Calcium channel diversity in the cardiovascular system

Cardiology Division, University of Connecticut School of Medicine, Farmington, USA.

The flux of calcium ions (Ca2+) into the cytosol, where they serve as intracellular messengers, is regulated by two distinct families of Ca2+ channel proteins. These are the intracellular Ca2+ release channels, which allow Ca2+ to enter the cytosol from intracellular stores, and the plasma membrane Ca2+ channels, which control Ca2+ entry from the extracellular space. Each of these two families of channel proteins contains several subgroups. The intracellular channels include the large Ca2+ channels ("ryanodine receptors") that participate in cardiac and skeletal muscle excitation-contraction coupling, and smaller inositol trisphosphate (InsP3)-activated Ca2+ channels. The latter serve several functions, including the pharmacomechanical coupling that activates smooth muscle contraction, and possibly regulation of diastolic tone in the heart. The InsP3-activated Ca2+ channels may also participate in signal transduction systems that regulate cell growth. The family of plasma membrane Ca2+ channels includes L-type channels, which respond to membrane depolarization by generating a signal that opens the intracellular Ca2+ release channels. Calcium ion entry through L-type Ca2+ channels in the sinoatrial (SA) node contributes to pacemaker activity, whereas L-type Ca2+ channels in the atrioventricular (AV) node are essential for AV conduction. The T-type Ca2+ channels, another member of the family of plasma membrane Ca2+ channels, participate in pharmacomechanical coupling in smooth muscle. Opening of these channels in response to membrane depolarization participates in SA node pacemaker currents, but their role in the working cells of the atria and ventricle is less clear. Like the InsP3-activated intracellular Ca2+ release channels, T-type plasma membrane channels may regulate cell growth. Because most of the familiar Ca2+ channel blocking agents currently used in cardiology, such as nifedipine, verapamil and diltiazem, are selective for L-type Ca2+ channels, the recent development of drugs that selectively block T-type Ca2+ channels offers promise of new approaches to cardiovascular therapy.

This article has been cited by other articles:

				M. Maruyama, B.-Y. Li, H. Chen, X. Xu, L.-S. Song, S. Guatimosim, W. Zhu, W. Yong, W. Zhang, G. Bu, et al. FKBP12 Is a Critical Regulator of the Heart Rhythm and the Cardiac Voltage-Gated Sodium Current in Mice Circ. Res., April 29, 2011; 108(9): 1042 - 1052. [Abstract] [Full Text] [PDF]

				Y.-G. Sun, Y.-X. Cao, W.-W. Wang, S.-F. Ma, T. Yao, and Y.-C. Zhu Hydrogen sulphide is an inhibitor of L-type calcium channels and mechanical contraction in rat cardiomyocytes Cardiovasc Res, September 1, 2008; 79(4): 632 - 641. [Abstract] [Full Text] [PDF]

				M.-G. Feng, M. Li, and L. G. Navar T-type calcium channels in the regulation of afferent and efferent arterioles in rats Am J Physiol Renal Physiol, February 1, 2004; 286(2): F331 - F337. [Abstract] [Full Text] [PDF]

				J.-Y. Min, A. Meissner, J. Wang, and J. P. Morgan Mibefradil Improves {beta}-Adrenergic Responsiveness and Intracellular Ca2+ Handling in Hypertrophied Rat Myocardium Exp Biol Med, May 1, 2002; 227(5): 336 - 344. [Abstract] [Full Text] [PDF]

				M. S. Kapiloff, N. Jackson, and N. Airhart mAKAP and the ryanodine receptor are part of a multi-component signaling complex on the cardiomyocyte nuclear envelope J. Cell Sci., September 1, 2001; 114(17): 3167 - 3176. [Abstract] [Full Text] [PDF]

				B. J. Kneale, P. J. Chowienczyk, S. E. Brett, D. J. Coltart, and J. M. Ritter Gender differences in sensitivity to adrenergic agonists of forearm resistance vasculature J. Am. Coll. Cardiol., October 1, 2000; 36(4): 1233 - 1238. [Abstract] [Full Text] [PDF]

				T. B. Levine, P. J. L. M. Bernink, A. Caspi, U. Elkayam, E. M. Geltman, B. Greenberg, W. J. McKenna, J. K. Ghali, T. D. Giles, A. Marmor, et al. Effect of Mibefradil, a T-Type Calcium Channel Blocker, on Morbidity and Mortality in Moderate to Severe Congestive Heart Failure : The MACH-1 Study Circulation, February 22, 2000; 101(7): 758 - 764. [Abstract] [Full Text] [PDF]

				J.-Y. Min, S. Sandmann, A. Meissner, T. Unger, and R. Simon Differential Effects of Mibefradil, Verapamil, and Amlodipine on Myocardial Function and Intracellular Ca2+ Handling in Rats with Chronic Myocardial Infarction J. Pharmacol. Exp. Ther., December 1, 1999; 291(3): 1038 - 1044. [Abstract] [Full Text]

				S. Sandmann, J.-Y. Min, A. Meissner, and T. Unger Effects of the calcium channel antagonist mibefradil on haemodynamic parameters and myocardial Ca2+-handling in infarct-induced heart failure in rats Cardiovasc Res, October 1, 1999; 44(1): 67 - 80. [Abstract] [Full Text] [PDF]

				S. Sandmann, H. Spitznagel, O. Chung, Qin-Gui Xia, S. Illner, G. Janichen, B. Rossius, M. J.A.P Daemen, and T. Unger Effects of the calcium channel antagonist mibefradil on haemodynamic and morphological parameters in myocardial infarction-induced cardiac failure in rats Cardiovasc Res, August 1, 1998; 39(2): 339 - 350. [Abstract] [Full Text] [PDF]

				L. L. Cribbs, J.-H. Lee, J. Yang, J. Satin, Y. Zhang, A. Daud, J. Barclay, M. P. Williamson, M. Fox, M. Rees, et al. Cloning and Characterization of {alpha}1H From Human Heart, a Member of the T-Type Ca2+ Channel Gene Family Circ. Res., July 13, 1998; 83(1): 103 - 109. [Abstract] [Full Text] [PDF]

				C. A. Muller, L. H. Opie, J. McCarthy, D. Hofmann, C. A. Pineda, and M. Peisach Effects of mibefradil, a novel calcium channel blocking agent with T-type activity, in acute experimental myocardial ischemia: maintenance of ventricular fibrillation threshold without inotropic compromise J. Am. Coll. Cardiol., July 1, 1998; 32(1): 268 - 274. [Abstract] [Full Text] [PDF]