INVITED REVIEW
Regulation of cardiac and smooth muscle Ca2+ channels (CaV1.2a,b) by protein kinases

Kathleen D. Keef1, Joseph R. Hume1,2, and Juming Zhong2

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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INTRODUCTION
STRUCTURE OF CARDIAC AND...
PKG REGULATION OF CA2+...
PKA REGULATION OF CA2+...
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REGULATION OF CAV1.2 CHANNELS...
REFERENCES

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


    INTRODUCTION
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ABSTRACT
INTRODUCTION
STRUCTURE OF CARDIAC AND...
PKG REGULATION OF CA2+...
PKA REGULATION OF CA2+...
PKC REGULATION OF CAV1.2...
G PROTEIN SUBUNIT REGULATION...
REGULATION OF CAV1.2 CHANNELS...
REFERENCES

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 alpha 1-subunits encoded by four separate genes that give rise to CaV1.1, CaV1.2, CaV1.3, and CaV1.4 (formerly alpha 1S, alpha 1C, alpha 1D, and alpha 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).


    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 alpha 1-subunit and several auxiliary subunits including an intracellularly located beta -subunit and an extracellularly located, disulfide-linked alpha 2/delta -subunit (Fig. 1). The cardiac and smooth muscle alpha 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 alpha 1-subunit contains ~2,170 amino acids (11, 37, 73, 81, 90, 92, 119, 160, 185). The alpha 1-subunit defines the ionic pore of the channel and contains four repeats, each with six transmembrane segments. Cardiac and smooth muscle alpha 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 alpha 1-subunit. A proline-rich domain between residues 1973 and 2001 of the alpha 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 alpha 1-subunit.


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Fig. 1.   Model of the cardiac and smooth muscle CaV1.2 channel (alpha 1) and associated auxiliary subunits. In addition to the pore-forming alpha 1-subunit, there is an intracellularly localized beta -subunit and an extracellularly located, disulfide-linked alpha 2/delta -subunit. Sites of divergence between the cardiac and smooth muscle alpha 1-subunits are indicated at the NH2 terminus, in the hydrophobic segments IS6 and IVS3 and by an insertion between I and II cytoplasmic linker. Evidence points to a functional role for cGMP-dependent protein kinase (PKG) phosphorylation of CaV1.2a at serine 533 (82). The same PKG phosphorylation site exists in CaV1.2b (i.e., serine 528). Evidence also suggests a functional role for cAMP-dependent protein kinase (PKA) phosphorylation of CaV1.2a at serine 1928 (34, 50, 131). The same PKA phosphorylation site exists in CaV1.2b (i.e., serine 1923). Additional studies suggest that phosphorylation of serine residues 478 and 479 on the beta 2a-subunit also are involved in functional regulation of channels by PKA (18). Although ~18 potential protein kinase C (PKC) phosphorylation sites exist on the alpha 1-subunit, no studies to date have clearly identified a role for these sites in channel activation. However, recent studies suggest that threonine-27 and threonine-31 on CaV1.2a are involved in PKC-induced inhibition of the channel (115). These sites are not present on CaV1.2b.

Four different genes encode mammalian voltage-gated Ca2+ channel beta -subunits (beta 1-beta 4; Ref. 11). In addition, each of the four gene products can be alternatively spliced, giving rise to two to four splice variants per beta -subunit. Overall, these beta -subunits vary from ~53 to 71 kDa (for review, see Refs. 12 and 37). In cardiac muscle the beta 2-subunit predominates (49, 59, 77, 134), whereas in smooth muscle at least three different beta -subunits (i.e., beta 1b, beta 2, and beta 3, 54-68 kDa molecular mass) have been identified (10, 31, 54, 77, 176). In contrast to the alpha 1-subunit, the beta -subunit does not contain putative transmembrane domains, although there are hydrophobic regions. The beta -subunit tightly binds to a highly conserved 18-amino acid sequence in the cytoplasmic linker between repeats I and II of the alpha 1-subunit (136). beta -Subunits target the alpha 1-subunit to the plasma membrane (12, 48, 53, 196) and facilitate CaV1.2 channel currents (12, 32, 53, 76, 122, 154). The beta 2a-subunit is unique in that it is posttranslationally palmitoylated by addition of a 16-carbon palmitic acid group to cysteine residues of the beta -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 alpha 2/delta complex consists of an extracellularly located alpha 2-subunit linked via a disulfide bond to a membrane-spanning delta -subunit. The alpha 2 and delta  proteins are encoded by a single gene (35). alpha 2/delta -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).


    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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Fig. 2.   Mechanisms proposed for cGMP-induced inhibition of CaV1.2 channels. In this schematic, guanylyl cyclase (G cyclase) is activated by nitric oxide (NO) to give rise to an increase in cGMP levels. cGMP then activates PKG to directly phosphorylate the alpha 1-subunit of the Ca2+ channel. Another possibility is that PKG activates a protein phosphatase (PP), which then dephosphorylates the channel. Finally, cGMP may stimulate phosphodiesterase 2 (PDE2), which reduces cAMP levels and thus reduces stimulation of the channel by PKA. AKAP, A-kinase anchoring protein; A cyclase, adenylyl cyclase.

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 alpha 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 beta - or the alpha 2/delta -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 the alpha 1-subunit of CaV1.2a (82) have yet to be repeated for CaV1.2b.

The 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.


    PKA REGULATION OF CA2+ CHANNELS
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INTRODUCTION
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PKG REGULATION OF CA2+...
PKA REGULATION OF CA2+...
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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 beta -adrenoceptors leads to enhanced single-channel activity as well as a three- to sevenfold increase in whole cell current in cardiac cells (114, 150, 171, 173) (see Fig. 3). Recent reports suggest that beta 1-adrenergic receptors, which couple exclusively to the G protein Gs, produce a more widespread increase in cAMP levels in the cell (i.e., diffuse activation), whereas beta 2-adrenergic receptors, which can be coupled to both Gs and Gi, produce a more localized activation of CaV1.2a channels (24). Early studies directed toward determining whether PKA phosphorylates CaV1.2 channels were complicated by the fact that the majority of biochemically isolated alpha 1-subunits undergo a proteolytic cleavage that removes a substantial portion of the COOH-terminal tail (22, 36, 68, 99, 202). In 1992, Yoshida and coworkers (202) showed that PKA-induced phosphorylation occurred in the 250-kDa form of the alpha 1-subunit but not in the truncated 200-kDa form. Later studies confirmed the importance of the COOH-terminal tail and identified serine 1928 as the site of PKA-induced phosphorylation (34, 50, 68, 120, 131). Interestingly, although the COOH-terminal of the alpha 1-subunit is cleaved, Hosey and colleagues (49, 51) have provided evidence that the cleaved portion of the alpha 1-subunit remains associated with the "body" and thus may still be involved in PKA-induced regulation of the channel. Other studies have shown that the cardiac beta -subunit also is phosphorylated during activation of the adenylyl cyclase/PKA pathway (50, 58, 137), and the sites of phosphorylation appear to be three loose consensus sites for PKA in the COOH terminus rather than the two strong consensus sites identified for PKA (52). In a later study, two of these three sites (i.e., serine-478 and serine-479) were shown to be critical for PKA-induced regulation of the alpha 1-subunit (18). The relative contribution of the alpha 1- vs. beta 2-subunit phosphorylation to PKA regulation of CaV1.2a in vivo has yet to be determined and, indeed, may change with development and/or other conditions present in the cell. There are reports that PKA-induced phosphorylation of the alpha 1-subunit is dependent on localizing PKA to the vicinity of the channel via A-kinase anchoring protein (AKAP) (Fig. 3), whereas phosphorylation of the beta 2a-subunit does not require AKAP (50). However, another study failed to reproduce a PKA-dependent increase in current amplitude in HEK-293 cells expressing the cardiac alpha 1- and beta 2a-subunits, even when these subunits were coexpressed with AKAP79 (33).


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Fig. 3.   Mechanisms proposed for beta -adrenergic stimulation of CaV1.2 channels. beta -Adrenergic receptors (beta -AR) are stimulated with agonists such as isoproterenol. The beta -receptor is coupled to the G protein Gs, which leads to activation of the G protein subunits Galpha s and Gbeta gamma . Galpha s stimulates A cyclase, leading to enhanced levels of cAMP that activate PKA localized to the region of CaV1.2 via an AKAP. PKA is then proposed to activate the Ca2+ channel via phosphorylation of one or more of the Ca2+ channel subunits. In contrast, Gbeta gamma is proposed to lead to stimulation of PKC, possibly via phosphatidylinositol 3-kinase, leading to phosphorylation of 1 or more of the Ca2+ channel subunits. Finally, evidence exists for direct activation of CaV1.2 via a direct membrane-delimited action of Galpha s on the channel.

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 beta -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 beta -subunit (60). Despite studies that suggest an obligatory role for additional regulatory subunits, several studies have reported PKA-induced enhancement of expressed alpha 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 alpha 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 alpha 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 Galpha s enhances CaV1.2b currents (193, 205), an effect blocked by PKA inhibitors (205); 5) the catalytic subunit of PKA enhances whole cell CaV1.2b currents, an effect blocked by PKA inhibitors (144); and 6) application of the catalytic subunit of PKA to the cytosolic surface of inside-out patches increases the open probability of CaV1.2b channels (166). In addition, the smooth muscle alpha 1-subunit shares 93% homology with the cardiac alpha 1-subunit (92, 185) and contains the same consensus PKA phosphorylation site (73). Also, as in cardiac muscle, there is evidence that the actions of PKA on CaV1.2b channels requires targeting via an AKAP (206). All of these observations strongly suggest that PKA is likely to have a similar action on both CaV1.2b and CaV1.2a channels (Fig. 3). However, the response to PKA differs in two respects. First, most studies to date have not reported a significant effect of cAMP on the shape of the current-voltage (I-V) relationship of CaV1.2b channels in smooth muscle cells (80, 151). In contrast, a number of studies of cardiac muscle have noted a shift to the left of the I-V relationship with cAMP (see, for example, Ref. 6). Second, the cAMP pathway in cardiac muscle leads to a 3- to 7-fold increase in CaV1.2 channel currents, whereas in smooth muscle the stimulation is more modest, i.e., ranging between a 0.5- and 2-fold increase.

The stimulatory effect of PKA on cardiac CaV1.2a channels corresponds well with the known positive inotropic effect of beta -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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Fig. 4.   Mechanisms proposed for cGMP stimulation and cAMP inhibition of CaV1.2 channels (red arrows). Cross talk between the cyclic nucleotides may lead to cAMP-induced activation of PKG to inhibit the channel or cGMP-induced activation of PKA to stimulate the channel. Cross talk is more likely to occur when higher levels of cyclic nucleotide are achieved in the cell. Finally, cGMP also has been reported to inhibit PDE3, which leads to an increase in cAMP levels and, hence, stimulation of the channel via PKA.

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 alpha 1-subunit of CaV1.2b was coexpressed with the skeletal muscle beta 1a-subunit. cAMP produced current stimulation only in the presence of the beta -subunit. The authors suggested that the kind of beta -subunit present in a tissue may underlie tissue-specific effects of cAMP/PKA. However, other beta -subunits (e.g., beta 2 or beta 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 beta -subunit (87). Two other studies have failed to show enhancement of the CaV1.2b alpha 1-subunit by cAMP/PKA in an expression system (89, 209). In one case the alpha 1-subunit was expressed with beta 2- and alpha 2/delta -subunits in HEK-293 cells (209), and in the other case the alpha 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.


    PKC REGULATION OF CAV1.2 CHANNELS
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PKG REGULATION OF CA2+...
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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 alpha , beta I, beta II, gamma ), 2) novel or new PKCs (nPKC) that are activated by diacylglycerol or phorbol ester but are not Ca2+ dependent (delta , epsilon , theta , eta , L, µ), and 3) atypical PKCs (aPKC) that are not activated by diacylglycerol, phorbol ester, or Ca2+ (lambda /iota , zeta ) (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 the alpha 1- and beta 2-subunits of CaV1.2a are phosphorylated by PKC in vitro with a stoichiometry of 2-3 moles of phosphate per mole of alpha 1-subunit and 1-2 moles of phosphate per mole of beta 2a-subunit (137). The first 46 amino acid residues at the NH2-terminal end of the cardiac alpha 1-subunit have been shown to inhibit channel activity, and it has been suggested that PKC may enhance CaV1.2a channel activity by relieving NH2-terminal inhibition (153). In this scheme, the site of PKC phosphorylation is left undefined except to exclude the NH2-terminal region per se from phosphorylation (155). PKC generally has been reported to activate CaV1.2a channels in heterologous systems (17, 153, 158), but there are exceptions (115). Some studies in native cells have reported PKC-mediated stimulation of CaV1.2a (41, 67, 110), whereas others report inhibition (204). Current stimulation with phorbol esters sometimes has been reported to be transient and followed by later current inhibition (97, 172), with the later effect being PKC independent (5, 17, 97, 172). Furthermore, there is preliminary evidence to suggest that different PKC isoforms may produce opposing actions on CaV1.2a, with cPKCs producing inhibition of CaV1.2a but nPKCs enhancing channel current (63). A recent study by McHugh et al. (115) of Ca2+ channels expressed in TSA-201 cells suggests that inhibition of channel activity by PKC occurs through phosphorylation of threonine-27 and threonine-31 at the NH2-terminal region of the alpha 1-subunit. These data underscore the need for additional studies to clarify the possibly complex nature of PKC-induced effects on CaV1.2a.

Role 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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ABSTRACT
INTRODUCTION
STRUCTURE OF CARDIAC AND...
PKG REGULATION OF CA2+...
PKA REGULATION OF CA2+...
PKC REGULATION OF CAV1.2...
G PROTEIN SUBUNIT REGULATION...
REGULATION OF CAV1.2 CHANNELS...
REFERENCES

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 alpha 1B) are inhibited by G protein-activated PKC and by the direct binding of Gbeta gamma to the alpha 1-subunit (78). Direct Gbeta gamma 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 Galpha 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 Galpha s on CaV1.2a channels was from studies showing that the GTP analog guanosine 5'-O-(3-thiotriphosphate) (GTPgamma S) prolonged the survival of excised Ca2+ channels and that Ca2+ channels incorporated into a lipid bilayer could be activated independently of cAMP, ATP, PKA, and the PKC activator phorbol ester. Preactivated Gs protein and the Galpha s subunit also were shown to mimic the effects of GTPgamma S on channels in excised patches or in lipid bilayers (79, 197). Additional studies have reported that beta -adrenergic stimulation of CaV1.2a channels could not be explained solely by a PKA-dependent pathway, i.e., isoproterenol still increased CaV1.2a current by 35-80% in the presence of inhibitors of the adenylyl cyclase/PKA pathway in guinea pig ventricular myocytes (20, 130, 156), whereas forskolin, which is not G protein linked, was blocked entirely by the same maneuvers. In contrast, other studies have reported that the stimulatory effect of isoproterenol on CaV1.2a is blocked entirely by PKA inhibitors in several different animal species (29, 65, 66, 83).

Recent studies have provided further evidence for a membrane-delimited gating of CaV1.2a by Galpha s subunits. The whole cell Ca2+ channel current in cardiac myocytes from transgenic mice overexpressing cardiac Galpha s is 490% higher than in cells from wild-type control animals (98). Furthermore, in Xenopus oocytes, antisense knockdown of endogenous Galpha s reduced currents of expressed CaV1.2a channels, whereas coexpression of Galpha s with CaV1.2a enhanced currents (15). Interestingly, PKA inhibitors did not have any detectable action on the effects of Galpha 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 beta 2-adrenergic receptor (15). The authors concluded that coexpression of Galpha s, but not its acute activation via beta -adrenergic receptors, enhances CaV1.2a currents via a PKA-independent pathway. A recent study of CaV1.2a and beta 2-subunits expressed in Chinese hamster fibroblasts with beta -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 Galpha s on CaV1.2a, although a high-affinity binding site for Galpha 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 Galpha s or Gbeta gamma 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 beta -adrenergic stimulation in cardiac myocytes identified by others may actually be due to Gbeta gamma -induced activation of PKC, rather than to a direct membrane-delimited effect of Galpha s.

Role of G Protein Subunits in Smooth Muscle

In 1994, Xiong and colleagues (195) reported that dialysis of cells with activated Galpha s gave rise to stimulation of Ca2+ channel currents in rabbit portal vein myocytes. It was suggested that this effect represented a direct membrane-delimited action of Galpha s on the channel. We directly explored this issue by comparing the effect of dialyzing cells with either activated Galpha s or Gbeta 1gamma 2. Both Galpha s and Gbeta gamma stimulated CaV1.2b currents in rabbit portal vein myocytes, whereas inactive subunits [i.e., Galpha s-guanosine 5'-O-(2-thiodiphosphate) and nonprenylated Gbeta gamma ] were without effect. Of even greater interest was the observation that different second messenger pathways appeared to be involved in the actions of the two G protein subunits. Thus Galpha s enhanced current via the adenylyl cyclase/PKA pathway, whereas Gbeta gamma activated channels via a PKC-dependent pathway (205). Recently, we determined that both of these pathways also are present when endogenous Galpha s and Gbeta gamma are stimulated with isoproterenol (Fig. 3) (207). To date, Gbeta gamma dimers from four different sources all have been shown to stimulate CaV1.2b channels in a PKC-dependent manner. These include endogenous Gbeta 1gamma 3 coupled to G13 in rat portal vein (112), Gbeta gamma purified from rat brain Gi/Go (178), Gbeta 1gamma 2 purified from Sf9 cells (205), and endogenous Gbeta gamma coupled to Galpha s in rabbit portal vein cells (207). These data suggest that Gbeta gamma -induced stimulation of CaV1.2b channels may be a fairly ubiquitous feature of agonist-induced G protein stimulation. Under these circumstances, G protein specificity still could be conferred by the Galpha subunit coupled to Gbeta gamma . The notion that many different Gbeta gamma dimers exert similar effects certainly is not new. This was suggested early on (see, for example, Ref. 174) and has received continued support in more recent times (30, 143). The question of how Gbeta gamma leads to activation of PKC in this pathway has been only recently addressed. Studies of rat portal vein myocytes suggest that at least one mechanism involved is Gbeta gamma -induced stimulation of phosphatidylinositol 3-kinase (178). In most of the recent work on G protein subunit regulation, there has been little evidence to support the idea that either Galpha s or Gbeta gamma activates CaV1.2b channels via a direct membrane-delimited pathway.


    REGULATION OF CAV1.2 CHANNELS BY OTHER KINASES
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ABSTRACT
INTRODUCTION
STRUCTURE OF CARDIAC AND...
PKG REGULATION OF CA2+...
PKA REGULATION OF CA2+...
PKC REGULATION OF CAV1.2...
G PROTEIN SUBUNIT REGULATION...
REGULATION OF CAV1.2 CHANNELS...
REFERENCES

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 antagonize beta -adrenergic receptors (157). Together, these studies suggest that PTK may play a significant role in the regulation of cardiac CaV1.2 channels, but at present even the direction of this regulation appears to be controversial. Additional studies are required to better understand the possibly complicated role(s) that various PTKs play in modulating CaV1.2a activity. Caution is advisable as well when interpreting results using PTK antagonists, which may have more than one site of action.

Evidence 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 alpha 1-subunit by PTK (8). It is possible that PTK phosphorylates a similar site on the alpha 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 from -90 to 0 mV in rabbit and ferret ventricular myocytes induced a staircase increase in Ca2+ current. This effect was completely abolished by dialyzing cells with either the CaMKII inhibitor CaMKII(290-309) or CaMKII(273-302). Similar results have been observed in rabbit ventricular myocytes (2). Constitutively active CaMK also markedly increases the open probability of single Ca2+ channel currents in murine ventricular myocytes recorded in inside-out patch configuration (42). The stimulatory effect of constitutively active CaMK required ATP and was not mimicked by CaM alone. It was blocked by the CaMK inhibitory peptide AC3-1 but not by either PKA or PKC inhibitory peptides. The authors suggested that CaMK phosphorylates a cell membrane-associated target protein, which gives rise to frequent, long openings of Ca2+ channels.

In 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 alpha 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 alpha 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 alpha 1 eliminates both forms of Ca2+-dependent automodulation of Ca2+ channels (210, 211). Whether this direct interaction between CaM and the channel alpha 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.


    ACKNOWLEDGEMENTS

We thank Dr. James Kenyon for careful reading of this manuscript and valuable suggestions.


    FOOTNOTES

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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