Calpains mediate calcium and chloride influx during the late phase of cell injury.
The role of Ca++ in cell death is controversial. Extracellular Ca++ influx and calpain activation occurred during the late phase of renal proximal tubule cell injury produced by the mitochondrial inhibitor antimycin A. Chelation of intracellular Ca++, extracellular Ca++, the calcium channel blocker nifedipine, calpain inhibitor 1 and the dissimilar calpain inhibitor PD150606 blocked antimycin A-induced influx of extracellular Ca++ and cell death. The calcium channel blocker verapamil was ineffective. Calpain inhibitor 1 and PD150606 were cytoprotective also against tetrafluoroethyl-L-cysteine-, bromohydroquinone-, oxidant (t-butylhydroperoxide)- and calcium ionophore (ionomycin)-induced cell death. Extracellular Ca++ influx was associated with the translocation of calpain activity from the cytosol to the membrane and was prevented by calpain inhibitor 1, PD150606 and nifedipine. Finally, nifedipine, calpain inhibitor 1, PD150606 and the Cl- channel inhibitors [5-nitro-2-(3-phenylpropylamino)-benzoate, niflumic acid, diphenylamine-2-carboxylate, and indanyloxyacetic acid] blocked the increase in Cl- influx that occurs during the late phase of cell injury and triggers terminal cell swelling and death. These data suggest that Ca++ and calpains play a common and critical role in renal proximal tubule cell death produced by diverse agents. In addition, calpain activation appears to play a dual role during the late phase of cell injury. Initial calpain activation elicits extracellular Ca++ influx through a nifedipine-sensitive pathway, resulting in calpain translocation to the membrane and in turn Cl- influx.
Waters
S L
SL
Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205-7199, USA.
Sarang
S S
SS
Wang
K K
KK
Schnellmann
R G
RG
D000179:Acrylates / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002154:Calpain / Q000502:physiology*; D016923:Cell Death; D002712:Chlorides / Q000378:metabolism*; D009543:Nifedipine / Q000494:pharmacology; D011817:Rabbits
D000179:Acrylates; D002712:Chlorides; C100442:PD 150606; D002154:Calpain; D009543:Nifedipine; D002118:Calcium