Store-Operated Calcium Entry Mediated by ORAI and STIM.

The calcium release-activated calcium (CRAC) channel, composed of ORAI and stromal interaction molecules (STIM), represents a prototypical example of store-operated calcium entry in mammals. The ORAI-STIM signaling occurs at membrane contact sites formed by close appositions between the endoplasmic reticulum (ER) and the plasma membrane. ORAI1 is a four-pass transmembrane protein that forms a highly calcium-selective ion channel in the plasma membrane. STIM1 is an ER-resident, a single-pass transmembrane protein that serves as a calcium sensor within the ER lumen and a potent activator of ORAI1 calcium channels. The intricate interplay between ORAI and STIM controls calcium entry into cells to regulate a myriad of physiological processes. We highlight herein the current knowledge on the structure-function relationship of CRAC channel, with a focus on key structural elements that mediate STIM1 conformational switch and the dynamic coupling between STIM1 and ORAI1. Furthermore, we discuss the physiological roles of STIM-ORAI signaling in various tissues and organs, as well as major pathological conditions arising from loss- or gain-of-function mutations in human ORAI1 and STIM1. © 2017 American Physiological Society. Compr Physiol 8:981-1002, 2018.

With the greatest care, stromal interaction molecule (STIM) proteins verify what skeletal muscle is doing.

Skeletal muscle contracts or relaxes to maintain the body position and locomotion. For the contraction and relaxation of skeletal muscle, Ca2＋ in the cytosol of skeletal muscle fibers acts as a switch to turn on and off a series of contractile proteins. The cytosolic Ca2＋ level in skeletal muscle fibers is governed mainly by movements of Ca2＋ between the cytosol and the sarcoplasmic reticulum (SR). Store-operated Ca2＋ entry (SOCE), a Ca2＋ entryway from the extracellular space to the cytosol, has gained a significant amount of attention from muscle physiologists. Orai1 and stromal interaction molecule 1 (STIM1) are the main protein identities of SOCE. This mini-review focuses on the roles of STIM proteins and SOCE in the physiological and pathophysiological functions of skeletal muscle and in their correlations with recently identified proteins, as well as historical proteins that are known to mediate skeletal muscle function. [BMB Reports 2018; 51(8): 378-387].