CRAC channels: activation, permeation, and the search for a molecular identity

The Ca 2+ release-activated Ca 2+ (CRAC) channel is a highly Ca 2+-selective store-operated channel that is expressed in T lymphocytes, mast cells, and other hematopoietic cells. In T cells, CRAC channels are essential for generating the prolonged intracellular Ca 2+ ([Ca 2+] i) elevation required for the expression of T-cell activation genes. Here we review recent work addressing CRAC channel regulation, pore properties, and the search for CRAC channel genes. Of the current models for CRAC current ( I CRAC) activation, several new studies argue against a conformational coupling mechanism in which IP 3 receptors communicate store depletion to CRAC channels through direct physical interaction. The study of CRAC channels has been complicated by the fact that they lose activity in the absence of extracellular Ca 2+. Attempts to maintain current size by removing intracellular Mg 2+ have been found to unmask Mg 2+-inhibited cation (MIC/MagNuM/TRPM7) channels, which have been mistaken in several studies for the CRAC channel. Recent studies under conditions that prevent MIC activation reveal that CRAC channels use high-affinity binding of Ca 2+ in the pore to achieve high Ca 2+ selectivity but have a surprisingly low conductance for both Ca 2+ (∼10 fS) and Na + (∼0.2 pS). Pore properties provide a unique fingerprint that provides a stringent test for potential CRAC channel genes and suggest models for the ion selectivity mechanism.