Stromal interaction molecule 1 and Calcium release-activated calcium channel protein 1 (STIM1/Orai1)

The STIM1/Orai1 complex constitutes the molecular basis of the calcium release-activated calcium (CRAC) channel, a primary pathway for store-operated calcium entry (SOCE) in non-excitable cells [1, 5]. Stromal interaction molecule 1 (STIM1) acts as a calcium sensor within the endoplasmic reticulum (ER) lumen; upon depletion of ER calcium stores, STIM1 oligomerizes and translocates to ER-plasma membrane junctions [2, 7]. There, it physically interacts with and gates Orai1, the pore-forming subunit located in the plasma membrane, allowing for a sustained influx of extracellular calcium [1, 9]. This signaling mechanism is essential for diverse physiological processes, most notably the activation and proliferation of T-lymphocytes and the regulation of gene expression via the NFAT pathway [1, 8]. Dysregulation of the STIM1/Orai1 complex is linked to a variety of human pathologies. Loss-of-function mutations lead to severe combined immunodeficiency (SCID)-like syndromes, while gain-of-function mutations are associated with myopathies and platelet disorders such as Stormorken syndrome [5, 8]. In oncology, the complex is often overexpressed and contributes to tumor cell migration and metastasis [1, 6]. Consequently, the STIM1/Orai1 interaction has emerged as a significant therapeutic target for inflammatory diseases, autoimmune disorders, and certain cancers, with several small-molecule inhibitors currently in clinical and preclinical development [6, 7, 11].

Other names

CRAC channelCalcium release-activated calcium channelSTIM1Orai1CRACM1TMEM142AGOKStore-operated calcium channel

Inhibition of store-operated calcium entry (SOCE) by blocking the Orai1 pore or preventing the physical interaction between the STIM1 calcium sensor and the Orai1 channel subunit [1, 2, 11].