Orai1 and STIM1 in ER/PM junctions: Roles in pancreatic cell function and dysfunction

Membrane contact sites (MCS) are critical junctions that form between the endoplasmic reticulum (ER) and membranes of various organelles, including the plasma membrane (PM). Signaling complexes, including mediators of Ca²⁺ signaling, are assembled within MCS, such as the ER/PM junction. This is most evident in polarized epithelial cells, such as pancreatic cells. Core Ca²⁺ signaling proteins cluster at the apical pole, the site of inositol 1,4,5-trisphosphate-mediated Ca²⁺ release and Orai1/transient receptor potential canonical-mediated store-dependent Ca²⁺ entry. Recent advances have characterized the proteins that tether the membranes at MCS and the role of these proteins in modulating physiological and pathological intracellular signaling. This review discusses recent advances in the characterization of Ca²⁺ signaling at ER/PM junctions and the relation of these junctions to physiological and pathological Ca²⁺ signaling in pancreatic acini.