CRAC Channel

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.

STIM1 proteins span through the membrane of the ER, are competent in sensing luminal Ca ²⁺ concentration, and in turn, are responsible for relaying the signal of Ca²⁺ store-depletion to pore-forming Orai1 proteins in the plasma membrane. A direct interaction of STIM1 and Orai1 allows for the re-entry of Ca²⁺ from the extracellular space. CRAC channels are critical for lymphocyte function and immune responses. A driving force in the quest for CRAC channel drugs has been the immunocompromised phenotype displayed by humans and mice with null or loss-of-function mutations in STIM1 or Orai1, suggesting that CRAC channel inhibitors could be useful therapeutics for autoimmune or inflammatory conditions.