Calcium entry and the control of calcium oscillations

During oscillatory Ca²⁺ signals, the agonist-induced enhanced entry of extracellular Ca²⁺ plays a critical role in modulating the frequency of the oscillations. Although it was originally assumed that the entry of Ca²⁺ under these conditions occurred via the well-known, and apparently ubiquitous, store-operated mechanism, subsequent studies suggested that this was unlikely. It is now known that, in many cell types, a novel non-capacitative Ca²⁺-selective pathway whose activation is dependent on arachidonic acid is responsible, and the channels involved [ARC channels (arachidonate-regulated Ca²⁺ channels)] have been characterized. These ARC channels co-exist with the store-operated CRAC channels (Ca²⁺-release-activated Ca²⁺ channel) in cells, but each plays a unique and non-overlapping role in Ca²⁺ signalling. In particular, it is the ARC channels that are specifically activated at the low agonist concentrations that give rise to oscillatory Ca²⁺ signals and provide the predominant mode of Ca²⁺ entry under these conditions. The indications are that Ca²⁺ entry through the ARC channels increases the likelihood that low concentrations of Ins(1,4,5)P₃ will trigger repetitive Ca²⁺ release. At higher agonist concentrations, store-depletion is more complete and sustained resulting in the activation of CRAC channels. At the same time the ARC channels are turned off, resulting in what we have described as a reciprocal regulation of these two distinct Ca²⁺ entry pathways.