Figure 1

Regulatory mechanism of [Ca²⁺] _i homeostasis. (A) Store-operated calcium entry (SOCE) in non-excitable cells. The activation of surface receptors stimulates phospholipase C (PLC) to increase the second messenger inositol-1,4,5-trisphosphate (IP3), which binds to the IP3 receptor in the endoplasmic reticulum (ER) membrane and causes rapid and transient Ca²⁺ release from the ER lumen. The decrease in ER luminal Ca²⁺ results in the opening of the plasmalemmal store-operated Ca²⁺ (SOC) channel, leading to the elevated intracellular Ca²⁺ levels ([Ca²⁺]_i). (B) Domain architecture of the ER Ca²⁺ sensor stromal interaction molecule 1 (STIM1) protein. STIM1 is a single-transmembrane protein that is mainly localized in the endoplasmic reticulum (ER). The luminal N-terminus contains a canonical EF hand motif that binds Ca²⁺, a hidden EF hand that does not bind Ca²⁺, and a sterile α-motif (SAM) domain that is important for STIM1 oligomerization. The cytosolic C-terminus contains the coiled-coil domains, a STIM-Orai activating region (SOAR) or CRAC activation domain (CAD), and serine or proline (S/P)-rich segments and lysine (K)-rich clusters. The SOAR/CAD domain is essential for the gating of Orai1. The predicted protein-protein interaction domains in STIM1 include the SAM domain, coiled-coil domains, SOAR/CAD domain, S/P-rich segments and K-rich clusters. (C) Predicted topology of the plasmalemmal SOC channel Orai1. Orai1 consists of four transmembrane domains (TM1-TM4) and intracellular N- and C-termini. It is suggested that the TM1 lines the central pore of Orai1 channel. The short C-terminal putative coiled-coil domain is important for binding to the SOAR/CAD domain of STIM1, and its disruption impairs STIM1-mediated activation of Orai1 channel. Hexagonal structures represent glycosyl residues attached to an arginine (N)-linked glycosylation site (N²²³).