1 Department of Physiology and Cell Biology and 2 Department of Pharmacology, University of Nevada School of Medicine, Reno, Nevada 89557
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ABSTRACT |
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High voltage-activated Ca2+ channels of the CaV1.2 class (L-type) are crucial for excitation-contraction coupling in both cardiac and smooth muscle. These channels are regulated by a variety of second messenger pathways that ultimately serve to modulate the level of contractile force in the tissue. The specific focus of this review is on the most recent advances in our understanding of how cardiac CaV1.2a and smooth muscle CaV1.2b channels are regulated by different kinases, including cGMP-dependent protein kinase, cAMP-dependent protein kinase, and protein kinase C. This review also discusses recent evidence regarding the regulation of these channels by protein tyrosine kinase, calmodulin-dependent kinase, purified G protein subunits, and identification of possible amino acid residues of the channel responsible for kinase regulation.
cGMP-dependent protein kinase; cAMP-dependent protein kinase; protein kinase C; G proteins
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INTRODUCTION |
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CAV1.2
channels are members of the superfamily of voltage-dependent
Ca2+ channels that includes low voltage-activated, rapidly
inactivating channels and high voltage-activated channels. The
nomenclature for voltage-dependent Ca2+ channels has
recently changed from alphabetic descriptors, i.e., L-, N-, P/Q-, and
R-type, to names based on a system previously developed to describe
K+ channels. This system uses numerals to define families
and subfamilies of channels based on similarities in amino acid
sequences. Thus the CaV1 family includes Ca2+
channel 1-subunits encoded by four separate genes that
give rise to CaV1.1, CaV1.2,
CaV1.3, and CaV1.4 (formerly
1S,
1C,
1D, and
1F,
respectively) (see Ref. 43). This review focuses specifically on signaling pathways involved in the regulation of
cardiac and smooth muscle CaV1.2 channels.
CaV1.2 channels in both cardiac and smooth muscle
contribute to contraction by delivering extracellular Ca2+
to the cytoplasm and as a trigger for Ca2+-induced
Ca2+ release. A number of excellent reviews have been
published in recent years on Ca2+ channels (7, 37,
40, 55, 73, 74, 85, 114, 162, 163). The specific focus
of this review, therefore, is on the most recent advances in our
understanding of CaV1.2a and CaV1.2b channel
regulation in cardiac and smooth muscle by cGMP-dependent protein
kinase (PKG), cAMP-dependent protein kinase (PKA), and protein kinase C (PKC).
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STRUCTURE OF CARDIAC AND SMOOTH MUSCLE CA2+ CHANNELS |
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The Ca2+ channels examined in this review are
multisubunit protein complexes composed of a pore-forming
1-subunit and several auxiliary subunits including an
intracellularly located
-subunit and an extracellularly located,
disulfide-linked
2/
-subunit (Fig.
1). The cardiac and smooth muscle
1-subunits are splice variants of the same gene and are
designated CaV1.2a and CaV1.2b, respectively.
CaV1.2a and CaV1.2b exhibit 93% homology in
amino acid sequence. The molecular mass of each is ~240 kDa, and each
1-subunit contains ~2,170 amino acids (11, 37,
73, 81, 90, 92, 119, 160, 185). The
1-subunit
defines the ionic pore of the channel and contains four repeats, each
with six transmembrane segments. Cardiac and smooth muscle
1-subunits are distinguished by a minor difference in
the NH2 terminus, in the hydrophobic segments IS6 and IVS3,
and by an insertion in the I-II cytoplasmic linker in the smooth
muscle subunit (Fig. 1) (9, 37, 92, 119). Splice variants
of CaV1.2 have been reported to exist within a single
tissue (10, 44). An interesting new twist in the story are
recent reports suggesting that the COOH-terminal end of
CaV1.2a is cleaved in vivo but remains colocalized with the "body" of the
1-subunit. A proline-rich domain
between residues 1973 and 2001 of the
1-subunit has been
identified as the mediator of the COOH-terminal membrane association
(49, 51). Because the COOH-terminal region suppresses
CaV1.2 channel activity (182), the channel
could be regulated by changes in the association of the COOH-terminal
fragment with the body of the
1-subunit.
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Four different genes encode mammalian voltage-gated Ca2+
channel -subunits (
1-
4; Ref.
11). In addition, each of the four gene products can be
alternatively spliced, giving rise to two to four splice variants per
-subunit. Overall, these
-subunits vary from ~53 to 71 kDa (for
review, see Refs. 12 and 37). In cardiac muscle the
2-subunit predominates (49, 59, 77, 134),
whereas in smooth muscle at least three different
-subunits (i.e.,
1b,
2, and
3, 54-68
kDa molecular mass) have been identified (10, 31, 54, 77,
176). In contrast to the
1-subunit, the
-subunit does not contain putative transmembrane domains, although
there are hydrophobic regions. The
-subunit tightly binds to a
highly conserved 18-amino acid sequence in the cytoplasmic linker
between repeats I and II of the
1-subunit
(136).
-Subunits target the
1-subunit to
the plasma membrane (12, 48, 53, 196) and facilitate
CaV1.2 channel currents (12, 32, 53, 76, 122,
154). The
2a-subunit is unique in that it is
posttranslationally palmitoylated by addition of a 16-carbon palmitic
acid group to cysteine residues of the
-subunit through a labile
thioester linkage (26, 27). This palmitoylation confers
unique regulatory properties on CaV1 channels
(138), although it is uncertain whether such palmitoylated
subunits actually exist in either cardiac or smooth muscle cells.
The 2/
complex consists of an extracellularly
located
2-subunit linked via a disulfide bond to a
membrane-spanning
-subunit. The
2 and
proteins
are encoded by a single gene (35).
2/
-Subunits (~175 kDa) have been identified in both
cardiac (37, 49, 183) and smooth muscle (3).
This subunit appears to increase Ca2+ channel currents
(91, 154) but also has been associated with prevention of
prepulse facilitation (33).
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PKG REGULATION OF CA2+ CHANNELS |
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PKG catalyzes the phosphorylation of a number of intracellular proteins that modulate muscle contraction. Two main types of PKG are present in eukaryotic cells, type I and type II (104). Type I PKG is a homodimer, and each subunit has a mass of ~78 kDa. Type II PKG also exists as a dimer whose subunit mass is ~86 kDa. The regulatory and catalytic domains of this molecule are both contained within a single polypeptide sequence. PKG type I is widely distributed and is isolated from soluble extracts of tissues, whereas PKG type II is a particulate form of the enzyme and has a limited tissue distribution. PKG type I is present in both cardiac and smooth muscle cells, although the level of PKG is much greater in smooth muscle than in cardiac muscle (106). This difference is attributable to some degree to a developmental decline in PKG levels from newborn to adult heart (95).
Role of PKG in Cardiac Muscle
In cardiac muscle there is continued controversy concerning the role of the cGMP/PKG pathway in the regulation of myocardial function (94). Although a number of studies have reported cGMP/PKG-mediated inhibition of CaV1.2a channels (13, 61, 64, 82, 103, 116, 145, 169, 170, 179), others have reported the opposite effect, particularly when cAMP levels are elevated (62, 88, 96, 128, 145). However, in most cases where stimulation has been observed, the proposed mechanism was not direct PKG-mediated activation of CaV1.2a but, rather, indirect mechanisms. For example, cGMP inhibits phosphodiesterase 3 (PDE3) (177). A reduction in PDE3 activity could lead to enhanced cAMP levels and, consequently, Ca2+ channel stimulation (88, 128). However, in the case of newborn rabbit ventricular cells, the stimulatory effect of cGMP on CaV1.2a appeared to be directly related to PKG, because it was abolished by the PKG inhibitor KT-5823 but not by the PKA inhibitor 5-22 or the PDE inhibitor IBMX (96).Three different mechanisms have been suggested to account for
cGMP-induced inhibition of CaV1.2 channels, i.e.,
1) direct phosphorylation of the channel by PKG,
2) PKG-induced activation of a phosphatase, leading to
dephosphorylation of the channel, and 3) cGMP
stimulation of phosphodiesterase 2 (PDE2), leading to a reduction in
cAMP levels. The implication of the second and third possibilities
listed is that cGMP reduces the phosphorylation of CaV1.2
produced by PKA. Each of these possibilities is discussed below and is
illustrated in Fig. 2.
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Evidence to support the notion that PKG directly phosphorylates
Ca2+ channels has been derived from functional studies of
CaV1.2a channels expressed in oocytes (82). In
this study, PKG was activated by addition of the membrane-permeant
species 8-bromoguanosine 3',5'-cyclic monophosphate (8-Br-cGMP). This
cyclic nucleotide inhibited wild-type Ca2+ channel
currents. In contrast, when serine residue 533 of the 1-subunit was replaced with alanine, 8-Br-cGMP no longer
had an effect on channel activity, suggesting that PKG produces
inhibition by phosphorylating the channel at serine 533 (82). The actions of 8-Br-cGMP appeared to be independent
of either the
- or the
2/
-subunit of
CaV1.2a because inhibition still occurred in the absence of
these subunits.
Protein phosphorylation represents a balance between kinase and phosphatase activity. Thus second messenger pathways that modify this balance can upregulate or downregulate channel activity to meet physiological demands. An additional mechanism by which PKG, in particular, could inhibit Ca2+ channel activity is through stimulation of phosphatase activity, leading to dephosphorylation of the channel. When inhibitors of either protein phosphatase 1 (PP1) or 2A (PP2A) are applied to cardiac myocytes, Ca2+ channel stimulation generally has been observed, suggesting that there is both basal phosphorylation and dephosphorylation of the channel (for review, see Ref. 69). The notion that PKG may exert its effect by activating a phosphatase is not new. Smooth muscle myosin phosphatase is a known target of PKG, and activation of this phosphatase contributes to the well-known phenomenon of myofilament "desensitization" (72, 180). In addition, there is evidence suggesting that the actions of cGMP on Ca2+-activated K+ channels in rat pituitary tumor cells are due to PKG-induced stimulation of PP2A (187). In a more recent study, 8-Br-cGMP was reported to inhibit IBMX-stimulated Ca2+ channel currents in guinea pig ventricular myocytes, and this effect was abolished by the type 1 and 2A phosphatase inhibitor okadaic acid, leading to the conclusion that PKG inhibited the channels by activation of a phosphatase (145).
Another means by which Ca2+ channel phosphorylation could be reduced is to increase the rate of breakdown of cAMP by PDEs. A number of different isoenzymes of PDEs exist in cells, and these have been subdivided into seven families. At least four of these families (i.e., PDE1-4) are present in cardiac muscle (177). PDE1 and PDE2 hydrolyze both cAMP and cGMP, whereas PDE3 and PDE4 hydrolyze cAMP. PDE2 is stimulated by cGMP, whereas PDE3 is inhibited by cGMP and PDE4 is insensitive to cGMP (135). In some tissues, cGMP may stimulate CaV1.2a channel currents via inhibition of PDE3 (88, 128), whereas in others, cGMP may inhibit CaV1.2a channel current by stimulating PDE2 (45, 117). This opposing effect of cGMP on PDE2 vs. PDE3 serves to underscore the complexity of interpreting studies in which cGMP is applied to cells.
Role of PKG in Smooth Muscle
In contrast to its role in cardiac muscle, the role of PKG as an important mediator of vascular relaxation is well established (for review, see Ref. 19), particularly with regard to the actions of the endothelium-relaxing factor nitric oxide (NO) and nitrovasodilators such as sodium nitroprusside. PKG reduces cytoplasmic Ca2+ concentration via several mechanisms, and a number of studies suggest that one of these mechanisms is the inhibition of CaV1.2b channels. For example, CaV1.2b currents are reduced by NO and by NO donors such as sodium nitroprusside and by the membrane-permeable analog 8-Br-cGMP (1, 14, 80, 93, 109, 111, 139, 144, 167, 195). Current inhibition is reversed with PKG blockers (144, 167). However, the mechanism by which PKG reduces CaV1.2b channel activity is still unknown. Mutation experiments such as those described for theThe notion that PKG inhibits CaV1.2b via the activation of a phosphatase is an intriguing one. Application of inhibitors that block both PP1 and PP2A (e.g., okadaic acid and calyculin A) have generally increased Ca2+ channel activity (46, 56, 100, 123, 124), suggesting that basal channel activity is determined by a balance of kinase and phosphatase activity. Some studies in smooth muscle have directly applied activated phosphatases to isolated patches or to the whole cell via cell dialysis. These studies have generally revealed inhibition of channel activity, i.e., the opposite effect [e.g., PP2A application (56, 70) or PP2B application (148)]. To date, there have been no studies directly linking activation of a phosphatase to the PKG-induced inhibition of CaV1.2b channels observed in smooth muscle.
Five of the seven PDE isoenzyme families have been identified in vascular smooth muscle, including PDE1-4 and PDE5, which is a cGMP-hydrolyzing PDE (for review, see Ref. 135). PDE3 accounts for approximately half of the cAMP-hydrolyzing activity in the pulmonary artery and aorta (140, 141). To date, there are no studies investigating the possible role of cGMP activation of PDE2 to account for the inhibitory effect of cGMP on CaV1.2b.
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PKA REGULATION OF CA2+ CHANNELS |
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PKA is a tetramer consisting of two catalytic subunits bound to a regulatory subunit dimer. Like PKG, PKA is ubiquitously expressed in smooth muscle and cardiac muscle. Initially, two different forms of the regulatory subunit were defined, i.e., R-I and R-II, where the PKA-RI complex is essentially cytosolic and the PKA-RII complex almost exclusively membrane bound. However, recent molecular cloning techniques have revealed significant heterogeneity in both the catalytic and regulatory subunits of PKA (165).
Role of PKA in Cardiac Muscle
The cardiac CaV1.2a channel has long been recognized as a target of the adenylyl cyclase/PKA pathway. Stimulation of
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Additional complications have arisen in attempts to demonstrate a
functional correlate of PKA-induced phosphorylation in expression systems. Although some studies have reported PKA-induced stimulation of
cardiac CaV1.2a currents (50, 90, 150, 199,
202), others have failed to show any effect of PKA (33,
118, 209). A variety of explanations have been offered for the
negative results, including the importance of auxiliary subunits,
particularly the -subunit (90) and, more recently, the
need for channel targeting of PKA by AKAP (50). One report
suggested that an additional, as yet unidentified, component of the
pathway is important for PKA-induced regulation of the Ca2+
channel, because PKA failed to stimulate CaV1.2a channels
unless oocytes were injected with mRNA from cardiac cells
(23). Yet another study suggested that PKA leads to
phosphorylation of a 700-kDa protein that couples to the cardiac
-subunit (60). Despite studies that suggest an
obligatory role for additional regulatory subunits, several studies
have reported PKA-induced enhancement of expressed
1-subunits of CaV1.2a in the absence of
other regulatory proteins (150, 202). In summary, evidence exists in both native cells and expression systems to suggest that PKA
can stimulate cardiac CaV1.2a channels via direct
phosphorylation of serine 1928 on the
1-subunit.
However, additional sites appear to contribute to this process. The
variable results reported from expression systems may be related to
differences in the cell types used, differences in the regulatory
proteins coexpressed with the
1-subunit, and the
activity of other enzymes in the cells (e.g., PDEs, phosphatases) that
modify the basal levels of phosphorylation of the channel. Indeed, in
some studies, although activated PKA was reported to be without effect
on channel activity, inhibition of endogenous PKA decreased channel
activity, suggesting that the CaV1.2a channels were
maximally phosphorylated under basal conditions (131, 132,
159).
Role of PKA in Smooth Muscle
In contrast to the general agreement concerning the actions of the adenylyl cyclase/PKA pathway on cardiac CaV1.2a channels, the details of how PKA modulates CaV1.2b channels in smooth muscle, and, indeed, even the direction of this modulation has remained somewhat controversial. Over the past 12 years, the adenylyl cyclase/PKA pathway has been reported to inhibit (109, 161, 195), to enhance (47, 80, 84, 93, 113, 144, 151, 164, 166, 206), or to have no effect (121, 127, 184) on smooth muscle CaV1.2b channels. However, a preponderance of recent evidence has gradually accumulated to suggest that PKA can modulate smooth muscle CaV1.2b channels in a similar manner to that described for cardiac CaV1.2a channels. Specifically, studies of various smooth muscle cells have shown that 1) the membrane-permeable analog 8-Br-cAMP enhances CaV1.2b channel currents (80, 144), an effect blocked by PKA inhibitors (87, 206); 2) the adenylyl cyclase activator forskolin enhances CaV1.2b channel currents (80, 151), an effect blocked by PKA inhibitors (200); 3) activation of adenylyl cyclase with isoproterenol enhances CaV1.2b channel currents (80, 93, 151, 161, 194), an effect blocked by PKA inhibitors (206); 4) activation of adenylyl cyclase with the G protein subunit GThe stimulatory effect of PKA on cardiac CaV1.2a channels
corresponds well with the known positive inotropic effect of
-adrenoceptor stimulation in this muscle. However, in smooth muscle,
agonists that activate adenylyl cyclase typically cause relaxation,
making it more difficult to reconcile a stimulatory effect of PKA on CaV1.2b currents. It is possible that the Ca2+
entry associated with PKA stimulation is specifically targeted to
events that are unrelated to global cytoplasmic Ca2+
concentration; e.g., an increase in the subsarcolemmal Ca2+
concentration may be coupled to enhancement of
Ca2+-activated K+ channel activity
(57). Alternatively, the enhanced Ca2+ entry
may serve to fill stores in the sarcoplasmic reticulum (SR).
Some of the controversy surrounding the actions of cAMP on
CaV1.2b channels may be related to the higher levels of PKG
present in smooth muscle compared with cardiac muscle
(106). Neither cAMP nor cGMP display absolute specificity
for their respective kinases, i.e., the equilibrium dissociation
constant for activation of PKG by cAMP is ~10-fold greater than that
for PKA (see, for example, Ref. 39). Thus some of
the actions of cAMP that have been attributed to PKA on
CaV1.2b channels may, in fact, be due to PKG. In support of
this hypothesis are studies showing that higher concentrations of
8-Br-cAMP and forskolin lead to inhibition of CaV1.2b
channel currents and that this effect is blocked by PKG inhibitors
(80, 144). These data suggest that CaV1.2b
channels can be inhibited by "cross-over" activation of PKG by
cAMP. Cross-over activation of PKG by cAMP also has been proposed by
others to contribute to the effects of cAMP (see, for example, Refs.
105 and 186). Interestingly, in the presence of PKG
inhibitors the reverse cross-over activation can be demonstrated as
well, i.e., cGMP activation of PKA, leading to stimulation of
CaV1.2b channel current (144). A similar
action of cGMP on PKA has been proposed to underlie the NO-induced
relaxation in PKG-I-deficient mice (146). This "cross
talk" between cyclic nucleotides and protein kinases is illustrated
in Fig. 4.
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Only one study to date has demonstrated enhancement of
CaV1.2b channel currents with raised cAMP in an expression
system (90). In this study, the 1-subunit
of CaV1.2b was coexpressed with the skeletal muscle
1a-subunit. cAMP produced current stimulation only in
the presence of the
-subunit. The authors suggested that the kind of
-subunit present in a tissue may underlie tissue-specific effects of
cAMP/PKA. However, other
-subunits (e.g.,
2 or
3) were not tested in this study. A recent study of A7r5
cells also suggests that cAMP-dependent stimulation of the channel
requires a functional
-subunit (87). Two other studies
have failed to show enhancement of the CaV1.2b
1-subunit by cAMP/PKA in an expression system (89,
209). In one case the
1-subunit was expressed with
2- and
2/
-subunits in HEK-293
cells (209), and in the other case the
1-subunit was expressed alone in Chinese hamster ovary
cells (89). This variability between studies of expressed smooth muscle CaV1.2b channels is similar to the
variability reported for the actions of PKA on expressed cardiac
CaV1.2a channels.
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PKC REGULATION OF CAV1.2 CHANNELS |
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Eleven isoforms of PKC have been identified in mammalian tissues,
and these are divided into three groups: 1) classic or
conventional PKCs (cPKC) that are activated by diacylglycerol or
phorbol ester and are Ca2+ sensitive (including ,
I,
II,
), 2) novel or new PKCs (nPKC) that are activated
by diacylglycerol or phorbol ester but are not Ca2+
dependent (
,
,
,
, L, µ), and 3) atypical PKCs
(aPKC) that are not activated by diacylglycerol, phorbol ester, or
Ca2+ (
/
,
) (for review, see Ref. 75).
Role of PKC in Cardiac Muscle
In cardiac muscle PKC phosphorylates a variety of different proteins that contribute to myocardial excitability and contraction. Among these is the CaV1.2a channel. Both theRole of PKC in Smooth Muscle
PKC has been reported to enhance CaV1.2b channel currents in various smooth muscle preparations (28, 101, 102, 125, 147, 152, 175, 178, 205). As with CaV1.2a, stimulation of CaV1.2b is sometimes followed by current inhibition (147). A number of different agonists, including norepinephrine, endothelin, angiotensin II, and serotonin, have been suggested to stimulate CaV1.2b channels via a PKC-dependent mechanism (for review, see Ref. 55). Because agonists that activate PKC often produce inositol 1,4,5-trisphosphate-induced release of Ca2+ from the SR, the PKC-induced channel stimulation can be masked by Ca2+-induced inactivation of channels (71, 86). Little is known about the mechanisms underlying CaV1.2b channel modulation by PKC. ![]() |
G PROTEIN SUBUNIT REGULATION OF CAV1.2 CHANNELS |
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The PKA and PKC pathways discussed above are generally linked to
agonist-induced activation of G protein subunits. Activated G protein
subunits can regulate different ionic channels not only through
intracellular second messenger pathways but also through a direct
membrane-delimited gating of channels. For example, neuronal CaV2.2 channels (formerly N-type or 1B) are
inhibited by G protein-activated PKC and by the direct binding of
G
to the
1-subunit (78). Direct
G
binding takes place in the intracellular loop between repeat I
and II as well as in a second downstream sequence (38). However, the requisite binding motif for this interaction is absent in
CaV1.2 channels. In the case of CaV1.2
channels, evidence has been presented to suggest a direct
membrane-delimited activation of CaV1.2a and
CaV1.2b channels by the G protein subunit
G
s; however, these effects are controversial (29,
170).
Role of G Protein Subunits in Cardiac Muscle
The first evidence suggesting a direct membrane-delimited action of GRecent studies have provided further evidence for a membrane-delimited
gating of CaV1.2a by Gs subunits. The whole
cell Ca2+ channel current in cardiac myocytes from
transgenic mice overexpressing cardiac G
s is 490%
higher than in cells from wild-type control animals (98).
Furthermore, in Xenopus oocytes, antisense knockdown of
endogenous G
s reduced currents of expressed
CaV1.2a channels, whereas coexpression of G
s
with CaV1.2a enhanced currents (15). Interestingly, PKA inhibitors did not have any detectable action on the
effects of G
s in either the transgenic mice or the
oocyte model. In fact, a small cAMP-dependent decrease of current was observed in oocytes coexpressed with CaV1.2a and the
2-adrenergic receptor (15). The authors
concluded that coexpression of G
s, but not its acute
activation via
-adrenergic receptors, enhances CaV1.2a
currents via a PKA-independent pathway. A recent study of
CaV1.2a and
2-subunits expressed in Chinese
hamster fibroblasts with
-adrenoceptors also suggested the presence
of an additional cAMP-independent mechanism of channel activation
(198). Thus controversy continues to surround the
issue of direct membrane-delimited effects of G
s on
CaV1.2a, although a high-affinity binding site for
G
s on CaV1.2a has yet to be identified.
In our recent studies of G protein activation of native guinea pig
cardiac CaV1.2a channel currents, we did not obtain any evidence to suggest the presence of a direct membrane-delimited pathway
for either Gs or G
activation of the channel
(208). Rather, the pathways involved appeared to be very
similar in nature to those described below for G protein regulation of
smooth muscle CaV1.2b channels (see also Ref.
205 as well as Fig. 3), leaving open the possibility that
the PKA-independent effect of
-adrenergic stimulation in cardiac
myocytes identified by others may actually be due to G
-induced
activation of PKC, rather than to a direct membrane-delimited effect of
G
s.
Role of G Protein Subunits in Smooth Muscle
In 1994, Xiong and colleagues (195) reported that dialysis of cells with activated G ![]() |
REGULATION OF CAV1.2 CHANNELS BY OTHER KINASES |
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Recent studies suggest that the activity of CaV1.2 channels in cardiac and smooth muscle cells also is regulated by other kinases, especially by protein tyrosine kinase (PTK) and calmodulin-dependent kinase (CaMK). Although this review focuses mainly on CaV1.2 channel regulation by PKG, PKA, and PKC, a summary of recent reports of channel regulation by PTK and CaMK follows.
Role of PTK
Tyrosine phosphorylation is an important regulator of cell function not only for growth-related responses such as gene transcription and cell division but also for rapid cellular responses such as cell adhesion and muscle contraction. Early studies on possible regulation of cardiac Ca2+ channels by PTK indicated that genistein, a specific PTK inhibitor, dose-dependently reduced CaV1.2 channel currents in rat (201) and guinea pig ventricular myocytes (25). However, in these studies, daidzein, an inactive analog of genistein, exerted the same inhibitory effect on Ca2+ channel current as genistein. In contrast, several other studies have reported inhibition of Ca2+ channel currents with PTK blockers that was not mimicked by daidzein (126, 181). In feline atrial myocytes, genistein was reported to have a biphasic effect on Ca2+ channel currents when examined with the whole cell perforated-patch recording method (181). Both inhibition and stimulation with genistein were not mimicked by daidzein but were abolished by the tyrosine phosphatase inhibitor vanadate. Interestingly, current stimulation was absent when the conventional whole cell patch recording method was used. The authors concluded that genistein inhibits Ca2+ channel current by blocking membrane-bound PTKs and stimulates Ca2+ channel current by blocking cytosolic PTKs. Others have reported that PTK inhibition leads only to current stimulation and have suggested a PKC-dependent mechanism (16). A recent report further proposes that PTK also may directly antagonizeEvidence that vascular CaV1.2b channels are regulated by PTK also has been provided. Wijetunge et al. (188) reported that CaV1.2b current in rabbit ear artery myocytes was significantly reduced by both genistein and tyrphostin 23 but not by daidzein. Inhibition of tyrosine phosphatases (190) or activation of endogenous c-Src tyrosine kinase (189) increased current in the same cell preparation. PTK inhibitors antagonized these stimulatory effects, suggesting a possible role for endogenous c-Src tyrosine kinase in the modulation of vascular Ca2+ channels (189, 191). In rat portal vein myocytes, genistein also reduced whole cell Ca2+ channel currents, whereas daidzein was without effect (107). Further studies of these cells revealed that genistein also decreased the mean open time and prolonged closed time of single channels (108).
Although the evidence to date suggests a possible role of PTK in the
regulation of CaV1.2 channels, no studies have yet extended this work to PTK regulation of expressed cardiovascular
CaV1.2 channels. A recent study of neuronal
CaV1.2 channels indicated that potentiation of current by
insulin-like growth factor 1 required phosphorylation of the
1-subunit by PTK (8). It is possible that
PTK phosphorylates a similar site on the
1-subunit of
cardiovascular CaV1.2 channels.
Role of CaMK
Ca2+-dependent inactivation and facilitation of CaV1.2 channels are well-known phenomena, and both forms of channel autoregulation appear to involve calmodulin (CaM). A number of different studies suggest that CaMK may be responsible for the positive-feedback, Ca2+-dependent facilitation of CaV1.2 channels (42, 168, 192, 203). An early study by Yuan and Bers (203) indicated that repetitive membrane depolarization fromIn contrast to CaM-dependent facilitation, some studies have proposed
that CaM-dependent inactivation may result from channel dephosphorylation by the CaM-dependent phosphatase calcineurin (4, 21, 148). On the other hand, others have proposed that CaM directly interacts with the Ca2+ channel
1-subunit and that channel phosphorylation is not
involved (see, for example, Refs. 129, 133,
142, and 211). Some studies have gone so far as to
suggest that direct binding of CaM to the
1-subunit is a
key step in both Ca2+-dependent inactivation and
facilitation of CaV1.2 channels. Recently, it has been
shown that mutations in a consensus CaM-binding IQ motif in the
COOH-terminal tail of
1 eliminates both forms of Ca2+-dependent automodulation of Ca2+ channels
(210, 211). Whether this direct interaction between CaM
and the channel
1-subunits is sufficient to induce both
Ca2+-dependent inactivation and facilitation requires
further study, as does the question of the role of CaMK in the process
of autoregulation.
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ACKNOWLEDGEMENTS |
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We thank Dr. James Kenyon for careful reading of this manuscript and valuable suggestions.
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FOOTNOTES |
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This work was supported by National Heart, Lung, and Blood Institute Grants HL-40399 (to K. D. Keef and J. R. Hume) and HL-49254 (to J. R. Hume) and by an American Heart Association Western Affiliate Grant-in-Aid (to J. Zhong).
Address for reprint requests and other correspondence: K. Keef, Dept. of Physiology and Cell Biology/MS 352, Univ. of Nevada School of Medicine, Reno, NV 89557 (E-mail: kathy{at}physio.unr.edu).
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