A capacitative calcium current in cultured skeletal muscle cells is mediated by the calcium-specific leak channel and inhibited by dihydropyridine compounds.
Calcium stores from cultured skeletal muscle cells were depleted using cyclopiazonic acid (CPA), a reversible inhibitor of Ca2+-ATPases at the sarcoplasmic reticulum. Store depletion led to activation of the calcium-specific leak channel, as assayed using single-channel patch clamp analysis and rates of manganese influx and quenching of fura-2 fluorescence. Two novel dihydropyridine compounds inhibited this single-channel leak channel activity, the resting and depletion-induced manganese influx, and refilling of the CPA-depleted intracellular calcium store. These compounds represent the first antagonists for a calcium leak channel and for a channel that mediates a capacitative current. The development of the skeletal muscle capacitative current was inhibited by genistein, a tyrosine kinase inhibitor, but was not affected by okadaic acid, a phosphatase inhibitor, or econazole. Thus, the capacitative current in cultured skeletal muscle cells was mediated by the calcium leak channel and was inhibited by pharmacological antagonists and may provide a model system for uncovering the complete set of signals leading from store depletion to channel activation.
Hopf
F W
FW
Department of Molecular and Cell Biology, University of California at Berkeley, Berkeley, California, 94720, USA.
Reddy
P
P
Hong
J
J
Steinhardt
R A
RA
D000818:Animals; D015220:Calcium Channels / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D002478:Cells, Cultured; D004095:Dihydropyridines / Q000494:pharmacology*; D004121:Dimethyl Sulfoxide / Q000494:pharmacology; D004464:Econazole / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D019833:Genistein; D007211:Indoles / Q000494:pharmacology; D007529:Isoflavones / Q000494:pharmacology; D008345:Manganese / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism*; D009543:Nifedipine / Q000494:pharmacology
C101669:AN 1043; C101668:AN 406; D015220:Calcium Channels; D004095:Dihydropyridines; D004791:Enzyme Inhibitors; D007211:Indoles; D007529:Isoflavones; D008345:Manganese; D004464:Econazole; D019833:Genistein; D009543:Nifedipine; C000543:cyclopiazonic acid; D004121:Dimethyl Sulfoxide