Molecular physiology and pathophysiology of stromal interaction molecules

Ca²⁺ release from the endoplasmic reticulum is an important component of Ca²⁺ signal transduction that controls numerous physiological processes in eukaryotic cells. Release of Ca²⁺ from the endoplasmic reticulum is coupled to the activation of store-operated Ca²⁺ entry into cells. Store-operated Ca²⁺ entry provides Ca²⁺ for replenishing depleted endoplasmic reticulum Ca²⁺ stores and a Ca²⁺ signal that regulates Ca²⁺-dependent intracellular biochemical events. Central to connecting discharge of endoplasmic reticulum Ca²⁺ stores following G protein-coupled receptor activation with the induction of store-operated Ca²⁺ entry are stromal interaction molecules (STIM1 and STIM2). These highly homologous endoplasmic reticulum transmembrane proteins function as sensors of the Ca²⁺ concentration within the endoplasmic reticulum lumen and activators of Ca²⁺ release-activated Ca²⁺ channels. Emerging evidence indicates that in addition to their role in Ca²⁺ release-activated Ca²⁺ channel gating and store-operated Ca²⁺ entry, STIM1 and STIM2 regulate other cellular signaling events. Recent studies have shown that disruption of STIM expression and function is associated with the pathogenesis of several diseases including autoimmune disorders, cancer, cardiovascular disease, and myopathies. Here, we provide an overview of the latest developments in the molecular physiology and pathophysiology of STIM1 and STIM2. Impact statement Intracellular Ca²⁺ signaling is a fundamentally important regulator of cell physiology. Recent studies have revealed that Ca²⁺-binding stromal interaction molecules (Stim1 and Stim2) expressed in the membrane of the endoplasmic reticulum (ER) are essential components of eukaryote Ca²⁺ signal transduction that control the activity of ion channels and other signaling effectors present in the plasma membrane. This review summarizes the most recent information on the molecular physiology and pathophysiology of stromal interaction molecules. We anticipate that the work presented in our review will provide new insights into molecular interactions that participate in interorganelle signaling crosstalk, cell function, and the pathogenesis of human diseases.