Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.3.16 (calcineurin)
 17,112 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
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PMID:Calcineurin directs the reciprocal regulation of calcium entry pathways in nonexcitable cells. 1287 77

In many nonexcitable cells, stimulation with low agonist concentrations specifically activates Ca2+ entry via arachidonic acid-regulated, highly Ca2+-selective ARC channels. Only at high agonist concentrations are the more widely studied store-operated channels activated, producing sustained elevated cytosolic Ca2+ concentration signals. These signals activate calcineurin, which in turn inhibits the ARC channels, resulting in a "reciprocal regulation" of these two distinct Ca2+-entry pathways that may have important functional implications for the cell.
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PMID:ARC channels: a novel pathway for receptor-activated calcium entry. 1554 53

In many non-excitable cells, the predominant mode of agonist-activated Ca(2+) entry switches from the arachidonic acid-regulated Ca(2+) (ARC) channels at low agonist concentrations, to store-operated channels at high concentrations. Underlying this process is the inhibition of the ARC channels by a calcineurin-mediated dephosphorylation, which inhibits the ability of arachidonic acid to activate the channels. Following such a dephosphorylation, we found that restoration of the sensitivity of the ARC channels to arachidonic acid, as well as to low concentrations of carbachol, was specifically dependent on protein kinase A (PKA) activity. Inhibition of protein kinase C, protein kinase G or calmodulin-activated kinase had no effect. This action of PKA was unaffected by prolonged intracellular dialysis, whilst disruption of the binding of PKA to A-kinase anchoring proteins (AKAPs) inhibited currents through ARC channels, and blocked the PKA-dependent effects. AKAP79, a protein which scaffolds both PKA and calcineurin, was shown to be present in the cells. These data illustrate the significance of PKA-dependent phosphorylation and calcineurin-dependent dephosphorylation in the overall regulation of ARC channel activity, and indicate the key role of an AKAP, possibly AKAP79, in the spatial organization these processes.
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PMID:Arachidonate-regulated Ca2+-selective (ARC) channel activity is modulated by phosphorylation and involves an A-kinase anchoring protein. 1599 85