1141
Pleiotropic Regulation of Vascular Smooth
Muscle Tone by Cyclic
GMP-Dependent Protein Kinase
Thomas M. Lincoln, Padmini Komalavilas, Trudy L. Cornwell
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Abstract Cyclic GMP (cGMP) mediates vascular smooth
muscle relaxation in response to nitric oxide and atrial natriuretic peptides. One mechanism by which cGMP decreases
vascular tone is by lowering cytosolic Ca2+ levels in smooth
muscle cells. Although mechanisms by which cGMP regulates
cytosolic Ca2+ are unclear, an important role for the cGMPdependent protein kinase in regulating Ca2+ has been proposed. Cyclic GMP-dependent protein kinase has been shown
to regulate several pathways that control cytosolic Ca2+ levels:
inositol 1,4,5-trisphosphate production and action, Ca 2+ ATPase activation, and activation of Ca2+-activated K+ channels. The pleiotropic action of cGMP-dependent protein kinase is proposed to occur through the phosphorylation of
important proteins that control several signaling pathways in
smooth muscle cells. One potential target for cGMP-dependent protein kinase is the class of okadaic acid-sensitive
protein phosphatases that appears to regulate K+ channels
among other potentially important events to reduce cytosolic
Ca2+ and tone. In addition, cytoskeletal proteins are targets
for cGMP-dependent protein phosphorylation, and it is now
appreciated that the cytoskeleton may play a key role in signal
transduction. (Hypertension. 1994;23[part 2]:1141-1147.)
I
the cAMP-dependent protein kinase, little is known of
the function of the cGMP-dependent protein kinase.
Specific substrate proteins are not well characterized in
many instances, and the precise mechanism of cGMPdependent protein kinase in the relaxation of contracted vascular smooth muscle is still unclear. This is
partly because of the complex mechanisms by which
vascular smooth muscle cells regulate contractile activity as well as the apparently less ubiquitous role of
cGMP-dependent protein kinase in the regulation of
cellular activity.
The purpose of this article is to review the role of
cGMP and cGMP-dependent protein kinase in the
regulation of vascular tone. In addition, newly emerging
roles for this enzyme in the regulation of other vascular
activity such as growth and differentiation will be addressed. The various model systems used to define the
role of cGMP-dependent protein kinase will be discussed because our current information is derived from
a collection of studies performed in a variety of systems.
n the 1970s vasodilators such as nitroglycerin and
nitroprusside were found to relax blood vessels
through the generation of cyclic GMP (cGMP) in
smooth muscle cells. 13 Studies from the laboratories of
Ignarro (Gruetter et al4) and Murad (Arnold et al5)
identified the free radical nitric oxide (NO) as the
substance derived from these drugs that elevated cGMP
by activating soluble guanylate cyclase. In 1980,
Furchgott and colleagues (Reference 6 and Cherry et
al7) discovered an endothelium-derived substance that
relaxed contracted arterial strips. This substance,
termed endothelium-derived relaxing factor (EDRF),
elevated cGMP in vascular smooth muscle. 810 The
pharmacologic similarities between NO and EDRF led
Furchgott,11 Ignarro et al,12 and Palmer et al13 to
propose that EDRF was in fact NO. Thus began one of
the most fascinating areas of not only vascular biology
but intercellular communication in general.
The role of cGMP as a mediator of NO signaling has
recently focused attention on another area of investigation established in the mid-1970s, ie, the role of cGMPdependent protein kinase and other potential cGMP
receptor proteins in cell function. Vascular smooth
muscle cells are a rich source of cGMP-dependent
protein kinase,14 a serine-threonine protein kinase selectively activated by cGMP, and a member of the large
protein kinase family (see Reference 15 for a recent
review). Cyclic GMP-dependent protein kinase is
closely related in structure and function to the cyclic
AMP (cAMP)-dependent protein kinase, but unlike
From the Department of Pathology, Division of Molecular and
Cellular Pathology, The University of Alabama at Birmingham.
Correspondence to Dr Thomas M. Lincoln, Department of
Pathology, The University of Alabama at Birmingham, Birmingham, AL 35294.
Key Words • calcium • phosphorylation • ion channels
• phosphatases • cytoskeleton • nitric oxide • atrial
natriuretic factor
Regulation of Intracellular Calcium Levels by
Cyclic GMP
Early studies on the effects of cGMP on vascular
smooth muscle relaxation were performed on isolated
arterial strips. Several of these studies indicated that a
reduction in intracellular Ca 2+ ([Ca2"1"],) produced by
cGMP was an important component of the mechanism
of cGMP-dependent relaxation because enzymes whose
activity depended on elevated [Ca2+]j (phosphorylase b
kinase and myosin light chain kinase) were inhibited
after elevation of cGMP. 1617 In the early 1980s Morgan
and Morgan18 provided direct evidence using aequorinloaded smooth muscle strips in which several vasodilators reduced [Ca2+],. Subsequently, our laboratory (see
1142
Hypertension
Vol 23, No 6, Pan 2 June 1994
examined as potential targets for cGMP action, and
these are described below.
100
80
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60
40
20
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Time, frfn
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8
FIG 1. Une graphs show effects of 8-bromo-cyclic GMP (8-BrcGMP) on [Ca 2+ ]i levels in primary cultures of rat aortic smooth
muscle cells. Cells were prepared and plated as described,">-20
grown to confluence, and loaded with fura 2. Cultures were
incubated with different concentrations of 8-Br-cGMP for 15
minutes and treated with either 10 nmol/L arglnine vasopressin
at trie 1 -minute point (top) or 35 mmol/L KCI at the 2-minute point
(bottom). Insets show peak calcium response obtained at different 8-Br-cGMP concentrations. • indicates 0 /imol/L 8-Br-cGMP;
T, 1 jimol/L 8-Br-cGMP; • , 10 Aimol/L 8-Br-cGMP; and A, 100
Mmol/L 8-Br-cGMP. Data from Cornwell and Lincoln.20
Fig 1) demonstrated using the Ca2+-sensitive fluorometric probe fura 2 that the slowly hydrolyzed analogue of
cGMP, 8-bromo-cGMP, reduced [Ca2+], in primary
cultures of arterial smooth muscle cells treated with
either angiotensin II or depolarizing concentrations of
KCI.19 These studies confirmed the hypothesis that the
reduction of [Ca2+]j plays a major role in the relaxation
process by cGMP.
The effects of cGMP to inhibit [Ca2+], mobilization
caused by agonist-evoked mechanisms (ie, inositol 1,4,5trisphosphate [IP3]) or depolarization-induced Ca2+ uptake suggested that cGMP-dependent protein kinase
may regulate several processes simultaneously to reduce
[Ca2+]|. Thus, the search for regulatory pathways regulated by cGMP-dependent protein kinase has provided
a number of candidates for proteins whose phosphorylation may be stimulated by cGMP. In addition, a
number of steps in the [Ca2+], flux pathways have been
Inhibition of IP3 Formation
It is well known that cGMP-elevating agents induce
relaxation in vascular preparations contracted with agonists more effectively than those contracted by depolarization. This has led several investigators to examine
the effect of cGMP to inhibit agonist-evoked IP3 formation. Rapoport21 first demonstrated that nitrogen oxidecontaining vasodilators inhibited inositol phosphate accumulation in contracted aortic strips. A similar
proposal for the effects of cGMP on phosphoinositide
turnover in platelets had previously been made.22 The
mechanism of this action has not been elucidated. The
inhibition of phospholipase C by cGMP-dependent protein kinase has been proposed22-23 although no direct
effect of cGMP-dependent protein kinase on the phosphorylation of purified phospholipase C forms has been
reported. Hirata et al24 and Light et al25 suggested that
cGMP-dependent protein kinase inhibits phospholipase
C activation through phosphorylation of G proteins.
Ruth et al26 demonstrated that transfected cGMPdependent protein kinase inhibited IP3 formation and
thrombin-evoked [Ca2+], mobilization in CHO cells and
suggested that cGMP-dependent protein kinase could
inhibit G protein function in CHO cells. Unfortunately,
no direct effect of cGMP-dependent protein kinase on
G protein phosphorylation has been observed despite
repeated attempts. It is likely that an indirect inhibition
of phospholipase C occurs, presumably through the
phosphorylation of a regulatory protein for phospholipase C. One potential candidate for the cGMP-dependent protein kinase-mediated inhibition of IP3 formation is the actin-binding protein VASP (vasodilatorstimulated phosphoprotein). This 46/50-kD protein is
found in platelets and smooth muscle cells, and its
phosphorylation is stimulated by both cGMP- and
cAMP-dependent protein kinase in vitro and in vivo.27-28
VASP phosphorylation is correlated with the time- and
concentration-dependent inhibition of phospholipase C
activation in platelets. The mechanism by which VASP
phosphorylation regulates platelet phospholipase C activity is unknown, but because of its cytoskeletal localization,29 it could serve to shuttle phospholipase C from
the plasma membrane to the soluble fraction of cells.
This would in effect remove the enzyme from its substrate (phosphatidylinositol 4,5-bisphosphate) in the
cell.
Inhibition of Ca2+-Activated K+ Channels
Activation of Ca2+-activated K+ channels leads to
hyperpolarization in excitable cells and inhibits Ca 2+
entry through voltage-activated Ca2+ channels. Because
depolarizing concentrations of K+ would inhibit the
gating action of the Ca2+-activated K+ channel, agents
that activate this channel would be less effective in
relaxing depolarized tissues compared with agonistactivated tissues. Early observations indicated that NO
and 8-bromo-cGMP hyperpolarized smooth muscle,
suggesting that these mediators stimulated the Ca 2+ activated K+ channel.30-31 Subsequently, cGMP-dependent protein kinase was shown to activate Ca2+-activated K+ channels in both GH,C, cells32 and vascular
smooth muscle cells.33 In the case of the GH, cell
Lincoln et al
control
8br-cGMP
Cyclic GMP and Vascular Tone
1143
8br-cGMP+
imMTEA
M 0 0 OS 1 1
20
1.0
f
MOpA
50ms
10
0.3
PKG
CTXfoatm
0.15
Po
3 11
14 19
Time(min)
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+40 mV
OmV
cAMP+cGMP
CAMP
control
_r
22
"1
1
cAMP+cGMP
•OA
10 pA
50 ms
FIG 2. Recordings show effects of cyclic GMP (cGMP) and
cGMP-dependent protein kinase on Ca2+-activated K+ channels
in GH4C, cells. Top, Cell-free patches were incubated with 100
jtmol/L 8-bromo-cGMP (8br-cGMP) in the absence or presence
of 1 mmol/L tetraethylammonium (TEA), a K+ channel blocking
agent. Tracings demonstrate opening probability of at least two
or three channels. Middle, Cell-free patches were incubated with
catalytically active monomeric fragment (14) of cGMP-dependent protein kinase in the absence or presence of 30 nmol/L
charybdotoxin (CTX), a selective inhibitor of Ca2+-activated K+
channels. Tracings demonstrate stimulatory effect of cGMPdependent protein kinase (PKG) on the channel. Bottom, Cellfree patches were incubated with 100 /xmol/L cyclic AMP (cAMP)
alone, 100 /xmol/L cAMP in the presence of 100 /imol/L cGMP,
or both cyclic nucleotides in the presence of the protein phosphatase inhibitor okadaic acid (OA, 10 nmol/L). Tracings demonstrate that cGMP reverses the inhibitory effect of cAMP on
channel opening probability and that OA completely blocks
stimulatory effects of cGMP on channel opening. Data from
White et al. 32
channel, the most dramatic effect of cGMP-dependent
protein kinase was to increase the opening probability
of the channel, and cAMP decreased the probability of
channel opening (Fig 2). Interestingly, the effect of
cGMP-dependent protein kinase to stimulate the channel was blocked with the protein phosphatase inhibitor
okadaic acid. This suggests that the channel is inactive
in the phosphorylated state, whereas cGMP-dependent
dephosphorylation increases the opening probability.
The mechanism of action of cGMP-dependent protein
kinase to activate protein phosphatase is not well understood. Direct phosphorylation of protein phosphatase 1 or 2A (the phosphatases sensitive to okadaic acid
inhibition) has not been demonstrated. Thus, as in the
case for cGMP-dependent protein kinase inhibition of
phospholipase C, the effect of kinase appears to be the
phosphorylation of a protein that leads to activation of
the protein phosphatase. There appears to be a wide
2
J0
Mnutsi
FIG 3. Line graph shows effects of atrial natriuretic peptide II
2+
(ANP II) on Ca -ATPase activity, cyclic GMP (cGMP) levels, and
phospholamban phosphorylation in cultured rat aortic smooth
muscle cells. Cells in passage 2 were preincubated with a P for
2 hours as described40 and treated with 10 nmol/L ANP II for
indicated times. Phospholamban was immunoprecipttated and
resolved by 8% to 25% sodium dodecyl sulfate-polyacrylamide
gel electrophoresis, and the phosphorylated protein was detected by autoradiography. Data for phospholamban phosphorylation are shown in the top right comer with the time of ANP II
treatment indicated. Ca2+-ATPase and cGMP were determined
in parallel cultures as described.40 Data demonstrate a transient
activation of Ca2+-ATPase, phospholamban phosphorylation,
and cGMP elevation by ANP II. Data from Cornwell et aJ.40
tissue variability with the effects of cGMP on K+
channel activity. In rat aorta, for instance, charybdotoxin, tetraethylammonium, and other K+ channel inhibitors have no effect on cGMP-induced relaxation or
on cGMP-dependent inhibition of [Ca2+], flux.34 On the
other hand, swine carotid artery relaxation, like that of
bronchiolar smooth muscle, appears to depend at least
in part on K+ channel activation.35 Thus, it appears that
the effects of cGMP on inhibition of K+ channels vary
from tissue to tissue and perhaps from species to
species.
Activation of Ca2+-ATPase Activity
Cyclic GMP has been demonstrated to decrease
[Ca2+], levels in K+-treated arterial smooth muscle cells.
Because [Ca2+]; elevations in this instance are unrelated
to generation of IP3, it has been proposed that cGMP
leads to activation of Ca2+-ATPase activity.19 Direct
demonstration of such activation has been documented
in several instances,19'36-38 but the mechanism underlying Ca2+-ATPase activation is in some cases unclear.
One potential site of action of cGMP-dependent protein kinase is the sarcoplasmic reticulum Ca2+-ATPase
regulatory protein phospholamban. cGMP-dependent
protein kinase catalyzes the phosphorylation of this
protein in vitro39 and in intact early-passaged cultured
arterial smooth muscle cells.40-41 In the latter instance,
phosphorylation was correlated with Ca2+-ATPase activation (Fig 3) and a reduction in [Ca2+]|. Because
phospholamban is a substrate for both cAMP- and
cGMP-dependent protein kinases, it has been proposed
that colocalization of cGMP-dependent protein kinase
with the sarcoplasmic reticulum is an important factor
for cGMP-dependent phosphorylation of this protein.40
1144
Hypertension
Vol 23, No 6, Part 2 June 1994
Indeed, other smooth muscle sarcoplasmic reticulum
proteins such as the IP3 receptor are also phosphorylated in vitro and in intact aortic smooth muscle cells by
cGMP.42 The significance of this effect has yet to be
determined. Further support for a role for cGMP in the
regulation of sarcoplasmic reticulum Ca2+-ATPase was
obtained by Luo et al,43 who demonstrated that inhibitors of the ATPase [thapsigargin, cyclopiazonic acid,
and 2,5-di-(terf-butyl)-l,4-benzohydroquinone] blocked
nitroglycerin and atrial peptide-induced relaxation in
the contracted rabbit aorta. Thus, in at least some
smooth muscle preparations stimulation of Ca 2+ resequestration by cGMP-dependent phosphorylation plays
a role in relaxation.
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Inhibition of IP, Receptor Activity
Several investigators have suggested that cGMP elevations inhibit the release of Ca2+ from IP3-sensitive
storage sites in smooth muscle cells.44"47 Murthy et al47
found that both cGMP and cAMP inhibited the IP3dependent increase in agonist-evoked Ca2+ transients
and suggested that cGMP-dependent protein kinase
may inhibit IP3 receptor function. Recently, our laboratory has demonstrated that the IP3 receptor purified
from cerebellum is an excellent substrate protein for
cGMP-dependent protein kinase.42 Like the cAMPdependent protein kinase, the cGMP-dependent enzyme catalyzes the phosphorylation of serine-1755 in
the protein. Supattapone et al48 suggested that the
phosphorylation of this residue by cAMP-dependent
protein kinase inhibits the capacity of IP3 to release
Ca2+ from brain microsomes. A similar situation may
exist for cGMP-dependent phosphorylation of the protein because the IP3 receptor from primary cultures of
vascular smooth muscle cells is phosphorylated in the
intact cell. However, more studies are needed to verify
this action of cGMP.
Decreased Sensitivity of Contractile Proteins
A number of studies have suggested that cGMP
inhibits the sensitivity of contractile proteins to the
effects of Ca 2+ . 4951 This would be predicted to inhibit
contractile activity even in the presence of elevated
[Ca2+]|. Unfortunately, little is known regarding the
mechanism of regulation of Ca 2+ sensitivity of contractile proteins, and few regulatory contractile proteins
have been shown to be phosphorylated using cGMPdependent protein kinase. It is conceivable that the
effects of cyclic nucleotides to decrease the sensitivity of
contractile proteins to Ca 2+ may be indirect. Perhaps as
with the activation of Ca2+-activated K+ channels, the
effects of cGMP-dependent protein kinase are related
to activation of protein phosphatases, thereby resulting
in the dephosphorylation of contractile proteins such as
myosin light chain. Clearly, more work is required to
define this potential effect of cGMP.
Pleiotropic Role of cGMP in the Regulation of
Vascular Smooth Muscle Tone
If one thing is obvious from the current literature and
from the discussion thus far, it is that cGMP and
cGMP-dependent protein kinase control several processes that regulate [Ca2+], and tone in vascular smooth
muscle. This seems appropriate in view of the fact that
smooth muscle cells must maintain an intracellular
concentration of Ca2+ of approximately 100 nmol/L
against an extracellular concentration of Ca2+ exceeding
1 mmol/L. The consequences of inefficient regulation of
[Ca2+], would be vascular hypercontractility and spasm,
vessel occlusion, decreased tissue perfusion, and eventually tissue death. In addition, the inappropriate regulation of tone in arteriolar segments would result in
increased cardiac work, leading eventually to inefficient
cardiac function and failure. Thus, redundant systems
for regulating vascular tone are essential to provide for
careful circulatory control. It is therefore expected that
the NO-cGMP signaling pathways would be involved in
a number of important control points in the regulation
of vascular tone. It is likely that vascular smooth muscle
cells derived from some vessels may rely more heavily on
one type of control system than another. In the rat
aortic smooth muscle cell, for example, cGMP-dependent protein kinase is primarily localized to the sarcoplasmic reticulum where [Ca2+], fluxes appear to be
regulated via the phosphorylation of proteins such as
the IP3 receptor and phospholamban. In other vessels
such as the carotid artery the regulation of Ca2+activated K+ channels by cGMP-dependent protein
kinase may be more important in controlling [Ca2+],.
Still, there may be mechanisms as yet not described that
are regulated by cGMP-dependent protein kinase that
may be involved in regulating contractile activity in all
smooth muscle cells. One possibility, as illustrated in
Fig 4, is the regulation of protein phosphatase activity,
' which may underlie the regulation not only of K+
channels but of phospholipase C activity, contractile
proteins, and ATPases. Such a scheme may involve the
regulation of phosphorylation of cytoskeletal proteins
that could be involved in trafficking of proteins between
the plasma membrane and cytosolic compartments.
Regulation of Vascular Smooth Muscle
Cell Proliferation
Medial layer vascular smooth muscle cells exist as
differentiated, contractile cells in blood vessels. Under
physiological stimuli (eg, angiogenesis) or pathological
situations (eg, restenosis after angioplasty), vascular
smooth muscle cells undergo waves of proliferation,
resulting in the expansion of the medial layer, or in the
case of restenosis, migration of the cells into the intimal
space of blood vessels where the cells proliferate. In
addition to proliferation, vascular smooth muscle cells
also undergo morphologic and phenotypic changes resulting in cellular dedifferentiation.52-53 These cells acquire the capacity to synthesize and secrete large
amounts of extracellular matrix proteins, which make
up a large part of the neointimal mass in restenotic
tissue. The process of proliferation and phenotypic
modulation has been studied extensively over the last
decade. Growth factors such as platelet-derived growth
factor, epidermal growth factor, and basic fibroblast
growth factor have all been implicated in the onset of
proliferation, migration, and phenotypic dedifferentiation (see Reference 54 for a review). Processes that
oppose proliferation and phenotypic modulation are
less well understood. In 1989 Garg and Hassid55-5* and
Abell et al57 demonstrated that vasodilators that elevate
cGMP inhibit cultured smooth muscle cell proliferation.
The attractiveness of this hypothesis was that endothe-
Lincoln et al
Ca - tctivttad K - dmwut
CYTOSKELETON
phcMpboburtm
tnt P3 receptor
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Ca
SARCOPLASMC RTTICULUM
FIG 4. Diagram illustrates pleiotroplc actions of cyclic GMPdependent protein kinase (cGMP-PK) In smooth muscle cells.
cGMP-dependent protein kinase, through direct phosphorylatlon
of phospholamban and the inositol 1,4,5-trisphosphate (Ins P3 on
figure) receptor could stimulate sequestration of Ca 2+ into sarcoplasmic reticulum. Likewise, cGMP-dependent protein kinase,
through phosphorylation of cytoskeletal proteins such as vasodilator-stimulated phosphoprotein (VASP), could in some undefined
manner activate protein phosphatase 2A (PP2A). Activation of
PP2A by cGMP-dependent protein kinase phosphorytation of
cytoskeletal proteins could then stimulate Ca2+-activated K+
channels and inhibit phospholipase C activity and contractile
protein function through dephosphorylation. cAMP-PK indicates
cyclic AMP-dependent protein kinase.
Hum-derived NO could contribute to smooth muscle cell
quiescence and that damage to the endothelium could
be a trigger for proliferation.
More recently, however, the role of NO in the inhibition of vascular smooth muscle cell growth has been
questioned.58 Studies from Hassid's laboratory (Cahill
and Hassid59 and Garg and Hassid60) have shown that
the effects of cGMP-elevating agents to inhibit thymidine incorporation into DNA and to inhibit proliferation may be unrelated to cGMP generation. Thus, the
high concentrations of NO-generating drugs or atrial
peptides often used in cultured cell experiments could
inhibit vascular smooth muscle cell proliferation by
nonselective mechanisms. This seems especially relevant in that passaged vascular smooth muscle cells
express very low levels of cGMP-dependent protein
kinase.20 Hence, the extremely high levels of cGMP
produced (more than 20-fold in many cases) could act
nonselectively to inhibit cell proliferation. cAMP is
known to be antiproliferative for smooth muscle cells in
vitro, so it is conceivable that high levels of cGMP could
activate cAMP-dependent protein kinase to inhibit
growth. Forte et al61 have demonstrated just such a
phenomenon in intestinal epithelial cells in which heatstable enterotoxin is capable of producing high enough
cGMP to activate the cAMP-dependent protein kinase
and stimulate Cl~ transport. Thus, the role for cGMP
Cyclic GMP and Vascular Tone
1145
and NO in regulating vascular smooth muscle cell
growth is unclear at present. It should be noted that
practically all studies of vascular smooth muscle cell
growth have used passaged cells that have already
undergone phenotypic modulation or dedifferentiation
in culture. The relevance of these models to the in vivo
situation is not established.
A more important but less thoroughly investigated
role for cGMP may be in the regulation of the smooth
muscle cell phenotype. As mentioned above, vascular
smooth muscle cells placed in culture rapidly dedifferentiate. Concurrently, the cells cease to express cGMPdependent protein kinase. Thus, evaluation of the role
of cGMP in morphologic and phenotypic events is
difficult because the cultured cells do not express the
receptor protein for cGMP. Recent studies in our
laboratory using cultured vascular smooth muscle cells
stably transfected with the cDNA encoding cGMPdependent protein kinase l a demonstrate that cGMP
evokes a morphology similar to that of contractile,
nonmodulated cells.62 Whether these cells are in fact
identical to medial layer, contractile cells is not known.
Nevertheless, this transfected cell system could represent an important model system for studying cGMPdependent protein kinase and phenotypic control in
vascular cells.
Summary and Perspective
The emergence of NO as a general paracrine regulator of cellular activity has resulted in a newly awakened
interest in the role of cGMP in cell function. Much of
the current investigation in this field is still at the level
of NO and cGMP synthesis. However, to fully appreciate and understand the variety of NO-cGMP signaling
mechanisms, it is important to understand the "downstream" effects of cGMP in cells. This means an understanding of the biologic role of cGMP-dependent protein kinase, the major receptor protein for cGMP in
cells. To date, relatively few laboratories are actively
engaged in probing the role of this enzyme in cellular
activity despite a general appreciation of its importance.
It is becoming clear that cGMP-dependent protein
kinase may control a large number of diverse cellular
activities, and thus it is rather naive to assume that any
one action of the enzyme or any one phosphorylated
protein explains its role, even in smooth muscle relaxation. Perhaps many of the targets of cGMP-dependent
protein phosphorylation may be events that have not
been biochemically elucidated, such as the activation of
protein phosphatases. In any event, the frontiers for
research in the NO-cGMP signaling pathways in cells
will include cGMP-dependent protein kinase.
Ack nowledgmen ts
Portions of this work were supported by grants from the
National Institutes of Health (HL-34646) and the National
Science Foundation (DCB 9118405) to T.M.L. T.L.C. was
supported by a Grant-in-Aid from the American Heart Association, Alabama Affiliate, Inc, and P.K. is a postdoctoral
fellow of the American Heart Association, Alabama Affiliate,
Inc.
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Abstract.
Pleiotropic regulation of vascular smooth muscle tone by cyclic GMP-dependent protein
kinase.
T M Lincoln, P Komalavilas and T L Cornwell
Hypertension. 1994;23:1141-1147
doi: 10.1161/01.HYP.23.6.1141
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