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Am J Physiol Cell Physiol 280: C1327-C1339, 2001;
0363-6143/01 $5.00
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Vol. 280, Issue 5, C1327-C1339, May 2001

Molecular identification of a TTX-sensitive Ca2+ current

Silvia Guatimosim1,2,*, Eric A. Sobie1,2,*, Jader dos Santos Cruz1,2,3,*, Laura A. Martin1,2, and W. J. Lederer1,2

1 Department of Physiology, University of Maryland School of Medicine, and 2 Medical Biotechnology Center, University of Maryland Biotechnology Institute, Baltimore, Maryland 21201; and 3 Laboratorio de Membranas Excitáveis, Departamento de Bioquimica e Imunologia, Universidade Federal de Minas Gerais, Belo Horizonte-MG, Brazil

The TTX-sensitive Ca2+ current [ICa(TTX)] observed in cardiac myocytes under Na+-free conditions was investigated using patch-clamp and Ca2+-imaging methods. Cs+ and Ca2+ were found to contribute to ICa(TTX), but TEA+ and N-methyl-D-glucamine (NMDG+) did not. HEK-293 cells transfected with cardiac Na+ channels exhibited a current that resembled ICa(TTX) in cardiac myocytes with regard to voltage dependence, inactivation kinetics, and ion selectivity, suggesting that the cardiac Na+ channel itself gives rise to ICa(TTX). Furthermore, repeated activation of ICa(TTX) led to a 60% increase in intracellular Ca2+ concentration, confirming Ca2+ entry through this current. Ba2+ permeation of ICa(TTX), reported by others, did not occur in rat myocytes or in HEK-293 cells expressing cardiac Na+ channels under our experimental conditions. The report of block of ICa(TTX) in guinea pig heart by mibefradil (10 µM) was supported in transfected HEK-293 cells, but Na+ current was also blocked (half-block at 0.45 µM). We conclude that ICa(TTX) reflects current through cardiac Na+ channels in Na+-free (or "null") conditions. We suggest that the current be renamed INa(null) to more accurately reflect the molecular identity of the channel and the conditions needed for its activation. The relationship between INa(null) and Ca2+ flux through slip-mode conductance of cardiac Na+ channels is discussed in the context of ion channel biophysics and "permeation plasticity."

tetrodotoxin; excitation-contraction coupling; sodium channel; calcium channel; ventricular myocyte

* S. Guatimosim, E. A. Sobie, and J. dos Santos Cruz contributed equally to this work.




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