Inositol 1,4,5-trisphosphate-induced Ca2+ release is inhibited by mitochondrial depolarization.
We investigated the consequences of depolarizing the mitochondrial membrane potential (Deltapsi(mit)) on Ca(2+) signals arising via inositol 1,4,5-trisphosphate receptors (InsP(3)R) in hormone-stimulated HeLa cells. Carbonyl cyanide p-trifluoromethoxyphenylhydrazone (FCCP) or a mixture of antimycin A+oligomycin were found to rapidly depolarize Deltapsi(mit). Mitochondrial depolarization enhanced the number of cells responding to a brief application of a Ca(2+)-mobilizing hormone and prolonged the recovery of cytosolic Ca(2+) after washout of the hormone; effects consistent with the removal of a passive Ca(2+) buffer. However, with repeated application of the same hormone concentration both the number of responsive cells and peak Ca(2+) changes were observed to progressively decline. The inhibition of Ca(2+) signalling was observed using different Ca(2+)-mobilizing hormones and also with a membrane-permeant Ins(1,4,5)P(3) ester. Upon washout of FCCP, the Ca(2+) signals recovered with a time course similar to the re-establishment of Deltapsi(mit). 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 Ca(2+)-store loading appeared to underlie the inhibition of Ca(2+) signalling. We therefore suggest that local changes in one or more of these factors, as a consequence of depolarizing Deltapsi(mit), prevents InsP(3)R activation.
Collins
T J
TJ
Laboratory of Molecular Signalling, The Babraham Institute, Babraham, Cambridge CB2 4AT, UK.
Lipp
P
P
Berridge
M J
MJ
Li
W
W
Bootman
M D
MD
D000255:Adenosine Triphosphate / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology; D000968:Antimycin A / Q000031:analogs & derivatives* / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000187:drug effects*; D002259:Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone / Q000494:pharmacology; D002463:Cell Membrane Permeability; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D006367:HeLa Cells; D006632:Histamine / Q000494:pharmacology; D006801:Humans; D006863:Hydrogen-Ion Concentration; D015544:Inositol 1,4,5-Trisphosphate / Q000494:pharmacology*; D007425:Intracellular Membranes / Q000187:drug effects / Q000378:metabolism; D008274:Magnesium / Q000378:metabolism; D008564:Membrane Potentials / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D010084:Oxidation-Reduction / Q000187:drug effects; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism; D013997:Time Factors
C032456:antimycin; D002259:Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone; D000968:Antimycin A; D006632:Histamine; D015544:Inositol 1,4,5-Trisphosphate; D000255:Adenosine Triphosphate; D017027:Protein Tyrosine Phosphatases; D008274:Magnesium; D002118:Calcium