© 2000 American Heart Association, Inc.
Review |
Regulation of Cardiac L-Type Calcium Channels by Protein Kinase A and Protein Kinase C
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 
1C
(Cav1.2) subunit. Both
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 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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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. 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. [Abstract] [Full Text] [PDF]
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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. [Abstract] [Full Text] [PDF]
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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. [Abstract] [Full Text] [PDF]
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R. Wolk Calcineurin, myocardial hypertrophy, and electrical remodeling Cardiovasc Res, February 1, 2003; 57(2): 289 - 293. [Full Text] [PDF]
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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. [Abstract] [Full Text] [PDF]
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I. Findlay Voltage-dependent inactivation of L-type Ca2+ currents in guinea-pig ventricular myocytes J. Physiol., December 1, 2002; 545(2): 389 - 397. [Abstract] [Full Text] [PDF]
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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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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. [Full Text] [PDF]
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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. [Abstract] [Full Text] [PDF]
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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. [Abstract] [Full Text] [PDF]
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 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. [Abstract] [Full Text] [PDF]
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 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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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. [Abstract] [Full Text] [PDF]
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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. [Abstract] [Full Text] [PDF]
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 J. S. Trimmer Unexpected Cross Talk: Small GTPase Regulation of Calcium Channel Trafficking Sci. Signal., January 8, 2002; 2002(114): pe2 - pe2. [Abstract] [Full Text] [PDF]
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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. [Abstract] [Full Text] [PDF]
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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. [Abstract] [Full Text] [PDF]
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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. [Abstract] [Full Text] [PDF]
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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. [Abstract] [Full Text] [PDF]
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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. [Abstract] [Full Text] [PDF]
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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]
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