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Abstract
Issue Title: Channelopathies
Store-operated Ca^sup 2^sup +^^ entry (SOCE) is an important Ca^sup 2+^ influx pathway in many non-excitable and some excitable cells. It is regulated by the filling state of intracellular Ca^sup 2+^ stores, notably the endoplasmic reticulum (ER). Reduction in [Ca^sup 2+^]^sub ER^ results in activation of plasma membrane Ca^sup 2+^ channels that mediate sustained Ca^sup 2+^ influx which is required for many cell functions as well as refilling of Ca^sup 2+^ stores. The Ca^sup 2+^ release activated Ca^sup 2+^ (CRAC) channel is the best characterized SOC channel with well-defined electrophysiological properties. In recent years, the molecular components of the CRAC channel, long mysterious, have been defined. ORAI1 (or CRACM1) acts as the pore-forming subunit of the CRAC channel in the plasma membrane. Stromal interaction molecule (STIM) 1 is localized in the ER, senses [Ca^sup 2+^]^sub ER^, and activates the CRAC channel upon store depletion by binding to ORAI1. Both proteins are widely expressed in many tissues in both human and mouse consistent with the widespread prevalence of SOCE and CRAC channel currents in many cells types. CRAC channelopathies in human patients with mutations in STIM1 and ORAI1 are characterized by abolished CRAC channel currents, lack of SOCE and--clinically--immunodeficiency, congenital myopathy, and anhydrotic ectodermal dysplasia. This article reviews the role of ORAI and STIM proteins for SOCE and CRAC channel function in a variety of cell types and tissues and compares the phenotypes of ORAI1 and STIM1-deficient human patients and mice with targeted deletion of Orai and Stim genes.[PUBLICATION ABSTRACT]