Orai channels are pore forming proteins which underlie calcium release-activated calcium (CRAC) channels. When calcium is lost from the endoplasmic reticulum, they form complexes with STIM (stromal interaction molecule) proteins to trigger calcium entry following store depletion [1].

The pathophysiological effect of functional CRAC channel deficiency can be caused by loss-of-function mutations in ORAI1 or STIM molecules. Such CRAC channelopathies are characterised by impaired immune cell function and have been identified as an underlying cause of primary immunodeficiency with predominant features that resemble severe combined immunodeficiency disease.
ORAI1 and ORAI2 proteins form heteromeric complexes that constitute the pore of Ca²⁺ release-activated Ca²⁺ (CRAC) channels. Mice with double Orai1/Orai2 knockout have severely impaired T cell function.

* Key recommended reading is highlighted with an asterisk

* Lewis RS. (2020) Store-Operated Calcium Channels: From Function to Structure and Back Again. Cold Spring Harb Perspect Biol, 12 (5). DOI: 10.1101/cshperspect.a035055 [PMID:31570335]

1. Lewis RS. (2020) Store-Operated Calcium Channels: From Function to Structure and Back Again. Cold Spring Harb Perspect Biol, 12 (5). DOI: 10.1101/cshperspect.a035055 [PMID:31570335]

2. Liardo E, Pham AT, Ghilardi AF, Zhelay T, Szteyn K, Gandi NL, Ekkati A, Koerner S, Kozak JA, Sun L. (2024) Discovery of selective Orai channel blockers bearing an indazole or a pyrazole scaffold. Eur J Med Chem, 278: 116805. [PMID:39232360]