Reciprocal regulation of capacitative and arachidonate-regulated noncapacitative Ca2+ entry pathways.
Receptor-activated Ca(2+) entry is usually thought to occur via capacitative or store-operated Ca(2+) channels. However, at physiological levels of stimulation, where Ca(2+) store depletion is only transient and/or partial, evidence has suggested that an arachidonic acid-dependent noncapacitative Ca(2+) entry is responsible. Recently, we have described a novel arachidonate-regulated Ca(2+)-selective (ARC) conductance that is entirely distinct from store-operated conductances in the same cell. We now show that these ARC channels are indeed specifically activated by low agonist concentrations and provide the predominant route of Ca(2+) entry under these conditions. We further demonstrate that sustained elevations in cytosolic Ca(2+), such as those resulting from activation of store-operated Ca(2+) entry by high agonist concentrations, inhibit the ARC channels. This explains earlier failures to detect the presence of this noncapacitative pathway in experiments where store-operated entry had already been fully activated. The result is that the respective activities of ARC and store-operated Ca(2+) channels display a unique reciprocal regulation that is related to the specific nature of the [Ca(2+)](i) signals generated at different agonist concentrations. Importantly, these data show that at physiologically relevant levels of stimulation, it is the noncapacitative ARC channels that provide the predominant route for the agonist-activated entry of Ca(2+).
Mignen
O
O
Department of Pharmacology and Physiology, University of Rochester Medical Center, Rochester, New York 14642, USA.
Thompson
J L
JL
Shuttleworth
T J
TJ
D000470:Alkaloids / Q000494:pharmacology; D016718:Arachidonic Acid / Q000502:physiology*; D044182:Benzylisoquinolines; D002118:Calcium / Q000378:metabolism*; D002217:Carbachol / Q000494:pharmacology; D002460:Cell Line; D006801:Humans; D017136:Ion Transport; D018408:Patch-Clamp Techniques
D000470:Alkaloids; D044182:Benzylisoquinolines; D016718:Arachidonic Acid; C009438:tetrandrine; D002217:Carbachol; D002118:Calcium