Calcium entry through L-type calcium channels causes mitochondrial disruption and chromaffin cell death.
Sustained, mild K+ depolarization caused bovine chromaffin cell death through a Ca(2+)-dependent mechanism. During depolarization, Ca(2+) entered preferentially through L-channels to induce necrotic or apoptotic cell death, depending on the duration of the cytosolic Ca(2+) concentration ([Ca(2+)](c)) signal, as proven by the following. (i) The L-type Ca(2+) channel activators Bay K 8644 and FPL64176, more than doubled the cytotoxic effects of 30 mm K+; (ii) the L-type Ca(2+) channel blocker nimodipine suppressed the cytotoxic effects of K+ alone or K+ plus FPL64176; (iii) the potentiation by FPL64176 of the K+ -evoked [Ca(2+)](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 [Ca(2+)](c) that, in turn, increased [Ca(2+)](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 Ca(2+) overload through L-channels. These results suggest that Ca(2+) 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 Ca(2+) channels is not shared by other subtypes of high threshold voltage-dependent neuronal Ca(2+) channels (i.e. N, P/Q) expressed by bovine chromaffin cells.
Cano-Abad
M F
MF
Instituto de Farmacologia Teófilo Hernando, Departamento de Farmacologia, Facultad de Medicina, Universidad Autónoma de Madrid, C/Arzobispo Morcillo 4, Madrid 28029, Spain.
Villarroya
M
M
García
A G
AG
Gabilan
N H
NH
López
M G
MG
D000313:Adrenal Medulla / Q000166:cytology / Q000502:physiology; D000818:Animals; D017209:Apoptosis; D002118:Calcium / Q000378:metabolism*; D002120:Calcium Channel Agonists / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020746:Calcium Channels, L-Type / Q000378:metabolism*; D002417:Cattle; D019439:Chromaffin Cells / Q000166:cytology / Q000502:physiology*; D003574:Cytochrome c Group / Q000378:metabolism; D019610:Cytoprotection; D005609:Free Radicals / Q000378:metabolism; D008928:Mitochondria / Q000502:physiology*; D009336:Necrosis; D009553:Nimodipine / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology
D002120:Calcium Channel Agonists; D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D003574:Cytochrome c Group; D005609:Free Radicals; D011758:Pyrroles; C071658:FPL 64176; D009553:Nimodipine; D002118:Calcium