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Pflugers Arch - Eur J Physiol (2010) 460:417435 DOI 10.1007/s00424-009-0777-5
ION CHANNELS, RECEPTORS AND TRANSPORTERS
CRAC channelopathies
Stefan Feske
Received: 24 November 2009 /Accepted: 15 December 2009 /Published online: 29 January 2010 # Springer-Verlag 2010
Abstract Store-operated Ca2+ entry (SOCE) is an important Ca2+ influx pathway in many non-excitable and some excitable cells. It is regulated by the filling state of intracellular Ca2+ stores, notably the endoplasmic reticulum (ER). Reduction in [Ca2+]ER results in activation of plasma membrane Ca2+ channels that mediate sustained Ca2+ influx which is required for many cell functions as well as refilling of Ca2+ stores. The Ca2+ release activated Ca2+ (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 [Ca2+]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 clinicallyimmunodeficiency, 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.
Keywords ORAI1 . STIM1 . CRAC . SOCE . Store-operated calcium entry . Ca2+ . Tcells . B cells .
Mast cells . Lymphocytes . Immunodeficiency. SCID . Signal transduction . Myopathy. Muscle . Ectodermal dysplasia . Amelogenesis . Platelets . Gene-targeting . Mice
AbbreviationsCRAC Calcium release activated calcium (channel) EDA Anhydrotic ectodermal dysplasiaSCID Severe combined immunodeficiency SERCA Sarcoplasmic/endoplasmic reticulum Ca2+
ATPaseSOCE Store-operated calcium entry STIM1 Stromal interaction molecule 1 VSMC Vascular smooth muscle cells
Store-operated Ca2+ entry (SOCE) and CRAC channels
Initially known under the name capacitative Ca2+ entry, this Ca2+ influx pathway is now referred to mostly as store-operated Ca2+ entry...