Store‐Operated Calcium Entry Mediated by ORAI and STIM

ABSTRACT 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.