Authors: Attila Braun, David Varga-Szabo, Christoph Kleinschnitz, Irina Pleines, Markus Bender, Madeleine Austinat, Michael Bosl, Guido Stoll, Bernhard Nieswandt
Blood. 11/2008;
Platelet activation and aggregation at sites of vascular injury is essential for primary hemostasis, but is also a major pathomechanism underlying myocardial infarction and stroke. Changes inPlatelet activation and aggregation at sites of vascular injury is essential for primary hemostasis, but is also a major pathomechanism underlying myocardial infarction and stroke. Changes in [Ca(2+)]i are a central step in platelet activation. In non-excitable cells receptor-mediated depletion of intracellular Ca(2+) stores triggers Ca(2+) entry through store-operated calcium (SOC) channels. STIM1 has been identified as an endoplasmic reticulum (ER)-resident Ca(2+) sensor that regulates store-operated calcium entry (SOCE) in immune cells and platelets, but the identity of the platelet SOC channel has remained elusive. Orai1 (CRACM1) is the recently discovered SOC (CRAC) channel in T-cells and mast cells but its role in mammalian physiology is unknown. Here we report that Orai1 is strongly expressed in human and mouse platelets. To test its role in blood clotting, we generated Orai1-deficient mice and found that their platelets display severely defective SOCE, agonist-induced Ca(2+) responses, and impaired activation and thrombus formation under flow in vitro. As a direct consequence, Orai1-deficiency in mice results in resistance to pulmonary thromboembolism, arterial thrombosis and ischemic brain infarction, but only a mild bleeding time prolongation. These results establish Orai1 as the long-sought platelet SOC channel and a crucial mediator of ischemic cardio- and cerebrovascular events.
