CaT1 manifests the pore properties of the calcium-release-activated calcium channel

The calcium-release-activated Ca2+ channel, I-CRAC(1-3), is a highly Ca2+-s elective ion channel that is activated on depletion of either intracellular Ca2+ levels or intracellular Ca2+ stores. The unique gating of I-CRAC has made it a favourite target of investigation for new signal transduction mec hanisms; however, without molecular identification of the channel protein, such studies have been inconclusive. Here we show that the protein CaT1 (re f. 4), which has six membrane-spanning domains, exhibits the unique biophys ical properties of I-CRAC when expressed in mammalian cells. Like I-CRAC, e xpressed CaT1 protein is Ca2+ selective, activated by a reduction in intrac ellular Ca2+ concentration, and inactivated by higher intracellular concent rations of Ca2+. The channel is indistinguishable from I-CRAC in the follow ing features: sequence of selectivity to divalent cations; an anomalous mol e fraction effect; whole-cell current kinetics; block by lanthanum; loss of selectivity in the absence of divalent cations; and single-channel conduct ance to Na+ in divalent-ion-free conditions. CaT1 is activated by both pass ive and active depletion of calcium stores. We propose that CaT1 comprises all or part of the I-CRAC pore.