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Circulation Research. 2000;87:1095-1102

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(Circulation Research. 2000;87:1095.)
© 2000 American Heart Association, Inc.


Review

Regulation of Cardiac L-Type Calcium Channels by Protein Kinase A and Protein Kinase C

Timothy J. Kamp, Johannes W. Hell

From the Departments of Medicine (T.J.K.), Physiology (T.J.K.), and Pharmacology (J.W.H.), University of Wisconsin, Madison, Wis.

Correspondence to Dr Timothy J. Kamp, University of Wisconsin–Madison, H6/343 Clinical Science Center, 600 Highland Ave, Madison, WI 53792-3248. E-mail tjk{at}medicine.wisc.edu

Abstract—Voltage-dependent L-type Ca2+ channels are multisubunit transmembrane proteins, which allow the influx of Ca2+ (ICa) essential for normal excitability and excitation-contraction coupling in cardiac myocytes. A variety of different receptors and signaling pathways provide dynamic regulation of ICa in the intact heart. The present review focuses on recent evidence describing the molecular details of regulation of L-type Ca2+ channels by protein kinase A (PKA) and protein kinase C (PKC) pathways. Multiple G protein–coupled receptors act through cAMP/PKA pathways to regulate L-type channels. ß-Adrenergic receptor stimulation results in a marked increase in ICa, which is mediated by a cAMP/PKA pathway. Growing evidence points to an important role of localized signaling complexes involved in the PKA-mediated regulation of ICa, including A-kinase anchor proteins and binding of phosphatase PP2a to the carboxyl terminus of the {alpha}1C (Cav1.2) subunit. Both {alpha}1C and ß2a subunits of the channel are substrates for PKA in vivo. The regulation of L-type Ca2+ channels by Gq-linked receptors and associated PKC activation is complex, with both stimulation and inhibition of ICa being observed. The amino terminus of the {alpha}1C subunit is critically involved in PKC regulation. Crosstalk between PKA and PKC pathways occurs in the modulation of ICa. Ultimately, precise regulation of ICa is needed for normal cardiac function, and alterations in these regulatory pathways may prove important in heart disease.


Key Words: L-type calcium channel • protein kinase C • protein kinase A • heart • regulation • phosphorylation




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Effects of C-type natriuretic peptide on ionic currents in mouse sinoatrial node: a role for the NPR-C receptor
Am J Physiol Heart Circ Physiol, May 1, 2004; 286(5): H1970 - H1977.
[Abstract] [Full Text] [PDF]


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J. Physiol.Home page
W. H. duBell and T. B. Rogers
Protein phosphatase 1 and an opposing protein kinase regulate steady-state L-type Ca2+ current in mouse cardiac myocytes
J. Physiol., April 1, 2004; 556(1): 79 - 93.
[Abstract] [Full Text] [PDF]


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Circ. Res.Home page
W. G. Pyle and R. J. Solaro
At the Crossroads of Myocardial Signaling: The Role of Z-Discs in Intracellular Signaling and Cardiac Function
Circ. Res., February 20, 2004; 94(3): 296 - 305.
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Am. J. Physiol. Heart Circ. Physiol.Home page
S. A. McDowell, E. McCall, W. F. Matter, T. B. Estridge, and C. J. Vlahos
Phosphoinositide 3-kinase regulates excitation-contraction coupling in neonatal cardiomyocytes
Am J Physiol Heart Circ Physiol, February 1, 2004; 286(2): H796 - H805.
[Abstract] [Full Text] [PDF]


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J. Physiol.Home page
I. Findlay
Physiological modulation of inactivation in L-type Ca2+ channels: one switch
J. Physiol., January 15, 2004; 554(2): 275 - 283.
[Abstract] [Full Text] [PDF]


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J. Biol. Chem.Home page
J. J. Saucerman, L. L. Brunton, A. P. Michailova, and A. D. McCulloch
Modeling {beta}-Adrenergic Control of Cardiac Myocyte Contractility in Silico
J. Biol. Chem., November 28, 2003; 278(48): 47997 - 48003.
[Abstract] [Full Text] [PDF]


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J. Biol. Chem.Home page
V. G. Robu, E. S. Pfeiffer, S. L. Robia, R. C. Balijepalli, Y. Pi, T. J. Kamp, and J. W. Walker
Localization of Functional Endothelin Receptor Signaling Complexes in Cardiac Transverse Tubules
J. Biol. Chem., November 28, 2003; 278(48): 48154 - 48161.
[Abstract] [Full Text] [PDF]


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J. Neurosci.Home page
B. Dasgupta, L. L. Dugan, and D. H. Gutmann
The Neurofibromatosis 1 Gene Product Neurofibromin Regulates Pituitary Adenylate Cyclase-Activating Polypeptide-Mediated Signaling in Astrocytes
J. Neurosci., October 1, 2003; 23(26): 8949 - 8954.
[Abstract] [Full Text] [PDF]


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J. Physiol.Home page
J. Jurevicius, V A. Skeberdis, and R. Fischmeister
Role of cyclic nucleotide phosphodiesterase isoforms in cAMP compartmentation following {beta}2-adrenergic stimulation of ICa,L in frog ventricular myocytes
J. Physiol., August 15, 2003; 551(1): 239 - 252.
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J. Physiol.Home page
P. Tosetti, V. Parente, V. Taglietti, K. Dunlap, and M. Toselli
Chick RGS2L demonstrates concentration-dependent selectivity for pertussis toxin-sensitive and -insensitive pathways that inhibit L-type Ca2+ channels
J. Physiol., May 15, 2003; 549(1): 157 - 169.
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Proc. Natl. Acad. Sci. USAHome page
C. Erxleben, C. Gomez-Alegria, T. Darden, Y. Mori, L. Birnbaumer, and D. L. Armstrong
Modulation of cardiac CaV1.2 channels by dihydropyridine and phosphatase inhibitor requires Ser-1142 in the domain III pore loop
PNAS, March 4, 2003; 100(5): 2929 - 2934.
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Cardiovasc ResHome page
R. Wolk
Calcineurin, myocardial hypertrophy, and electrical remodeling
Cardiovasc Res, February 1, 2003; 57(2): 289 - 293.
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J. Physiol.Home page
I. Findlay
{beta}-Adrenergic and muscarinic agonists modulate inactivation of L-type ca2+ channel currents in guinea-pig ventricular myocytes
J. Physiol., December 1, 2002; 545(2): 375 - 388.
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J. Physiol.Home page
I. Findlay
Voltage-dependent inactivation of L-type Ca2+ currents in guinea-pig ventricular myocytes
J. Physiol., December 1, 2002; 545(2): 389 - 397.
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EndocrinologyHome page
K. Kaneishi, Y. Sakuma, H. Kobayashi, and M. Kato
3',5'-Cyclic Adenosine Monophosphate Augments Intracellular Ca2+ Concentration and Gonadotropin-Releasing Hormone (GnRH) Release in Immortalized GnRH Neurons in an Na+-Dependent Manner
Endocrinology, November 1, 2002; 143(11): 4210 - 4217.
[Abstract] [Full Text] [PDF]


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Circ. Res.Home page
T. J. Kamp and J.-Q. He
L-Type Ca2+ Channels Gaining Respect in Heart Failure
Circ. Res., September 20, 2002; 91(6): 451 - 453.
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J. Neurosci.Home page
L. A. Birder, M. L. Nealen, S. Kiss, W. C. de Groat, M. J. Caterina, E. Wang, G. Apodaca, and A. J. Kanai
beta -Adrenoceptor Agonists Stimulate Endothelial Nitric Oxide Synthase in Rat Urinary Bladder Urothelial Cells
J. Neurosci., September 15, 2002; 22(18): 8063 - 8070.
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Circ. Res.Home page
I. Szokodi, P. Tavi, G. Foldes, S. Voutilainen-Myllyla, M. Ilves, H. Tokola, S. Pikkarainen, J. Piuhola, J. Rysa, M. Toth, et al.
Apelin, the Novel Endogenous Ligand of the Orphan Receptor APJ, Regulates Cardiac Contractility
Circ. Res., September 6, 2002; 91(5): 434 - 440.
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FASEB J.Home page
A. HOHAUS, V. PERSON, J. BEHLKE, J. SCHAPER, I. MORANO, and H. HAASE
The carboxyl-terminal region of ahnak provides a link between cardiac L-type Ca2+ channels and the actin-based cytoskeleton
FASEB J, August 1, 2002; 16(10): 1205 - 1216.
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HypertensionHome page
Y. Akiyama-Uchida, N. Ashizawa, A. Ohtsuru, S. Seto, T. Tsukazaki, H. Kikuchi, S. Yamashita, and K. Yano
Norepinephrine Enhances Fibrosis Mediated by TGF-{beta} in Cardiac Fibroblasts
Hypertension, August 1, 2002; 40(2): 148 - 154.
[Abstract] [Full Text] [PDF]


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J. Physiol.Home page
I. Findlay
{beta}-Adrenergic stimulation modulates Ca2+- and voltage-dependent inactivation of L-type Ca2+ channel currents in guinea-pig ventricular myocytes
J. Physiol., June 15, 2002; 541(3): 741 - 751.
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J. Biol. Chem.Home page
Y. Blumenstein, N. Kanevsky, G. Sahar, R. Barzilai, T. Ivanina, and N. Dascal
A Novel Long N-terminal Isoform of Human L-type Ca2+ Channel Is Up-regulated by Protein Kinase C
J. Biol. Chem., January 25, 2002; 277(5): 3419 - 3423.
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Sci SignalHome page
J. S. Trimmer
Unexpected Cross Talk: Small GTPase Regulation of Calcium Channel Trafficking
Sci. Signal., January 8, 2002; 2002(114): pe2 - pe2.
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Am. J. Physiol. Heart Circ. Physiol.Home page
V. M. Vizgirda, G. M. Wahler, K. L. Sondgeroth, M. T. Ziolo, and D. W. Schwertz
Mechanisms of sex differences in rat cardiac myocyte response to beta -adrenergic stimulation
Am J Physiol Heart Circ Physiol, January 1, 2002; 282(1): H256 - H263.
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Am. J. Physiol. Cell Physiol.Home page
K. D. Keef, J. R. Hume, and J. Zhong
Regulation of cardiac and smooth muscle Ca2+ channels (CaV1.2a,b) by protein kinases
Am J Physiol Cell Physiol, December 1, 2001; 281(6): C1743 - C1756.
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Am. J. Physiol. Cell Physiol.Home page
J. Z. Rappoport, M. S. Lipkowitz, and R. G. Abramson
Localization and topology of a urate transporter/channel, a galectin, in epithelium-derived cells
Am J Physiol Cell Physiol, December 1, 2001; 281(6): C1926 - C1939.
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Am. J. Physiol. Heart Circ. Physiol.Home page
M. J. Davis, X. Wu, T. R. Nurkiewicz, J. Kawasaki, P. Gui, M. A. Hill, and E. Wilson
Regulation of ion channels by protein tyrosine phosphorylation
Am J Physiol Heart Circ Physiol, November 1, 2001; 281(5): H1835 - H1862.
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Am. J. Physiol. Cell Physiol.Home page
L. Formigli, F. Francini, E. Meacci, M. Vassalli, D. Nosi, F. Quercioli, B. Tiribilli, C. Bencini, C. Piperio, P. Bruni, et al.
Sphingosine 1-phosphate induces Ca2+ transients and cytoskeletal rearrangement in C2C12 myoblastic cells
Am J Physiol Cell Physiol, June 1, 2002; 282(6): C1361 - C1373.
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Circ. Res.Home page
M. G. Vila Petroff, J. M. Egan, X. Wang, and S. J. Sollott
Glucagon-Like Peptide-1 Increases cAMP but Fails to Augment Contraction in Adult Rat Cardiac Myocytes
Circ. Res., August 31, 2001; 89(5): 445 - 452.
[Abstract] [Full Text] [PDF]