receptor; eNOS, endothelial nitric
oxide synthase; ER, estrogen receptor; GPCR, G protein-coupled receptor; GPR30, GPCR 30; GR, glucocorticoid receptor; MARRS, membraneassociated, rapid response steroid binding protein; MISS, membraneinitiated steroid signaling; MNAR, modulator of nongenomic actions of
steroid receptors; mPR, membrane PR; MR, mineralocorticoid receptor;
NO, nitric oxide; PGMRC1, progesterone membrane receptor component-1; PI3K, phosphotidylinositol 3-kinase; PKC, protein kinase C; PR,
progesterone receptor; ROS, reactive oxygen species; TR, thyroid receptor; VSM, vascular smooth muscle.
II. Estrogen Receptors
A. Introduction
1
Terminology was suggested by the Working Group at the Federation of American Societies for Experimental Biology (FASEB) Summer
Conference on Rapid Steroid Signaling, Aspen, Colorado, July 2002
(211).
Endocrine Reviews is published by The Endocrine Society (http://
www.endo-society.org), the foremost professional society serving the
endocrine community.
Compelling evidence for the rapid effects of estrogen now
exists. E2 rapidly activates several protein kinases [e.g.,
MAPKs, phosphotidylinositol 3-kinase (PI3K), and protein
kinase C (PKC)] and phosphatases, as well as the release of
several cyclic amines (cAMP, cGMP) and calcium, in a variety of cell types (5, 6). These signals subsequently mediate
726
Hammes and Levin • Extranuclear Steroid Receptors
the posttranslational modification of many proteins, especially by phosphorylation. As a result, enzymes are rapidly
induced (6, 7), and cell functions are modulated (8). Rapid
signaling by estrogen correlates to the membrane localization
of classical estrogen receptors (ERs), but not to their nuclear
localization (9).
B. Nature of membrane estrogen receptors
1. Isoforms and sizes. The identity of the cytoplasmic/membrane ER has been an issue of debate. Initial data suggested
that the membrane-localized estrogen binding protein
shared epitope homology to classical (nuclear) ER␣, based
upon immunological identification (10, 11). Accordingly, expression of classical ER␣ or ER␤ in ER-null cells results in
both nuclear and membrane-localized functional pools of
estrogen binding proteins (12). Furthermore, breast cancer
MCF-7 cells that lack nuclear ER␣ (13) or endothelial cells
(EC) from combined ER␣/ER␤-deleted mice (14) do not
demonstrate a functional estrogen binding protein at the cell
surface (15). Genetic approaches using antisense oligonucleotides (11), as well as small interfering RNA directed against
classical ER␣ (13) or ER␤ (14, 15), also eliminate estrogen
binding and membrane-initiated steroid signaling (MISS).
Finally, membrane ERs isolated from breast cancer cells are
identical to the nuclear ER␣ by mass spectrometry (15).
Approximately 5–10% of endogenous cellular ER␣ is
present at the membrane, determined by Scatchard analysis
of ligand saturation binding (15). Interestingly, receptors
expressed by transfection also show approximately the same
number of receptors at the membrane in the absence of subcellular targeting (12). This suggests the presence of a saturable transport mechanism for the membrane-bound ER pool
(see Section II.B.3). Notably, ER at the membrane and in the
nucleus exhibit the same high-picomolar affinity for ligand.
The majority of work in the area of membrane-initiated
estrogen signaling identifies a 66-kDa protein as the predominant/exclusive ER␣ form at the plasma membrane in
multiple cell types (16, 17). However, truncated forms of ER␣
have also been described.
In both MCF-7 cells (13) and immortalized human ECs
(18), abundant 46-kDa receptor ER␣ (lacking the amino terminus) has been demonstrated at the plasma membrane.
However, antibodies directed against either the amino or
carboxyl terminus of the protein detect ER␣ in human breast
cancer specimens (mainly in the nucleus), suggesting the
presence of full length, 66-kDa receptor. Regarding vascular
cells, several groups working with freshly isolated EC or
aorta from rodents or ECs from human umbilical veins have
only described a 66-kDa receptor (15, 16, 19). These ER␣ exist
in the caveolae and noncaveolae rafts of EC membranes and
stimulate rapid signaling to endothelial nitric oxide synthase
(eNOS) activation and nitric oxide (NO) production (20).
Thus, the functional importance of the smaller isoform, described in only a few reports, is unknown.
Additional membrane receptors of 36-kDa size have been
isolated mainly from ER-positive breast cancer cell lines and
from some human cancers (21). The vast majority of studies
in breast cancer do not mention these low-molecular weight
isoforms that are apparently low in abundance. ER␤ has been
Endocrine Reviews, December 2007, 28(7):726 –741 727
much less well characterized, but endogenous membranelocalized receptors have been described as approximately 60
kDa in size (22). A functional 54-kDa ER␤ receptor also exists
at the membrane of EC (16).
2. G protein-coupled receptor 30 (GPR30) and other putative ERs.
A few reports describe the orphan G protein-coupled receptor (GPCR), GPR30, as an ER (23, 24). This protein has been
reported to respond to estrogen with high affinity and low
capacity binding (25) at both the plasma membrane and
endoplasmic reticulum. E2 has been reported to engage this
protein to stimulate kinase activation, calcium signaling, and
epidermal growth factor (EGF) receptor (EGFR) transactivation in ER-negative breast cancer cells. It has not been demonstrated that this receptor mediates G protein activation in
response to E2, as shown for the endogenous or expressed
classical ER␣ (12, 20). Furthermore, many laboratories have
found that classical ER-negative breast cancer cells do not
respond to E2 with any biological functions.
In contrast, multiple groups have described collaboration
between membrane-localized ER␣ and GPR30, presumably
at the membrane of several hormone-sensitive cell lines. In
endometrial and ovarian cancer cells, as well as keratinocytes, ER␣ and GPR30 mediate rapid kinase signaling by E2
to c-fos or cyclin D1 up-regulation and proliferation (26 –28).
A second GPCR at the membrane, Edg-3, is the binding
protein for sphingosine-1 phosphate (29). In MCF-7 cells,
membrane ER signaling to EGFR transactivation and ERK
may cause sphingosine kinase to release sphingosine, resulting in feed-forward engagement of Edg-3 for further signaling (30). It is unclear from many of these reports whether the
GPCR, as opposed to ER, activates the G protein; it may be
that the GPR30 or Edg3 serves as a linker or scaffold protein
to help assemble the signal complex that is required for ER
signaling (31). Proteins such as the modulator of nongenomic
actions of steroid receptors (MNAR) (32), Shc (33), caveolin-1
(9), and striatin (34) have been described to serve these purposes for membrane ER signaling in several cell types. Importantly, most of these studies do not support the idea that
GPR30 functions as a stand-alone ER in the absence of classical ER. It is conceptually possible that some cells might lack
GPR30 or other downstream signaling proteins, and therefore rapid signaling by E2 is not evident even when membrane ER␣ is present.
Additional estrogen binding proteins that mediate rapid
actions of E2 in the central nervous system have also been
functionally implicated in E2 rapid signaling, but the nature
of these proteins is currently undefined (35, 36). In both
platelets and T-lymphocytes, a body of data implicates undetermined, but nonclassical estrogen binding proteins in the
actions of E2. However, recent work implicates ER␤ as mediating E2 rapid actions in platelets (37, 38) and ER␣ or ER␤
as supporting E2-induced kinase activation to suppress Tcell cytokine production and transcription factor activity
(39, 40).
3. Membrane localization and function. Endogenous ER␣ and
ER␤ proteins exist at the plasma membrane of many cell
types, but are variable in their expression. Abundant ␣ and
␤ ER are present at the cell surface of ECs and cardiomyo-
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Endocrine Reviews, December 2007, 28(7):726 –741
cytes as both homo- and heterodimers (15, 16, 20, 22). In
contrast, breast cancer cells express much more plasma membrane ER␣ than ER␤, consistent with much of E2 rapid signaling being mediated through the ␣ isoform in these cells
(13, 15).
The endogenous ER␣ exists as a monomer at the cell surface in the absence of E2 and rapidly dimerizes upon addition
of ligand to the cell (14). Dimerization is known to be crucial
to nuclear ER function (41), and evidence links this modification of membrane ER to rapid G protein activation and
downstream signaling (14). Dimerization may not be required for estrogen-induced signaling to eNOS activation in
ECs (42).
At the surface of several cell types, ER␣ and ER␤ are
localized to isolated caveolae rafts (13, 42– 44). Here, many
signaling molecules congregate in a spatially confined area
that facilitates rapid signaling (Fig. 1). These signal proteins
include G proteins, growth factor receptors (EGFR, IGF-I
receptor), non-growth factor tyrosine kinases (Src, Ras),
linker proteins (MNAR, striatin), and orphan GPCRs. The
signalsome complex provides the necessary protein interactions for membrane ER to transactivate growth factor receptors (30, 33, 45) or engage and directly activate G proteins (14,
20), depending upon cell context. Various domains of ER␣
contact discrete signal proteins, including the amino-terminal A/B (striatin, Shc) and carboxyl-terminal E (MNAR)
domains (32–34). However, A/B domain-deleted ER␣ still
translocates to the membrane and activates ERK comparably
to full-length ER (9), emphasizing the point that the precise
assembly sequence of multiprotein complexes dictating specific signals to select cell biology events is not known. Undoubtedly, the particular complex assembled in a specific
context provides signal specificity. For instance, membrane
ER␣ activates many but not all G proteins in response to E2,
and one or two G proteins are often linked to the activation
of selective kinase cascades (12, 31).
FIG. 1. Translocation of ER␣ to the plasma membrane. Palmitoylation at cysteine 447 of ER␣ promotes the association of the steroid receptor with
caveolin 1. The scaffolding domain of caveolin-1
(amino acids 80 –100) then facilitates the translocation of caveolin and ER to the caveolae rafts in the
membrane. Here, ER associates with a large protein
complex, changing in nature depending upon the cell
and signal context, to effect G protein activation and
downstream signaling to cell biology.
Hammes and Levin • Extranuclear Steroid Receptors
4. ER translocation. Because the endogenous ER exists as a
monomer at the cell surface, it is likely that transport of the
protein to the plasma membrane does not require dimerization. The structural requirements for membrane ER localization have been investigated. Expression of the E domain
alone into ER-null cells is sufficient for membrane localization and signaling (45), suggesting that this domain contains
the key residues that participate in transport to the membrane. Consistent with this idea, serine 522 of the E domain
was found to be important for membrane translocation, dictating a physical interaction with caveolin-1 protein that
functions to facilitate transport of ER␣ to caveolae (9). Furthermore, intestinal cancer cells lacking caveolin-1 but containing endogenous ER show only nuclear steroid receptors.
Expressing caveolin-1 in these cells results in a small population of ER translocating to the cell surface (9). Similarly,
caveolin-1 expression in MCF-7 cells facilitates ER␣ translocation to the membrane (44). Most epithelial cancer cells have
reduced (but not absent) caveolin-1, compared with normal
epithelial cells.
Once ER is localized to the membrane, caveolin-1 must be
displaced from ER for productive signaling in EC or MCF-7
cells (20, 44). A similar requirement of caveolin-1 displacement from the membrane is known for signaling by membrane growth factor tyrosine kinase receptors. However, the
ability of membrane ER to inhibit ERK MAPK in vascular
smooth muscle (VSM) cells correlates to a strong interaction
with caveolin-1 (44). Also, E2/ER differentially regulate
caveolin-1 synthesis, stimulating this scaffold in VSM cells
but inhibiting transcription and new caveolin-1 protein production in MCF-7 cells.
Another important determinant of membrane translocation is cysteine 447 in the E domain of ER␣. This residue has
been determined to be a palmitoylation site (46, 47), and
identification of cysteine 447 extends a previous observation
that truncated ER␣ in immortalized human ECs are palmi-
Hammes and Levin • Extranuclear Steroid Receptors
toylated (48). Both studies indicated that palmitoylation is
necessary for membrane localization of ER␣. Mechanistically, palmitoylation promotes a physical interaction of ER
with caveolin-1, thereby promoting membrane localization.
It is not clear where palmitoylation of ER occurs in the cell,
but this posttranslational lipidation occurs only on cytoplasmic/membrane ER, and not nuclear ER (49). This is consistent with the importance of this modification to promote
membrane transport. Why only a small percentage of ER
undergo palmitoylation and membrane localization despite
all ER containing the same sequence information is not clear.
Perhaps palmitoylation is a saturable process where the relevant palmitoylacyltransferase protein abundance is limiting. We speculate that palmitoylation occurs on a few ER at
any one time. Membrane-localized ER can also translocate to
non-clathrin-coated cell endosomes (50); the importance of
this for function, recycling, or degradation of membrane ER
is currently unknown.
Recently, additional sequences flanking cysteine 447 and
comprising a nine-amino acid membrane-localization motif
have been identified to promote palmitoylation of ER␣ (49).
Interestingly, this motif is highly conserved in the E domains
of ER␤, progesterone, androgen, and glucocorticoid receptors. Mutational analysis of this motif in all the sex steroid
receptors indicates that this structure dictates palmitoylation, membrane localization, and all membrane-initiated
signaling (49). In contrast, nuclear localization and function
of sex steroid receptors is not impaired by mutation of this
motif.
C. Functions of membrane estrogen receptors
1. Importance of rapid signaling by E2. Increasingly, the importance of rapid signal transduction to the biological actions
of sex steroids has been demonstrated. These signals modify
existing proteins (e.g., phosphorylation) and their functions
(6) and also modulate gene expression and hence production
of proteins (51). As examples, ERK signaling in response to
E2 increases c-fos expression in vivo and in vitro in multiple
cell types and prolactin gene expression in pituitary cells (52,
53). Hence, the concept that these signals are “nongenomic”
is simply inaccurate. The FASEB rapid steroid signaling
working group suggested adoption of the terms “membraneinitiated steroid signaling” (MISS) and “nuclear-initiated steroid signaling” (NISS). These distinctions also allow description of signaling originating from additional pools of ER (e.g.,
mitochondria, see Section II.C.4). Cross-talk between ER
pools also occurs, where a signal at one pool modulates the
signal from a second discrete pool (54). The full extent of this
integration is not well understood.
2. Impact of membrane signaling for transcription. As described
from the laboratory of Don Pfaff (54), rapid activation of ERK,
calcium, and perhaps other signals from membrane ER amplifies subsequent gene transcription originating from nuclear ER action. Rapid signaling can cause this in numerous
ways. First, ERK, PI3K, protein kinase A, or p21-kinase activation phosphorylate key residues of nuclear ER␣ (54). This
augments the transcriptional function of nuclear ER and may
contribute to tamoxifen resistance in breast cancer both in
Endocrine Reviews, December 2007, 28(7):726 –741 729
vitro and in vivo (55, 56). Interestingly, these signals are
known to be activated by growth factor receptors in breast
cancer (57), and membrane ERs can transactivate EGF family
and IGF-I receptors to stimulate identical signaling (6).
Second, kinase activation by estrogen phosphorylates and
thereby recruits coactivators to the nuclear ER transcriptional
complex (58). Examples include GRIP-1, SRC family proteins, and CBP (58 – 60). As a result, rapid signaling by E2 in
ECs quickly up-regulates many transcription factor and
structural genes, some contributing to the angiogenesis effects of E2 (61).
Third, signaling from membrane ERs may contribute to
gene transcription independently of nuclear ER. This may
involve posttranslational modification and recruitment of
AP-1 family partners to their cognate DNA binding sites,
mediating gene modulation (62). Other transcription factors
that contribute to gene regulation after rapid signaling by E2
are the Sp-1, nuclear factor ␬B, and signal transducers and
activators of transcription (Stat) 3 and 5 (51, 63, 64). Signaling
through PI3K/AKT phosphorylates and inactivates GSK-3B,
thereby promoting ␤-catenin translocation to the nucleus
(65). This contributes to cyclin D1 and c-myc induction in
breast cancer cells, two targets for estrogen function (66, 67).
Rapid signaling can also suppress transcription. E2 rapidly
activates PI3 and AKT kinases in many cell types. AKT phosphorylates and thus retains Forkhead (FOXO) family transcription factors in cytoplasm, preventing their induction of
cell death gene transcription (68, 69). PI3K/AKT signaling by
membrane ER is known to importantly contribute to cell
survival in many target cells (70 –72), in part likely to occur
through the mechanism described above. Because there are
more than 500 kinases coded for in the human genome, it is
apparent that kinase activation resulting from membrane ER
action is likely to be highly significant in ways currently
unappreciated.
Regarding breast cancer, aromatase inhibition has been
modeled by long-term culture of MCF-7 cells in estrogendeprived medium (73). Sustained signaling through ERK,
PI3K/AKT, and mTOR results in and mediates low concentration, E2 hypersensitivity in these cells. In another model,
continued exposure of MCF-7 cells to tamoxifen simulates
tamoxifen resistance. In these cells, a population of ER␣
moves out of the nucleus to physically associate with EGFR
and Src at the membrane. Inhibition of Src reverses tamoxifen
resistance (74).
3. Nontranscriptional functions of membrane ER signaling. Rapid
signaling by membrane ER modifies existing protein structure, affecting the cell distribution and function of the substrate protein. As examples, kinases and phosphatases can
themselves be regulated by calcium or phosphorylation. ER
signaling rapidly down-regulates MAPK phosphatase 1,
leading to the up-regulation of ERK activity in breast cancer
cells (75). PI3K activation in breast cancer cells phosphorylates the proapoptotic Bcl-2 protein BAD, sequestering BAD
in the cytoplasm through binding 14-3-3 proteins (76). Bcl-2
and Bcl-xl are subsequently released from complexing to
BAD through this mechanism, activating their prosurvival
functions. In bone cells, membrane ER signaling modulates
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Endocrine Reviews, December 2007, 28(7):726 –741
whether ERK signals predominantly in cytoplasm or nucleus, the latter contributing to osteocyte survival (77).
Membrane ER-initiated signaling through multiple kinases modulates the migration of ECs (8), monocytes (78),
breast cancer cells (79), and VSM cells (80). These pathways
depend upon the phosphorylation of multiple substrate proteins, altering the activity of these proteins that promote
motility.
Extranuclear estrogen signaling also modulates genes
whose products regulate phosphatase activity. Rapid signaling by membrane ER through PI3K stimulates the MCIP-1
(modulatory calcineurin-interacting protein 1) gene (22). The
MCIP protein clamps calcineurin (protein phosphatase 2B),
and down-regulates its activity, preventing the nuclear factor
of activated T cells family of transcription factors from moving to the nucleus of the cardiomyocyte. This is an important
mechanism through which rapid E2 signaling prevents cardiac hypertrophy (22).
4. ER in the mitochondria. In addition to cytoplasmic ER that
are tethered/adjacent to the cell membrane, there are discrete
cytoplasmic pools of these receptors. A prominent example
is mitochondria, where both classical ER isoforms are found
(81, 82). In breast cancer cell mitochondria, ER␤ is more
abundant than ER␣. Mitochondrial ER prevent radiationinduced cell death of breast cancer cells by mitigating mitochondrial reactive oxygen species (ROS) formation and
death kinase activation. This occurs through the rapid stimulation of mitochondrial MnSOD (manganese superoxide
dismutase) activity (83).
Signaling from the membrane to the mitochondria also
occurs. In cardiomyocytes exposed to hypoxia/normoxia injury, mitochondrial ROS formation triggers p38␣-induced
apoptosis. Membrane ER stimulates the rapid induction of
p38␤ activity through PI3K, leading to the inhibition of ROS
formation in mitochondria and resulting cell survival (71).
Mitochondrial ER also promotes the transcription of mitochondrial-encoded genes (84). It is likely that this ER pool
cross-talks with nuclear ER to coordinate the synthesis of
proteins that are essential for the normal respiratory function
of mitochondria.
D. Outcomes of extranuclear estrogen signaling
Many organ systems are impacted by rapid estrogen
signaling to the development, growth, survival, and function of cells. The mechanisms are often consistent from
system to system, with some unique aspects conveyed in
context. Multiple pathways involving ERK, PI3K, and PKC
result from upstream signaling (e.g., G proteins and Src
kinase) that triggers effector kinase action. A complete
depiction of all signaling studies is beyond the scope of
this review, but recent work that highlights the physiological impact of rapid signaling outside the reproductive
tract is presented (Table 1).
1. Bone. Rapid signaling by estrogenic compounds impacts
many aspects of bone cell biology. The survival (85) and
differentiation of osteoblasts (86) depends upon estrogen
activation of several kinase systems, including Src, ERK, and
PI3K. A purportedly selective agonist for the membrane ER,
Hammes and Levin • Extranuclear Steroid Receptors
TABLE 1. Membrane-initiated effects of steroids in vivo
Steroid
Estrogens
Progestins
Androgens
Glucocorticoids
Mineralocorticoids
Thyroid
Effect
Neuronal injury protection (94, 97)
Vasodilatation (106)
Arterial injury protection (108)
Cardiomyocyte injury protection (109)
Breast cancer proliferation and survival (209)
Fish oocyte maturation (125, 126)
X. leavis oocyte maturation (113, 132)
Prostate cell proliferation (210)
Suppression of ACTH release (157, 158)
Vasodilatation (161, 162)
Baroreflex attenuation (163)
Neuronal protection (189)
The best characterized in vivo rapid or membrane-initiated steroid
effects are listed in this table; their respective references are in parentheses.
estren, has been shown to trigger the Wnt/␤-catenin transcription system, impacting cell function. Estren also reverses bone loss in ovariectomized mice, possibly by signaling through membrane ER␣ (87). However, estren also
engages the androgen receptor (AR) (88), indicating that the
mechanisms of this compound’s effects are complex. E2induced defenses against ROS formation may prevent bone
loss and osteoclast formation (89, 90). In part, this may occur
from estrogen rapid signaling in mitochondria, as occurs in
breast cancer cells (83). Inhibition of osteocyte apoptosis occurs through nuclear-translocated ERK (77), and stimulation
of osteoclast death relies on prolonged ERK activation (91).
2. Central nervous system. Several laboratories have shown
that estrogens limit neuronal damage and death, possibly by
signaling through PI3K, PKC, ERK, or glycogen synthase
kinase 3-␤ (92–95). Models tested include brain injury created
by experimental cerebrovascular compromise (stroke) (92,
93) or the administration of glutamate (96), alcohol (94), or
MPTP (1-methyl 4-phenyl 1,2,3,6-tetrahydropyridine, a
chemical that creates a rodent model of Parkinson’s disease)
(97). Extranuclear ER in neurite extensions may mediate
these effects (98, 99).
Rapid signaling by E2 through ER␣ and ERK phosphorylates cAMP-response element binding protein (CREB) in
cortical neurons in vivo (52). Such signaling by E2 has also
been reported to modulate the plasticity of sexual behavior
in birds and fish (100, 101). Dendritic spine formation in
cortical and hippocampal neurons promotes synapse formation and plasticity. Rapid signaling by estrogen has been
found to contribute to these sex steroid effects in the brain
(102, 103). A more extensive review of the central nervous
system effects of rapid signaling by estrogen has recently
been published (54).
3. Cardiovascular. Rapid signaling by estrogen modulates EC
and VSM migration and proliferation (8, 80). In part this may
be related to the ability of estrogen to stimulate NO formation
in ECs through G␣i and G␤␥ proteins (104), activating PI3K
and ERK (7, 105). Both ER␣ and ER␤ have been implicated
in the rapid signaling to NO production in vivo, resulting in
rapid arterial dilation induced by the sex steroid (106). Rapid
signaling underlies the E2 activation of gene expression in
the heart (107), and PI3K activity has been implicated in the
Hammes and Levin • Extranuclear Steroid Receptors
molecular program by which E2 prevents cardiomyocyte
hypertrophy (22) and the response to arterial injury in vivo
(108). E2 also signals through PI3K (109) and p38␤ (71) to
prevent ischemia/reperfusion injury in the heart and in isolated cardiomyocytes.
III. Progesterone Receptors
A. Introduction
Progesterone plays a critical role in regulating multiple
reproductive processes, including follicle growth, oocyte
maturation, ovulation, implantation, and the maintenance of
pregnancy. In addition, progestins are critical mediators of
both normal and carcinogenic breast development. Several
studies suggest that extranuclear, transcription-independent
signaling may be important for many of these progestinmediated processes (110).
In general, transcription-independent progesterone effects
seem to be mediated via the classical progesterone receptor
(PR) B; however, similar to GPR30 and estrogens, membrane
progesterone binding proteins that appear to function as
GPCRs may also contribute to progestin-mediated signaling
outside of the nucleus.
B. Nature of membrane progesterone receptors
1. Classical PRs
a. Breast. As observed with classical ERs, the classical PRB
form can mediate progesterone-triggered activation of Src
and downstream MAPK signaling in breast cells (111). Unlike ER-mediated Src signaling, human PRB-induced Src activation is regulated by direct binding between a proline-rich
domain within the amino terminus of PRB and the SH3
domain of Src (Fig. 2). Mutation of the polyproline motif
abolishes both Src binding to and activation by PRB (111).
Although no evidence currently demonstrates that direct
PRB-mediated activation of Src is membrane initiated, evidence indicates that it is occurring outside of the nucleus
(112). In fact, PRB is detected at the cell membrane in some
FIG. 2. Progestins and androgens regulate kinase
and G protein signaling. Classical PRs and ARs transactivate the EGFR in response to ligand by signaling
through Src (left). Although human PRB can directly
activate Src, AR may utilize MNAR as a scaffold.
EGFR activation is mediated either intracellularly or
through the release of membrane-bound EGF-like
proteins (e.g., amphiregulin or HB-EGF). Activated
EGFR then promotes MAPK signaling, which subsequently enhances the activity of multiple nuclear
transcription factors. MAPK signaling also leads to
phosphorylation and nuclear accumulation of PRB.
In X. laevis oocytes, androgens promote maturation
by signaling through the AR and MNAR to suppress
constitutive G␤␥ and G␣s activity and lower intracellular cAMP (right). In fish, progestins promote oocyte maturation by signaling through a G␣i-coupled
mPR. Membrane-bound mPRs may also regulate
other G␣i-mediated processes in somatic cells, and
endosomal mPRs may regulate calcium flux in response to progestins.
Endocrine Reviews, December 2007, 28(7):726 –741 731
cells, and its sequence contains the palmitoylation site/membrane-localization signal found in multiple classical steroid
receptors (49). These findings therefore indicate that PRB is
at least in the appropriate location to initiate signaling from
the membrane.
Interestingly, as seen with other classical steroid receptors,
rapid PRB-mediated activation of Src leads to transactivation
of the EGFR, resulting in sustained MAPK signaling (113)
that may have significant biological effects. For example,
extranuclear PRB-mediated activation of Src, EGFR, and
MAPK appears to be critical for promoting transcription of
the cyclin D1 gene (112, 114), as well as sustained progesterone-mediated up-regulation of cyclin D1 protein expression (by increasing translation and/or stability) (113). Because the cyclin D1 promoter does not contain a classical PR
response element, these observations suggest that extranuclear PRB-mediated signaling rapidly activates or enhances
activity of alternative transcription factors that in turn
promote cell cycle progression and possibly proliferation
(113, 115).
In addition to PRB rapidly activating the EGFR, direct
activation of the EGFR conversely triggers phosphorylation
of PRB and its ligand-independent accumulation in the nucleus (116, 117). This further demonstrates the importance of
cross-talk between multiple receptor families (Fig, 2).
Finally, the amino-terminal proline-rich motif is relatively
specific for the human PRB (for example, it is not found in
the mouse PRB). This suggests that direct activation of Src by
PRB may be specific for both human breast cell development
and proliferation, as well as for the stimulation of breast
cancer progression.
b. Oocytes. Because steroid-mediated processes such as
breast cell proliferation involve both membrane- and nuclear-initiated steroid signaling, dissecting the relative physiological importance of each is often difficult. One of the oldest
models of true nongenomic steroid signaling is steroid-triggered maturation, or meiotic progression, of oocytes (118,
119) (Table 1). Significant evidence accumulated since the
1960s has shown that steroid-mediated oocyte maturation is
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Endocrine Reviews, December 2007, 28(7):726 –741
exclusively transcription independent. First, transcription is
almost completely suppressed during steroid-triggered maturation. Second, transcriptional inhibitors do not affect either
the rate or potency of steroid-mediated maturation. Finally,
enucleation of Xenopus oocytes does not alter steroid-mediated activation of MAPK, CDK1, or other cytoplasmic signals
that regulate meiosis.
Progesterone was long assumed to be the in vivo regulator
of Xenopus laevis oocyte maturation, because in vitro addition
of progesterone to oocytes promotes meiotic progression
(118, 120). With this in mind, the classical X. laevis PR has
been identified and characterized (121, 122). Increasing or
reducing X. laevis classical PR expression in oocytes modestly
enhances or reduces, respectively, progesterone-mediated
maturation. Furthermore, a small percentage of the Xenopus
classical PR associates with the plasma membrane when
overexpressed in COS cells (123). Additionally, membranetargeting of the classical Xenopus PR in oocytes slightly enhances progesterone-mediated maturation (124). Importantly, these manipulations of PR expression levels and
locations within oocytes only modestly alter progesteronemediated maturation. This suggests that alternative receptors must be involved in regulating progesterone-induced
maturation.
2. Alternative membrane PRs (mPRs)
a. mPRs. A novel class of PRs that might contribute to the
regulation of oocyte maturation, as well as to other progestinmediated reproductive processes, is the membrane PR family, or mPR. The first of these mPRs was cloned from oocytes
of the spotted seatrout (125, 126). Similar to frogs, progestins
trigger fish oocyte maturation, although the physiological
maturation-promoting steroid in seatrout is the progesterone
metabolite 21-trihydroxy-4-pregnen-3-one (20␤-S).
Interestingly, mPRs bear structural, but virtually no sequence, homology to the GPCR family. Binding studies
primarily using bacterially expressed mPR reveal specific,
high-affinity interactions between mPRs and progestins.
Furthermore, under some conditions, overexpression of
mPRs in breast cells mediates a pertussis toxin-sensitive decrease in intracellular cAMP in response to progestins, suggesting that mPRs may couple to G␣i at the cell surface (126)
(Fig. 2). This G␣I linkage is consistent with observations that
progesterone-induced fish oocyte maturation is inhibited by
pertussis toxin, and therefore implicates mPR as potential
regulators of progestin-induced oocyte maturation. Accordingly, injection of antisense oligonucleotides directed against
the mPR into zebrafish oocytes attenuates progestin-induced
oocyte maturation (126).
Because mPRs seem to be important regulators of progestin-induced oocyte maturation in fish and classical PRs are
clearly not sufficient to regulate the same process in frogs,
mPR could potentially regulate progesterone-induced maturation of Xenopus oocytes. Accordingly, overexpression of
a Xenopus isoform of the mPR in oocytes slightly enhances the
rate of progesterone-mediated maturation, whereas injection
of an anti-mPR antibody inhibits progesterone-induced maturation (127). However, these results are difficult to interpret
for several reasons. First, unlike in fish, overwhelming evidence demonstrates that G␣i does not regulate steroid-
Hammes and Levin • Extranuclear Steroid Receptors
triggered Xenopus oocyte maturation (128, 129), which is
inconsistent with the known signaling properties of the
mPRs. Second, substantial evidence suggests that androgens,
rather than progesterone, mediate oocyte maturation in frogs
(see Section IV.A.1), and evidence from several laboratories
shows that mPR do not bind androgen (126, 127, 130). Thus,
a generalized role of mPR in regulating oocyte maturation
remains to be elucidated.
Interestingly, mPRs have been detected in human myometrial tissue, where progesterone also appears to lower
intracellular cAMP levels in a pertussis toxin-sensitive fashion. Progestins also activate multiple kinase cascades in myometrial cells, possibly via mPR, ultimately resulting in the
enhanced activation of the classical PRB (130). These progestin-induced signals may play a role in regulating the
quiescent vs. contractile state of the myometrium at the end
of pregnancy. Furthermore, this cross-talk suggests that, in
some instances, progesterone-mediated biological effects
may require complex signaling interactions between multiple PRs.
In contrast to the aforementioned studies, overexpression
of an ovine mPR isoform in CHO cells results in a different
phenotype (131). Here, the mPR is present almost exclusively
in the endoplasmic reticulum, and progesterone triggers intracellular calcium mobilization, presumably from the endoplasmic reticulum. Similarly, stable expression of the human mPR␣, -␤, and -␥ proteins in both HEK293 and MDAMB-231 breast cells demonstrates expression predominantly
in the endoplasmic reticulum. Surprisingly, transfection-dependent progesterone binding or progesterone-mediated
signaling was not observed in these transfected cells (132).
Together, these studies indicate that detailed characterization of the mPR family of proteins will be required to elucidate its biological importance as a bona fide membrane PR,
including specific mPR knockouts in mouse models.
b. Progesterone membrane receptor component-1 (PGMRC1).
Another rapid transcription-independent progesterone-mediated phenomenon is the acrosomal reaction in sperm (133–
135). This response occurs within seconds to minutes after
exposure to progesterone, and progesterone binding sites
have been identified on the cell surface of sperm. Some
evidence suggests that a membrane-localized progesteronebinding protein termed PGRMC1 might be binding to progesterone and in part be regulating this process; however
direct evidence supporting its role in the acrosomal response
is still forthcoming (135). PGRMC1 and its binding partner,
plasminogen activator inhibitor RNA-binding protein-1
(PAIRBP1), are also expressed in primary human granulosa/
luteal cell cultures and may play a role in regulating antiapoptotic actions of progesterone (136). Despite these intriguing observations, however, rigorous demonstration of
progesterone-mediated signaling through PGRMC1 or its
homolog PGRMC2 has yet to be described. Interestingly,
PGRMC1 is also expressed in liver microsomes, and one
study suggests that it may in fact serve as an important
cofactor for multiple cytochrome p450 enzymes (137, 138).
These results put forth the intriguing possibility that PGMRC1 may not only be a PR, but might also assist in the
Hammes and Levin • Extranuclear Steroid Receptors
recruitment of sterols and related molecules to the active sites
of cytochrome p450 enzymes.
IV. Androgen Receptors
A. Function and importance
1. Oocytes. As mentioned, the modest effects of altering expression of classical PR or mPR on progesterone-induced X.
laevis oocyte maturation suggest that alternative receptors
must be involved. In fact, these differences are not only due
to alternative receptors, but also to alternative ligands. Interestingly, Xenopus oocytes express high levels of the cytochrome p450 enzyme CYP17, which converts progestins to
androgens. Thus, exposure of oocytes to progesterone results
in its rapid metabolism to the androgen androstenedione
(139 –142). Androgens such as androstenedione and testosterone are at least as potent as progesterone in promoting
oocyte maturation in vitro. Therefore, progesterone exposure
results in steroid signaling by two agonists, a progestin and
an androgen, which likely explains the partial effects of altering PR or mPR levels on progesterone-induced maturation
in vitro.
In addition to the androgen production from exogenous
progesterone added to isolated oocytes, human chorionic
gonadotropin treatment of follicles both in vitro and in vivo
induces 10-fold more testosterone production relative to progesterone (140, 143, 144). In vivo, blockade of androgen production significantly reduces human chorionic gonadotropin-induced oocyte maturation as well as ovulation (145).
These observations suggest that, contrary to previous assumptions, androgens rather than progesterone mediate oocyte maturation in ovulating X. laevis frogs (Table 1). Evidence suggests that the classical X. laevis AR mediates
nongenomic testosterone effects in oocytes, because reduction of classical AR activity abrogates androgen-mediated
signaling and maturation (140, 141, 145).
Similar to the ER, androgens (and possibly progestins)
appear to alter G protein signaling. In this situation, however, steroids inhibit constitutive G␣s and G␤␥ signaling that
hold oocytes in meiotic arrest (129, 146 –149). Accordingly,
electrophysiological studies demonstrate that androgens
rapidly attenuate G␤␥ signaling in oocytes through interactions with the classical AR (143). This possibly occurs
through the scaffolding actions of the MNAR (Fig. 2) (150).
2. Prostate. In addition to mediating androgen-triggered oocyte maturation, MNAR may regulate AR signaling in human somatic cells. Specifically, AR or EGFR activation leads
to AR-mediated activation of Src and subsequent downstream signals in prostate cancer LnCAP cells (151–153). This
may involve a direct interaction between AR and Src, as well
as an MNAR-regulated interaction (154). Furthermore, as
seen with the ER, AR signaling appears to originate in caveolae located within the plasma membrane (155, 156). Interestingly, AR and MNAR interact in an androgen-dependent
fashion to activate Src in LnCAP cells that require androgen
for growth but constitutively interact with and activate Src
in LnCAP cells that no longer require androgen for growth
(154). This observation suggests that: 1) AR/MNAR/Src in-
Endocrine Reviews, December 2007, 28(7):726 –741 733
teractions may be very important for androgen-mediated
prostate cell growth (Fig. 2); and 2) the inevitable androgenindependent growth of prostate cancer may be due in part
to constitutive activation of Src by the AR.
3. Testes. In Sertoli cells, testosterone is important for many
functions, including tubule development, spermatid growth,
and the release of mature spermatozoa (157). Very few transcriptional targets for testosterone have been identified in
Sertoli cells, suggesting that extranuclear androgen signaling
may be important for these processes. Accordingly, testosterone rapidly activates Src in Sertoli cells by signaling via the
AR, leading to activation of the EGFR and subsequent MAPK
signaling (158, 159). These events ultimately promote longterm activation of the CREB, resulting in up-regulation of
CREB-responsive genes in Sertoli cells. Because Src and
CREB are important for spermatozoa development, we speculate that extranuclear testosterone signaling may promote
these processes, although more detailed in vivo work is
needed to prove this hypothesis.
V. Glucocorticoid Receptors
A. Function and importance
1. Pituitary. A concern regarding the physiological importance of rapid nongenomic actions of sex steroids is that
quick changes in the serum concentrations of these hormones
are uncommon in vivo. Thus, the biological need for rapid
signaling is questioned. However, one clear example of rapid
steroid effects is the immediate suppression of ACTH secretion from the pituitary in patients treated with glucocorticoids (160, 161) (Table 1). This rapid inhibition of ACTH
release appears to be mediated by classical glucocorticoid
receptors (GRs) signaling via extranuclear pathways. Treatment of human pituitary folliculostellate cells with glucocorticoid leads to rapid phosphorylation of annexin-1, followed
by its translocation to the cell membrane where it contributes
to the inhibition of ACTH secretion (162). This rapid steroid
effect is blocked by the GR antagonist mifepristone, suggesting that classical receptors may be involved. Furthermore,
glucocorticoid-induced phosphorylation and translocation
of annexin-1 appears to be mediated through activation of
the extranuclear signaling molecules PKC, PI3K, and MAPK.
2. Hippocampus. Similar to observations in the pituitary, glucocorticoids trigger rapid signaling in the hippocampus. Introduction of stress-dose concentrations (10 –100 nm) of corticosterone to mouse CA1 pyramidal cells of the
hippocampus results in a rapid increase in the frequency of
excitatory postsynaptic potentials (163). This effect appears
to be regulated via the mineralocorticoid receptor (MR)
rather than the GR. This action is lost in mice lacking mineralocorticoid receptors in the hippocampus, and synthetic
GR antagonists do not inhibit the corticosterone effects.
These observations suggest that rapid responses to stress in
the hippocampus may be related to extranuclear cortisol
signaling, although further studies are needed.
3. Cardiovascular. Administration of glucocorticoids to patients with myocardial infarction or stroke leads to a rapid
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Endocrine Reviews, December 2007, 28(7):726 –741
and transient decrease in blood pressure associated with a
concomitant increase in coronary and cerebral blood flow
(164). In mice, administration of high-dose corticosteroids
after a transient ischemic/reperfusion injury decreases vascular inflammation and myocardial infarct size (165). This
effect appears to be mediated through classical GRs, because
it is blocked both in vitro and in vivo by GR antagonists.
Similar to estrogen effects in the vasculature, glucocorticoids
rapidly activate PI3K and Akt, which leads to an increase in
NO synthase activity. Importantly, the glucocorticoid effects
are lost in mice lacking eNOS, demonstrating the importance
of this enzyme for glucocorticoid-induced vasorelaxation.
4. Immune system. Glucocorticoids are known to have suppressive effects on immune function. Although the mechanisms regulating these suppressive effects are likely multifactorial, rapid GR-mediated signaling may be playing some
role in regulating T cell function. The GR appears to associate
with the T cell receptor signaling complex, and stimulation
of T cells with dexamethasone inhibits T cell receptor signaling by disrupting the T cell receptor complex (166).
VI. Mineralocorticoid Receptors
A. Function and importance
1. Cardiovascular. Another physiological example of rapid
steroid effects is the fast-acting attenuation of baroreflex sensitivity (the change in heart rate in response to increased
systemic vascular resistance) by the mineralocorticoid aldosterone (167). Although the underlying mechanisms are not
well characterized, rapid aldosterone-mediated signaling
has been observed in cardiovascular cells. For example, aldosterone triggers a rapid flux of intracellular calcium in
VSM cells (168, 169). This mineralocorticoid-mediated effect
may occur independently of the classical MR, because the
MR antagonist spironolactone does not block the aldosterone-triggered signals. Similarly, aldosterone activates both
a rapid calcium flux and PKC-dependent activation of the
Na⫹/K⫹ pump in rabbit cardiomyocytes, effects that are also
not blocked by spironolactone (170 –172). However, the aldosterone responses in cardiomyocytes are abrogated by
another MR antagonist, RU28318; suggesting that the pharmacology of rapid classical steroid receptor signaling may
differ from that of transcriptional signaling. Thus, the role of
the classical MR in mediating these effects is still uncertain.
More importantly, the physiological relevance of these observations in the heart is somewhat clouded by the absence
of the enzyme 11␤-hydroxysteroid dehydrogenase 2 in cardiomyocytes (173). This enzyme is very important because it
converts active corticosteroids (e.g., cortisol) to inactive corticosteroids (e.g., cortisone). Serum cortisol levels are normally significantly higher than aldosterone levels, and cortisol and aldosterone bind the MR with equal affinity.
Changes in aldosterone levels would therefore be expected
to have minimal effect on cortisol-saturated MRs in cardiomyocytes. Additional in vivo studies are needed to clarify the
physiological importance of the observed in vitro effects of
aldosterone in the vasculature.
2. Kidney. In contrast to cardiomyocytes, the kidney contains
sufficient 11␤-hydroxysteroid dehydrogenase 2 to inactivate
Hammes and Levin • Extranuclear Steroid Receptors
all local cortisol; thus, MRs in the kidney are extremely sensitive to small changes in aldosterone levels. Accordingly,
aldosterone rapidly activates Na⫹/H⫹ exchange through
PKC␣ and MAPK signaling in M1 corticol-collecting ducts.
Similarly, aldosterone increases Na⫹/H⫹ exchange in cultured kidney cells and promotes intracellular calcium flux
through cross-activation of the EGFR followed by MAPK
activation (174, 175). Finally, aldosterone rapidly inhibits
bicarbonate absorption and Na⫹/H⫹ exchange in the medullary thick ascending limb in a MAPK-dependent fashion
(176). All of these effects are not blocked by spironolactone,
bringing into question (but not ruling out) the importance of
the classical MR. Interestingly, aldosterone mediates activation of Src and MAPK signaling, as well as calcium flux,
when the MR is expressed in CHO and HEK cells (170).
Although Src and MAPK activation are blocked by spironolactone in these cells, calcium flux is unaffected by the MR
antagonist. This again suggests that the pharmacology of
MISS by mineralocorticoids, as well as the receptors mediating these responses, may differ depending upon the generated signal. More complete studies using genetic knockout
models will be needed to delineate the true role of the MR
in regulating these extranuclear mineralocorticoid effects in
both vascular and kidney cells.
VII. Thyroid Hormone Receptors
A. Functions
Rapid signaling by the thyroid hormones T3 and T4 is well
established. Fast-acting thyroid-mediated modulation of ion
channel function (177), erythrocyte membrane calciumATPase activity (178), or protein kinase A activation (179) has
been known for 40 yr. Interestingly, the ␣v␤3 integrin protein
is a potential cell surface receptor for T4 (180). Signaling from
the engagement of this integrin by T4 promotes ERK activation (181) and other rapid signals (182). Such signaling may
contribute to the effects of T4 or T3 to promote angiogenesis
(183), thyroid cancer and glioma cell proliferation and survival (184, 185), neural cell migration (186), and myocardial
function (187).
As seen with steroid hormones, rapid extranuclear T4 actions at the integrin receptor promote the nuclear transcription actions of the classical thyroid hormone receptor. This
includes both the acetylation and phosphorylation of thyroid
receptor (TR) ␤ (188), perhaps leading to the phosphorylation
and displacement of corepressors (SMRT and N-CoR) from
the nuclear TR transcriptosome (188). Rapid signaling by T4
has also been reported to modify nuclear ER function, and a
cross-interaction by estrogen and thyroid hormone for transcription has been reported (189, 190).
B. Classical thyroid receptors
Evidence also exists that the classical (nuclear) TR mediates rapid signaling by thyroid hormone. TR physically associates with p85␣ and up-regulates PI3K activity in ECs
(108).
A mutant TR␤1 receptor expressed in mice conveys thyroid hormone resistance but also leads to the development of
Hammes and Levin • Extranuclear Steroid Receptors
follicular thyroid cancer (191). The cancerous cells show activation of PI3K, AKT, and the downstream targets integrinlinked kinase and mTOR-S6 kinases. Many of these signaling
molecules are thought to contribute to the developmental
biology of the thyroid cancer, because human thyroid cancer
shows AKT overexpression, and Cowden’s syndrome patients (PTEN mutation) develop thyroid neoplasms (192,
193).
In ECs, TR␣1 expression greatly exceeds TR␤1 expression,
and only TR␣1 interacts with PI3K in thyroid hormonedependent fashion (108). TR␣1 activation results in eNOS
phosphorylation and activation, leading to decreased blood
pressure due to NO production. Thyroid hormone, probably
acting through TR␣1, also stimulates cerebral blood flow and
decreases the extent and functional consequence of brain
damage in mice after focal ischemia (194). These protective
effects of T3 are diminished in either eNOS or TR␣1/TR␤
knockout mice.
It is unclear at this point whether and how classical TR␣
or TR␤ translocates to the plasma membrane to promote
signaling. Also, it is unknown whether there is cooperation
between integrin receptors and classical TR to effect rapid
signaling by T3 or T4. In various cell contexts, there may be
a range of rapid responses to thyroid hormone linked to
activation of one or more TRs.
VIII. Vitamin D Receptors
1,25-Dihydroxyvitamin D3 binds to a protein that is considered part of the steroid receptor superfamily (195). Vitamin D stimulates the rapid absorption of calcium from the
intestine in various animal models and modulates insulin
secretion from the pancreas, migration of cells, and ionchannel opening in bone cells (osteoblasts) (reviewed in Ref.
196).
Although not yet isolated from the membrane, a caveolaeenriched membrane fraction from various cell types contains
a high-affinity 1,25-vitamin D3 binding protein (197). This
protein is detected in osteoblast membrane fractions with
antibodies to the classical “nuclear” vitamin D3 receptor.
Furthermore, several groups have shown that rapid, nontranscriptional effects of 1,25-dihydroxyvitamin D3 fail to
occur in mice that either have the DNA-binding domain of
the classical vitamin D receptor deleted (198) or lack classical
vitamin D receptor altogether (197, 199). This was extended
to a patient with vitamin D-resistant rickets, whose cells
carried a vitamin D receptor mutation and lacked rapid responses (194).
Rapid extranuclear signals stimulated by vitamin D3 include c-Src, PI3K, and phospholipase C activation (200, 201).
These signals lead to VSM migration (202) and the cell survival of osteoblasts and osteocytes (201). In part, the rapid
signaling by membrane vitamin D receptors modulates transcription, as shown by rapid phosphorylation of inhibitory
␬B␣, and subsequent nuclear factor ␬B translocation to the
nucleus of leukemia cells, contributing to cell differentiation
(203).
A second putative vitamin D receptor at the membrane of
intestinal and other cell types has recently been identified
Endocrine Reviews, December 2007, 28(7):726 –741 735
(204). Designated as MARRS (membrane-associated, rapid
response steroid binding protein), this protein (also known
as Erp57) seems to play a role in phosphate and perhaps
calcium uptake/transport in intestinal cells from younger
animals. A second function for MARRS may be related to
the observation that TGF␤ stimulates the transcription of
MARRS in intestinal cells (205). Perhaps this receptor provides a means of adapting to stress during inflammation.
Detailed studies of these two putative membrane vitamin
D3 binding proteins are ongoing.
IX. Summary
The many pathways of signal transduction that result from
membrane steroid receptor function influence all cellular
processes. However, it is unlikely that MISS is primarily
responsible for modulating the fundamental processes that
cells undergo in response to steroids. Rather, it is the convergence of signals at the membrane, cytoplasm, and nucleus
that results in the integrative effects of steroid hormones. For
instance, rapid signaling through kinases modulates mitochondrial ER functions and nuclear receptor-entrained gene
transcription. Likewise, nuclear ER-modulated gene transcription promotes the synthesis of functional proteins that
constitute essential mitochondrial respiratory complexes, as
well as signaling molecules acting at the membrane.
The challenge is to model these integrative functions in
vivo and in vitro, affording a better understanding of the
kinetics and pathways of steroid function. To define cell
surface ER action better, membrane-impermeable estrogen
conjugates, such as E2-BSA and E2-horseradish peroxidase,
have been used. However, after extended exposure to living
cells, E2-BSA may dissociate into BSA and E2 (206) requiring
filtration and careful handling. Recently, dendrimeric-conjugated estrogenic compounds have been used to exclude the
steroid from the cell interior. These compounds activate kinase signaling and unique gene profiles in breast cancer cells
(207, 208). The utility of dendrimeric ER agonists is limited
at present to in vitro studies, and ER isoform-specific dendrimeric agonists and antagonists are not yet available.
If these approaches can be applied to in vivo disease, such
models might create opportunities for the design of sophisticated new “synthetic” steroids that might selectively avoid
undesirable effects but promote desirable actions. In this
way, the ability of steroids to prevent inflammation, promote
cell differentiation, and augment cell survival and proliferation (when appropriate) can be maximized. Every eukaryotic system is importantly modulated by steroids; therefore
developing compounds that selectively target human organs
is a primary goal for the near future.
Acknowledgments
Address all correspondence and requests for reprints to: Stephen R.
Hammes, M.D., Ph.D., University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390-8857. E-mail:
[email protected]; or Ellis R. Levin, M.D., Medical
Service (111-I), Long Beach VA Medical Center/University of CaliforniaIrvine, 5901 East 7th Street, Long Beach, California 90822. E-mail:
[email protected]
736
Endocrine Reviews, December 2007, 28(7):726 –741
This work was supported by grants from the Research Service of the
Department of Veterans Affairs, National Institutes of Health Grants
CA-100366 and DK59913, and Welch Foundation Grant I-1506.
Disclosure Statement: The authors have nothing to disclose.
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Endocrine Reviews is published by The Endocrine Society (http://www.endo-society.org), the foremost professional society serving the
endocrine community.
Course Title: 2nd Annual International Adrenal Cancer Symposium: Clinical and Basic Science
Course Date: March 13–16, 2008
Location:
Biomedical Science Research Building
University of Michigan Medical School
Ann Arbor, MI 48109
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http://cme.med.umich.edu/events/
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