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Originally published In Press as doi:10.1074/jbc.M102334200 on August 10, 2001

J. Biol. Chem., Vol. 276, Issue 43, 39695-39704, October 26, 2001
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Calcium Entry through L-type Calcium Channels Causes Mitochondrial Disruption and Chromaffin Cell Death*

María F. Cano-AbadDagger §, Mercedes VillarroyaDagger , Antonio G. GarcíaDagger ||**, Nelson H. GabilanDagger Dagger , and Manuela G. LópezDagger §§

From the Dagger  Instituto de Farmacología Teófilo Hernando, Departamento de Farmacología, Facultad de Medicina, Universidad Autónoma de Madrid, C/Arzobispo Morcillo 4, Madrid 28029, Spain, || Servicio de Farmacología Clínica, Hospital de la Princesa, C/Diego de León 62, Madrid 28006, Spain, ** Instituto Universitario de Investigaciones Gerontológicas y Metabólicas, Hospital de la Princesa, C/Diego de León 62, Madrid 28006, Spain, and Dagger Dagger  Departamento de Bioquímica, Universidad Federal de Santa Catarina, Florianópolis 88049SC, Brasil

Sustained, mild K+ depolarization caused bovine chromaffin cell death through a Ca2+-dependent mechanism. During depolarization, Ca2+ entered preferentially through L-channels to induce necrotic or apoptotic cell death, depending on the duration of the cytosolic Ca2+ concentration ([Ca2+]c) signal, as proven by the following. (i) The L-type Ca2+ channel activators Bay K 8644 and FPL64176, more than doubled the cytotoxic effects of 30 mM K+; (ii) the L-type Ca2+ channel blocker nimodipine suppressed the cytotoxic effects of K+ alone or K+ plus FPL64176; (iii) the potentiation by FPL64176 of the K+-evoked [Ca2+]c elevation was totally suppressed by nimodipine. Cell exposure to K+ plus the L-type calcium channel agonist FPL64176 caused an initial peak rise followed by a sustained elevation of the [Ca2+]c that, in turn, increased [Ca2+]m and caused mitochondrial membrane depolarization. Cyclosporin A, a blocker of the mitochondrial transition pore, and superoxide dismutase prevented the apoptotic cell death induced by Ca2+ overload through L-channels. These results suggest that Ca2+ entry through L-channels causes both calcium overload and mitochondrial disruption that will lead to the release of mediators responsible for the activation of the apoptotic cascade and cell death. This predominant role of L-type Ca2+ channels is not shared by other subtypes of high threshold voltage-dependent neuronal Ca2+ channels (i.e. N, P/Q) expressed by bovine chromaffin cells.

* This work was supported in part by Dirección General de Investigación Científica y Técnica DGICYT Grants PM99-004 (to A. G. G.) and PM99-0006 (to M. G. L.) and "CAM Grupos Estratégicos del III PRICIT" (to A. G. G.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§ Postdoctoral fellow of Fundación Teófilo Hernando.

Postdoctoral fellow of Comunidad Autónoma of Madrid, Spain.

§§ To whom correspondence should be addressed: Dept. de Farmacología, Facultad de Medicina, Universidad Autónoma de Madrid, C/Arzobispo Morcillo 4, Madrid 28029, Spain. Tel.: 34-91-3975386; Fax: 34-91-3975397; E-mail: manuela.garcia@uam.es.

Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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