Reciprocal regulation of capacitative and arachidonate-regulated noncapacitative Ca2+ entry pathways

Receptor-activated Ca2+ entry is usually thought to occur via capacitative or store-operated Ca2+ channels. However, at physiological levels of stimul ation, where Ca2+ store depletion is only transient and/or partial, evidenc e has suggested that an arachidonic acid-dependent noncapacitative Ca2+ ent ry is responsible. Recently, we have described a novel arachidonate-regulat ed Ca2+-selective (ARC) conductance that is entirely distinct from store-op erated conductances in the same cell. We now show that these ARC channels a re indeed specifically activated by low agonist concentrations and provide the predominant route of Ca2+ entry under these conditions. We further demo nstrate that sustained elevations in cytosolic Ca2+, such as those resultin g from activation of store-operated Ca2+ entry by high This agonist concent rations, inhibit the ARC channels. explains earlier failures to detect the presence of this noncapacitative pathway in experiments where store-operate d entry had already been fully activated. The result is that the respective activities of ARC and store-operated Ca2+ channels display a unique recipr ocal regulation that is related to the specific nature of the [Ca2+](i) sig nals generated at different agonist concentrations. Importantly, these data show that at physiologically relevant levels of stimulation, it is the non capacitative ARC channels that provide the predominant route for the agonis t-activated entry of Ca2+.