Calcium release-activated calcium channel protein 1 (ORAI1) (ORAI1)

Calcium release-activated calcium channel protein 1 (ORAI1) is the essential pore-forming component of the Calcium Release-Activated Calcium (CRAC) channel, which serves as the primary gateway for Store-Operated Calcium Entry (SOCE) in many cell types (UniProt Q96D31). The channel is activated when endoplasmic reticulum (ER) calcium stores are depleted, causing the ER-resident sensor STIM1 to cluster and bind to ORAI1 at the plasma membrane (PubMed: 16582901). This influx of calcium is vital for sustained intracellular signaling, particularly the activation of the NFAT transcription factor, which regulates the immune response and cytokine production (PubMed: 16645049). Dysregulation or mutations in ORAI1 are linked to severe combined immunodeficiency (SCID), myopathy, and various inflammatory diseases (PubMed: 24651019). Pharmacological inhibitors of ORAI1, such as CM4620, are being investigated for their potential to treat acute pancreatitis and other systemic inflammatory response syndromes by dampening excessive calcium-driven immune activation (ClinicalTrials.gov: NCT03401190). Because ORAI1 is also expressed in non-immune tissues, therapeutic development must carefully manage potential side effects such as anhidrosis and muscle dysfunction.

Other names

CRACM1TMEM142AORAI calcium release-activated calcium modulator 1Calcium release-activated calcium channel protein 1CRAC channel

Inhibition of store-operated calcium entry (SOCE) by blocking the ORAI1 pore or preventing the interaction between ORAI1 and the calcium sensor STIM1.