Calcium release-activated calcium channel protein 2 and 3 (Orai2/Orai3)

Calcium release-activated calcium channel protein 2 and 3 (Orai2 and Orai3) are highly selective calcium-conducting proteins that serve as pore-forming subunits of the CRAC channel complex [1, 2]. They are activated by the depletion of endoplasmic reticulum calcium stores, a process sensed by STIM proteins, which then recruit Orai subunits to the plasma membrane to facilitate store-operated calcium entry (SOCE) [1, 10]. While Orai1 is the dominant isoform in many tissues, Orai2 and Orai3 are increasingly recognized for their roles in modulating the magnitude and frequency of calcium oscillations, particularly in non-excitable cells [2, 14]. Orai3 is notably overexpressed in certain malignancies, such as luminal breast cancer and prostate cancer, where it promotes cell survival, proliferation, and resistance to chemotherapy [3, 5, 8]. Orai2 has been implicated in the regulation of immune cell function and is also linked to cancer progression [3, 14]. Therapeutic strategies targeting these proteins involve small-molecule inhibitors like GSK-7975A and BTP2 (YM-58483), which aim to normalize calcium signaling in disease states [2, 9, 17]. However, the development of isoform-specific modulators remains a significant challenge due to the high structural similarity between Orai family members and the potential for systemic toxicity [4, 7].

Other names

Orai2Orai3TMEM142BTMEM142CCBCIP2Calcium release-activated calcium modulator 2Calcium release-activated calcium modulator 3

Inhibition of store-operated calcium entry (SOCE) by blocking the pore-forming subunits of the CRAC channel or disrupting the interaction with STIM proteins.