Inositol 1,4,5-trisphosphate-induced Ca2+ release is inhibited by mitochondrial depolarization

Collins, Tony J.; Lipp, Peter; Berridge, Michael J.; Li, Wenhong and Bootman, Martin D. (2000). Inositol 1,4,5-trisphosphate-induced Ca2+ release is inhibited by mitochondrial depolarization. Biochemical Journal, 347(2) pp. 593–600.



We investigated the consequences of depolarizing the mitochondrial membrane potential (ΔΨmit) on Ca2+ signals arising via inositol 1,4,5-trisphosphate receptors (InsP3R) in hormone-stimulated HeLa cells. Carbonyl cyanide p-trifluoromethoxyphenylhydrazone (FCCP) or a mixture of antimycin A+oligomycin were found to rapidly depolarize ΔΨmit. Mitochondrial depolarization enhanced the number of cells responding to a brief application of a Ca2+-mobilizing hormone and prolonged the recovery of cytosolic Ca2+ after washout of the hormone; effects consistent with the removal of a passive Ca2+ buffer. However, with repeated application of the same hormone concentration both the number of responsive cells and peak Ca2+ changes were observed to progressively decline. The inhibition of Ca2+ signalling was observed using different Ca2+-mobilizing hormones and also with a membrane-permeant Ins(1,4,5)P3) ester. Upon washout of FCCP, the CaCa2+ signals recovered with a time course similar to the re-establishment of ΔΨmit. Global measurements indicated that none of the obvious factors such as changes in pH, ATP concentration, cellular redox state, permeability transition pore activation or reduction in Ca2+-store loading appeared to underlie the inhibition of Ca2+ signalling. We therefore suggest that local changes in one or more of these factors, as a consequence of depolarizing ΔΨmit, prevents InsP3R activation.

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