This Article Full Text Full Text (PDF) All Versions of this Article: 97/12/1288    most recent 01.RES.0000196563.84231.21v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Pott, C. Articles by Goldhaber, J. I. Search for Related Content PubMed PubMed Citation Articles by Pott, C. Articles by Goldhaber, J. I. Related Collections Calcium cycling/excitation-contraction coupling Genetically altered mice Ion channels/membrane transport

Excitation–Contraction Coupling in Na⁺–Ca²⁺ Exchanger Knockout Mice

Reduced Transsarcolemmal Ca²⁺ Flux

From the Departments of Physiology and Medicine and the Cardiovascular Research Laboratories, David Geffen School of Medicine, University of California, Los Angeles.

Correspondence to Kenneth D. Philipson, Cardiovascular Research Laboratory, MRL 3-645, David Geffen School of Medicine, University of California, Los Angeles, CA 90095-1760. E-mail kphilipson{at}mednet.ucla.edu

Cardiac-specific Na⁺–Ca²⁺ exchanger (NCX) knockout (KO) mice surprisingly survive into adulthood without compensatory changes in protein expression levels. To determine how cardiac function is maintained in the absence of NCX, we investigated membrane currents, intracellular Ca²⁺, and action potentials (APs) in whole cell patch-clamped myocytes from wild-type (WT) and NCX knockout mice. There was no difference in resting Ca²⁺ or sarcoplasmic reticular Ca²⁺ load between KO and WT. During prolonged caffeine exposure, the decrease of the Ca²⁺ transient was drastically slowed in KO versus WT myocytes, indicating that no alternative Ca²⁺-extrusion mechanism is upregulated to compensate for the absence of NCX. Peak L-type Ca²⁺ current (I_Ca) was reduced by 62% in KO myocytes compared with WT. Nevertheless, the corresponding Ca²⁺ transients were similar, implying an increase in the gain of excitation–contraction coupling in KO cells. APs recorded from KO cells repolarized more rapidly than in WT. In WT myocytes, applying a KO AP waveform voltage clamp reduced Ca²⁺ influx via I_Ca by 59% compared with WT AP waveform clamps. Again, the corresponding Ca²⁺ transients remained similar. Our findings indicate that NCX KO myocytes limit Ca²⁺ influx to &20% of that in WT by reducing I_Ca and by abbreviating the AP. Contractility is maintained by an increase in the gain of excitation–contraction coupling resulting from both a more rapid repolarization of the AP and an as yet unidentified AP-independent mechanism.

Key Words: excitation–contraction coupling • Na⁺–Ca²⁺ exchanger • L-type Ca²⁺ channel • mouse • heart • action potential

This article has been cited by other articles:

				M. Jumabay, R. Zhang, Y. Yao, J. I. Goldhaber, and K. I. Bostrom Spontaneously beating cardiomyocytes derived from white mature adipocytes Cardiovasc Res, August 21, 2009; (2009) cvp267v2. [Abstract] [Full Text] [PDF]

				J. Wang, T. O. Chan, X.-Q. Zhang, E. Gao, J. Song, W. J. Koch, A. M. Feldman, and J. Y. Cheung Induced overexpression of Na+/Ca2+ exchanger transgene: altered myocyte contractility, [Ca2+]i transients, SR Ca2+ contents, and action potential duration Am J Physiol Heart Circ Physiol, August 1, 2009; 297(2): H590 - H601. [Abstract] [Full Text] [PDF]

				J. Inserte, J. A. Barrabes, V. Hernando, and D. Garcia-Dorado Orphan targets for reperfusion injury Cardiovasc Res, July 15, 2009; 83(2): 169 - 178. [Abstract] [Full Text] [PDF]

				M. A. Stagg, E. Carter, N. Sohrabi, U. Siedlecka, G. K. Soppa, F. Mead, N. Mohandas, P. Taylor-Harris, A. Baines, P. Bennett, et al. Cytoskeletal Protein 4.1R Affects Repolarization and Regulates Calcium Handling in the Heart Circ. Res., October 10, 2008; 103(8): 855 - 863. [Abstract] [Full Text] [PDF]

				J. Davis, M. V. Westfall, D. Townsend, M. Blankinship, T. J. Herron, G. Guerrero-Serna, W. Wang, E. Devaney, and J. M. Metzger Designing Heart Performance by Gene Transfer Physiol Rev, October 1, 2008; 88(4): 1567 - 1651. [Abstract] [Full Text] [PDF]

				B. O'Rourke The Ins and Outs of Calcium in Heart Failure Circ. Res., June 6, 2008; 102(11): 1301 - 1303. [Full Text] [PDF]

				S. Ozdemir, V. Bito, P. Holemans, L. Vinet, J.-J. Mercadier, A. Varro, and K. R. Sipido Pharmacological Inhibition of Na/Ca Exchange Results in Increased Cellular Ca2+ Load Attributable to the Predominance of Forward Mode Block Circ. Res., June 6, 2008; 102(11): 1398 - 1405. [Abstract] [Full Text] [PDF]

				D. W. Hilgemann On the physiological roles of PIP2 at cardiac Na+ Ca2+ exchangers and KATP channels: a long journey from membrane biophysics into cell biology J. Physiol., August 1, 2007; 582(3): 903 - 909. [Abstract] [Full Text] [PDF]

				N. Bhasin, S. R. Cunha, M. Mudannayake, M. S. Gigena, T. B. Rogers, and P. J. Mohler Molecular basis for PP2A regulatory subunit B56{alpha} targeting in cardiomyocytes Am J Physiol Heart Circ Physiol, July 1, 2007; 293(1): H109 - H119. [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]

				C. Pott, X. Ren, D. X. Tran, M.-J. Yang, S. Henderson, M. C. Jordan, K. P. Roos, A. Garfinkel, K. D. Philipson, and J. I. Goldhaber Mechanism of shortened action potential duration in Na+-Ca2+ exchanger knockout mice Am J Physiol Cell Physiol, February 1, 2007; 292(2): C968 - C973. [Abstract] [Full Text] [PDF]