Orais and STIMs: physiological mechanisms and disease.
Bottom Line: Orai and STIM proteins are almost ubiquitously expressed in human cells, where SOCE has been reported to play a relevant functional role.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.
Affiliation: Department of Physiology, University of Extremadura, Cáceres, Spain.Show MeSH
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Mentions: A great advances in the understanding of SOCE has been done over the last years. The discovery of Orai and STIM isoforms as essential players of SOCE, where the participation of TRPC proteins and IP3R has also been described [Refs. [141, 142]; Fig. 3), helped to unravel the function of this mechanism in cell physiology. The phenotypic analysis of patients lacking these proteins showed a major function of Orai1- and STIM1-dependent SOCE in cells of the immune system, skeletal muscle some ectodermal-derived tissues such as sweat glands and teeth. Interestingly, cardiomyopathies were not reported in these patients, indicating a more prominent role of Orai1- and STIM1-dependent SOCE in skeletal muscle fibres than in cardiomyocytes. Studies in Orai1- and STIM1-deficient murine transgenic models performed in parallel complemented our knowledge of the mechanisms underlying disease in the absence of these proteins. The similar phenotype found in mouse and humans indicates that transgenic models could be suitable models to investigate novel therapies based on Orai, STIM and SOCE modulation. In addition, these models provided insights of new functions of SOCE in other tissues and pathological evens, such as ischaemic stroke and autoimmune diseases. The in vivo roles of their homologues Orai2, Orai3 and in a less extent STIM2 are still unclear, having overlapping functions which their respective isoforms in vitro. A major role for STIM1 and Orai1 in all tissues is unlikely, regarding the presence of SOCE in many cell types which did not show altered function in patients or mice lacking functional Orai1 and STIM1. Current evidence points out these molecules as new therapeutic targets, especially those related with immune disorders, severe T cell–dependent inflammatory diseases or cancer. Existing studies revealed that compared to current treatments (FK506, CsA and OKT3), Orai1 inhibitors could have a potential for higher efficacy without the need for expensive and side-effect-prone co-administration of additional immunosuppressants such as glucocorticoids (reviewed in Ref. ). However, the presence of immune-unrelated pathologies in the Orai1- or STIM1-deficient patients and the ubiquitous expression pattern of these molecules are issues that still have to be addressed for complete validation of these proteins as suitable therapeutic targets. In addition, members of the TRPC family were recently found to interact directly or indirectly to both STIM1 and Orai1 [55, 144] (reviewed in Ref. ), indicating that such TRPC members could participate as SOCE components, or that Orai and STIM1 could be involved in regulation of TRPC-dependent Ca2+ entry as well . Because TRP channels are involved in a variety of physiological processes such as stress responses to noxious stimuli or thermo- and vasoregulation  (reviewed in Ref. ), the possibility that Orai or STIM inhibitors could elicit significant unwanted side effects by co-inhibition of other Orai- or STIM-interacting channels must be addressed as well .
Affiliation: Department of Physiology, University of Extremadura, Cáceres, Spain.