title: Regulation of STIM1/Orai1-dependent Ca2+ signalling in platelets.
abstract: Platelet secretion and aggregation as well as thrombus formation of blood platelets critically depend on increase of cytosolic Ca2+ concentration ([Ca2+]i) mainly resulting from intracellular Ca2+ release followed by store operated Ca2+ entry (SOCE) through Ca2+ release activated channels (CRAC). SOCE is in part accomplished by the pore forming unit Orai and its regulator stromal interaction molecule (STIM). Orai1 and STIM1 transcription is stimulated by NF-κB (nuclear factor kappa B). Serum- and glucocorticoid-inducible kinase 1 (SGK1) up-regulates NF-κB-activity in megakaryocytes and thus Orai1-expression and SOCE in platelets. SGK1 is thus a powerful regulator of platelet Ca2+-signalling and thrombus formation and presumably participates in the regulation of platelet activation by a variety of hormones as well as clinical conditions (e.g. type 2 diabetes or metabolic syndrome) associated with platelet hyperaggregability and increased risk of thromboocclusive events. SOCE in platelets is further regulated by scaffolding protein Homer and chaperone protein cyclophilin A (CyPA). Additional potential regulators of Orai1/STIM1 and thus SOCE in platelets include AMP activated kinase (AMPK), protein kinase A (PKA), reactive oxygen species, lipid rafts, pH and mitochondrial Ca2+ buffering. Future studies are required defining the significance of those mechanisms for platelet Orai1 abundance and function, for SOCE into platelets and for platelet function in cardiovascular diseases.
authors.affiliation: Florian Lang, MD, Department of Physiology, University of Tübingen, Gmelinstr. 5, 72076 Tübingen, Germany, Tel.: +49 7071 29 72194, Fax: +49 7071 29 5618, E-mail: florian.lang@uni-tuebingen.de.
authors.forename: F
authors.initials: F
authors.lastname: Lang
authors.forename: P
authors.initials: P
authors.lastname: Münzer
authors.forename: M
authors.initials: M
authors.lastname: Gawaz
authors.forename: O
authors.initials: O
authors.lastname: Borst
mesh_terms: D000818:Animals; D001792:Blood Platelets / Q000378:metabolism*; D015220:Calcium Channels / Q000378:metabolism*; D020013:Calcium Signaling; D003924:Diabetes Mellitus, Type 2 / Q000276:immunology*; D006801:Humans; D017874:Immediate-Early Proteins / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism*; D024821:Metabolic Syndrome / Q000276:immunology*; D016328:NF-kappa B / Q000378:metabolism; D009363:Neoplasm Proteins / Q000378:metabolism*; D000071740:ORAI1 Protein; D015539:Platelet Activation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D000071737:Stromal Interaction Molecule 1; D000099184:Serum-Glucocorticoid Regulated Kinases
chemical_list: D015220:Calcium Channels; D017874:Immediate-Early Proteins; D008565:Membrane Proteins; D016328:NF-kappa B; D009363:Neoplasm Proteins; D000071740:ORAI1 Protein; D017346:Protein Serine-Threonine Kinases; D017382:Reactive Oxygen Species; D000071737:Stromal Interaction Molecule 1; D000099184:Serum-Glucocorticoid Regulated Kinases; C510746:ORAI1 protein, human; C103530:STIM1 protein, human
keywords: Ca2+ (arterial thrombosis); Platelet physiology; kinases; polymorphisms; signal transduction