Orais and STIMs: physiological mechanisms and disease

Abstract

The stromal interaction molecules STIM1 and STIM2 are Ca2+ sensors, mostly located in the endoplasmic reticulum, that detect changes in the intraluminal Ca2+ concentration and communicate this information to plasma membrane store-operated channels, including members of the Orai family, thus mediating store-operated Ca2+ entry (SOCE). Orai and STIM proteins are almost ubiquitously expressed in human cells, where SOCE has been reported to play a relevant functional role. The phenotype of patients bearing mutations in STIM and Orai proteins, together with models of STIM or Orai deficiency in mice, as well as other organisms such as Drosophila melanogaster, have provided compelling evidence on the relevant role of these proteins in cellular physiology and pathology. Orai1-deficient patients suffer from severe immunodeficiency, congenital myopathy, chronic pulmonary disease, anhydrotic ectodermal dysplasia and defective dental enamel calcification. STIM1-deficient patients showed similar abnormalities, as well as autoimmune disorders. This review summarizes the current evidence that identifies and explains diseases induced by disturbances in SOCE due to deficiencies or mutations in Orai and STIM proteins.

Store-Operated Calcium Entry Promotes the Degradation of the Transcription Factor Sp4 in Resting Neurons

“…Deficiencies in STIM1 and Orai channels that cause aberrant SOCE contribute to the pathophysiology of cardiovascular, pulmonary, and autoimmune disorders (57, 58). For a long time, it has been recognized that dysregulation of Ca 2+ homeostasis is likely playing a central role in the etiology of neurodegenerative disorders (59, 60) and other recent evidence suggests that this may be also a feature that is common to several major psychiatric disorders (61).…”

Orai1 forms a signal complex with BKC a channel in mesenteric artery smooth muscle cells

“…Orai1 is widely expressed in many cell types, including vascular smooth muscle cells (VSMCs) and endothelial cells (Beech ; Berna‐Erro et al. ; Trebak ). Functionally, Orai1 activity is associated with vascular remodeling that relative to neointimal hyperplasia and angiogenesis.…”

STIM1 calcium sensor is required for activation of the phagocyte oxidase during inflammation and host defense

“…Stromalinteracting molecule 1 (STIM1) and STIM2 are the main calcium sensors within the ER that connect reduction of ER calcium stores to the plasma membrane channel proteins Orai1, -2, and -3. 7,8 Studies in neutrophil-like cell lines suggest that STIM1/Orai1-regulated calcium entry plays a significant role in activation of neutrophil phagocytosis and ROS production. 9,10 Neutrophils can also be activated by non-SOCE mechanisms that are independent of initial IP 3 -mediated depletion of ER calcium stores, primarily through transient receptor potential channel (TRPC) proteins.…”