Calcineurin directs the reciprocal regulation of calcium entry pathways in nonexcitable cells.
The reciprocal regulation of noncapacitative and capacitative (or store-operated) Ca2+ entry in nonexcitable cells (Mignen, O., Thompson, J. L., and Shuttleworth, T. J. (2001) J. Biol. Chem. 276, 35676-35683) represents a switching between two distinct Ca2+-selective channels: the noncapacitative arachidonate-regulated Ca2+ channels (ARC channels) and the store-operated Ca2+ channels (SOC channels). This switch is directly associated with the change from oscillatory to sustained Ca2+ signals as agonist concentrations increase and involves a Ca2+-dependent inhibition of the ARC channels. Here we show that this process is mediated via a calcineurin-dependent inhibition of the noncapacitative ARC channels. Pharmacological and molecular inhibition of calcineurin activity (using cyclosporin or the FK506 analogue ascomycin, and a transfected C-terminal domain of the calcineurin inhibitory protein CAIN, respectively) results in a complete reversal of the Ca2+-dependent inhibition of the ARC channels. Agonist concentrations that result in oscillatory Ca2+ signals and specifically activate Ca2+ entry through the ARC channels fail to increase calcineurin activity. However, agonist concentrations that activate the store-operated Ca2+ channels and produce prolonged increases in cytosolic Ca2+ concentrations increase calcineurin activity. Thus, calcineurin is the key mediator of the reciprocal regulation of these co-existing channels, allowing each to play a unique and non-overlapping role in Ca2+ signaling.
Mignen
Olivier
O
Department of Pharmacology and Physiology, University of Rochester Medical Center, Rochester, New York 14642, USA.
Thompson
Jill L
JL
Shuttleworth
Trevor J
TJ
D019703:Calcineurin / Q000378:metabolism*; D065095:Calcineurin Inhibitors; D002118:Calcium / Q000494:pharmacology; D015220:Calcium Channels / Q000378:metabolism; D020013:Calcium Signaling / Q000502:physiology*; D002147:Calmodulin / Q000037:antagonists & inhibitors; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D016572:Cyclosporine / Q000494:pharmacology; D006801:Humans; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology; D016559:Tacrolimus / Q000031:analogs & derivatives* / Q000494:pharmacology; D014162:Transfection
D065095:Calcineurin Inhibitors; D015220:Calcium Channels; D002147:Calmodulin; D002352:Carrier Proteins; D011994:Recombinant Proteins; D013449:Sulfonamides; C017967:W 7; D016572:Cyclosporine; C058028:immunomycin; D019703:Calcineurin; D002118:Calcium; D016559:Tacrolimus