The molecular physiology of CRAC channels

Abstract

The Ca2+release-activated Ca2+ (CRAC) channel is a highly Ca2+-selective store-operated channel expressed in T cells, mast cells, and various other tissues. CRAC channels regulate critical cellular processes such as gene expression, motility, and the secretion of inflammatory mediators. The identification of Orai1, a key subunit of the CRAC channel pore, and STIM1, the endoplasmic reticulum (ER) Ca2+ sensor, have provided the tools to illuminate the mechanisms of regulation and the pore properties of CRAC channels. Recent evidence indicates that the activation of CRAC channels by store depletion involves a coordinated series of steps, which include the redistributions of STIM1 and Orai1, direct physical interactions between these proteins, and conformational changes in Orai1, culminating in channel activation. Additional studies have revealed that the high Ca2+ selectivity of CRAC channels arises from the presence of an intrapore Ca2+ binding site, the properties of which are finely honed to occlude the permeation of the much more prevalent Na+. Structure-function studies have led to the identification of the potential pore-binding sites for Ca2+, providing a firm framework for understanding the mechanisms of selectivity and gating of the CRAC channel. This review summarizes recent progress in understanding the mechanisms of CRAC channel activation, pore properties, and modulation.

Fig. 1. Predicted topology of Orai1

Critical amino acids residues identified from structure-function and human linkage-analysis studies are highlighted. Mutations of E106 in TM1 and E190 in TM3 (yellow) affect ion selectivity and permeation, whereas mutations of the aspartate residues in the TM1-TM2 loop segment (D110/112/114, yellow) affect La³⁺ block while producing relatively small changes in ion permeation. An inherited mutation (R91W, red) produces non-functional CRAC channels and immunodeficiency in human patients.