Copyright © 2005, European Society of Cardiology
Na+–Ca2+exchange in the regulation of cardiac excitation–contraction coupling
aLaboratory of Muscle Research and Molecular Cardiology, Department of Internal Medicine III, University of Cologne, Joseph-Stelzmann-Str. 9, 50924 Cologne, Germany
bDepartments of Medicine and Physiology David Geffen School of Medicine at UCLA, Los Angeles, CA 90095-1679, United States
cCardiovascular Research Laboratories David Geffen School of Medicine at UCLA, Los Angeles, CA 90095-1679, United States
* Corresponding author. Tel.: +49 221 478 6205; fax: +49 221 478 6550. Email address: Hannes.Reuter{at}koeln.de
Cardiac sarcolemmal Na+–Ca2+ exchange is a central component of Ca2+ signaling essential for Ca2+ extrusion and contributing to a variable degree to the development of the systolic Ca2+ transient. Reports on differential gene expression of Na+–Ca2+ exchange in cardiac disease and the regulation of its thermodynamic equilibrium depending on intracellular gradients of ion concentrations between subcellular compartments have recently put a new complexion on Na+–Ca2+ exchange and its implications for excitation–contraction (E–C) coupling. Heart failure models and genetic approaches to regulate expression of the Na+–Ca2+ exchanger have improved our knowledge of exchanger function. Modest overexpression of the Na+–Ca2+ exchanger in heterozygous transgenic mice had minimal effects on E–C coupling and cardiac function. However, higher levels of Na+–Ca2+ exchange expression in homozygotes led to pathological hypertrophy and failure with an increased interaction between the L-type Ca2+ current and Na+–Ca2+ exchange and reduced E–C coupling gain. These results suggested that the Na+–Ca2+ exchanger is capable of modulating sarcoplasmic Ca2+ handling and at high expression levels may interact with the gating kinetics of the L-type Ca2+ current by means of regulating subsarcolemmal Ca2+ levels. Despite being a central component in the regulation of cardiac E–C coupling, a newly generated mouse model with cardiac-specific conditional knock-out of the Na+–Ca2+ exchanger is viable with unchanged Ca2+ dynamics in adult ventricular myocytes. Cardiac myocytes adapt well to knock-out of the exchanger, apparently by reducing transsarcolemmal fluxes of Ca2+ and increasing E–C coupling gain possibly mediated by changes in submembrane Ca2+ levels. For E–C coupling in the murine model, which relies primarily on sarcoplasmic Ca2+ regulation, this led to the suggestion that the role of Na+–Ca2+ exchange should be thought of as a Ca2+ buffering function and not as a major Ca2+ transporter in competition with the sarcoplasmic reticulum.
KEYWORDS Na/Ca-exchanger; e–c coupling; Membrane current; Heart failure; Ca-channel
Time for primary review 21 days
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  L. Boyman, H. Mikhasenko, R. Hiller, and D. Khananshvili Kinetic and Equilibrium Properties of Regulatory Calcium Sensors of NCX1 Protein J. Biol. Chem., March 6, 2009; 284(10): 6185 - 6193. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. S. C. Hamming, M. J. Riedel, D. Soliman, L. C. Matemisz, N. J. Webster, G. J. Searle, P. E. MacDonald, and P. E. Light Splice Variant-Dependent Regulation of {beta}-Cell Sodium-Calcium Exchange by Acyl-Coenzyme As Mol. Endocrinol., October 1, 2008; 22(10): 2293 - 2306. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Birinyi, A. Toth, I. Jona, K. Acsai, J. Almassy, N. Nagy, J. Prorok, I. Gherasim, Z. Papp, Z. Hertelendi, et al. The Na+/Ca2+ exchange blocker SEA0400 fails to enhance cytosolic Ca2+ transient and contractility in canine ventricular cardiomyocytes Cardiovasc Res, June 1, 2008; 78(3): 476 - 484. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Banyasz, I. Lozinskiy, C. E. Payne, S. Edelmann, B. Norton, B. Chen, Y. Chen-Izu, L. T. Izu, and C. W. Balke Transformation of adult rat cardiac myocytes in primary culture Exp Physiol, March 1, 2008; 93(3): 370 - 382. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. K. Landeen, D. A. Dederko, C. S. Kondo, B. S. Hu, N. Aroonsakool, J. H. Haga, and W. R. Giles Mechanisms of the negative inotropic effects of sphingosine-1-phosphate on adult mouse ventricular myocytes Am J Physiol Heart Circ Physiol, February 1, 2008; 294(2): H736 - H749. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Baggaley, S. McLarnon, I. Demeter, G. Varga, and J. I. E. Bruce Differential Regulation of the Apical Plasma Membrane Ca2+-ATPase by Protein Kinase A in Parotid Acinar Cells J. Biol. Chem., December 28, 2007; 282(52): 37678 - 37693. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. Schoner and G. Scheiner-Bobis Endogenous and exogenous cardiac glycosides: their roles in hypertension, salt metabolism, and cell growth Am J Physiol Cell Physiol, August 1, 2007; 293(2): C509 - C536. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Reppel, B. K. Fleischmann, H. Reuter, P. Sasse, H. Schunkert, and J. Hescheler Regulation of the Na+/Ca2+ exchanger (NCX) in the murine embryonic heart Cardiovasc Res, July 1, 2007; 75(1): 99 - 108. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. M. Yeung, G. M. Kravtsov, K. M. Ng, T. M. Wong, and M. L. Fung Chronic intermittent hypoxia alters Ca2+ handling in rat cardiomyocytes by augmented Na+/Ca2+ exchange and ryanodine receptor activities in ischemia-reperfusion Am J Physiol Cell Physiol, June 1, 2007; 292(6): C2046 - C2056. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Shepherd, V. Graham, B. Trevedi, and T. L. Creazzo Changes in regulation of sodium/calcium exchanger of avian ventricular heart cells during embryonic development Am J Physiol Cell Physiol, May 1, 2007; 292(5): C1942 - C1950. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. R. Cunha, N. Bhasin, and P. J. Mohler Targeting and Stability of Na/Ca Exchanger 1 in Cardiomyocytes Requires Direct Interaction with the Membrane Adaptor Ankyrin-B J. Biol. Chem., February 16, 2007; 282(7): 4875 - 4883. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. P. Ander, C. Hurtado, C. S. Raposo, T. G. Maddaford, J. F. Deniset, L. V. Hryshko, G. N. Pierce, and A. Lukas Differential sensitivities of the NCX1.1 and NCX1.3 isoforms of the Na+-Ca2+ exchanger to {alpha}-linolenic acid Cardiovasc Res, January 15, 2007; 73(2): 395 - 403. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. M. Piper and E. A. Martinson Cardiovascular Research speeds up-Even more Cardiovasc Res, March 1, 2006; 69(4): 773 - 776. [Full Text] [PDF]
|
|