Review: Structure and Activation Mechanisms of CRAC Channels

Abstract

Ca²⁺ release activated Ca²⁺ (CRAC) channels represent a primary pathway for Ca²⁺ to enter non-excitable cells. The two key players in this process are the stromal interaction molecule (STIM), a Ca²⁺ sensor embedded in the membrane of the endoplasmic reticulum, and Orai, a highly Ca²⁺ selective ion channel located in the plasma membrane. Upon depletion of the internal Ca²⁺ stores, STIM is activated, oligomerizes, couples to and activates Orai. This review provides an overview of novel findings about the CRAC channel activation mechanisms, structure and gating. In addition, it highlights, among diverse STIM and Orai mutants, also the disease-related mutants and their implications.

Keywords: CRAC channel; Calcium; Electrophysiology; FRET; Gain-of-function mutants; Orai gating; Orai1; STIM-Orai interaction; STIM1; Structural resolution.