STIM1 and store-operated Ca2+ entry (SOCE) in health and disease

Calcium (Ca 2+ ) is a universal second messenger with seminal function and pleiotropic effect across virtually all cell types and tissues. One of the main mechanisms controlling cellular Ca 2+ balance is store-operated Ca 2+ entry (SOCE), which essentially depends on the Ca 2+ sensor STIM1 and the Ca 2+ channel ORAI1. Together, STIM1 and ORAI1 regulate a broad range of signaling pathways and physiological processes including cell proliferation and migration, nerve conduction, immune response, thrombus formation, and muscle contraction. STIM1 activity is highly tissue-dependent and finely tuned by the cellular context and multiple regulatory layers such as post-translational modifications, alternative splicing, and the interaction with partner proteins. Conversely, STIM1 dysregulation through genetic mutations or environmental factors can profoundly impair Ca 2+ homeostasis and lead to human diseases. In this review, we explore the tissue-specific roles of STIM1, summarize the current knowledge on STIM1 regulation and function in immune cells, skeletal and cardiac muscle, platelets, secretory epithelial cells, and neurons, discuss the molecular and biochemical pathomechanisms underlying STIM1-related disorders including tubular aggregate myopathy (TAM), Stormorken syndrome (STRMK), immunodeficiency, neurodegeneration, and cancer, and shed light on the implication of STIM1 in the process of aging. Finally, we address the relevance of STIM1 and SOCE as therapeutic targets for both common and rare Ca 2+ -related disorders, and outline the emerging strategies aiming to restore Ca 2+ homeostasis and providing encouraging results from preclinical studies and early clinical trials.