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

The Ca²⁺ release-activated Ca²⁺ (CRAC) channel is a highly Ca²⁺ -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 Ca²⁺ ([Ca²⁺]_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 IP₃ 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 Ca²⁺. Attempts to maintain current size by removing intracellular Mg²⁺ have been found to unmask Mg²⁺-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 Ca²⁺ in the pore to achieve high Ca²⁺ selectivity but have a surprisingly low conductance for both Ca²⁺ (∼10fS) 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.