Orai1 (CRACM1) is the platelet SOC channel and essential for pathological thrombus formation.
Platelet activation and aggregation at sites of vascular injury are essential for primary hemostasis, but are also major pathomechanisms underlying myocardial infarction and stroke. Changes in [Ca(2+)](i) are a central step in platelet activation. In nonexcitable 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 mild bleeding time prolongation. These results establish Orai1 as the long-sought platelet SOC channel and a crucial mediator of ischemic cardiovascular and cerebrovascular events.
Braun
Attila
A
Rudolf Virchow Center, DFG Research Center for Experimental Biomedicine, Würzburg, Germany.
Varga-Szabo
David
D
Kleinschnitz
Christoph
C
Pleines
Irina
I
Bender
Markus
M
Austinat
Madeleine
M
Bösl
Michael
M
Stoll
Guido
G
Nieswandt
Bernhard
B
D000818:Animals; D001792:Blood Platelets / Q000378:metabolism* / Q000502:physiology; D001835:Body Weight / Q000235:genetics; D002545:Brain Ischemia / Q000235:genetics / Q000473:pathology; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D005260:Female; D006801:Humans; D008562:Membrane Glycoproteins / Q000235:genetics / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017202:Myocardial Ischemia / Q000235:genetics / Q000473:pathology; D000071740:ORAI1 Protein; D000071737:Stromal Interaction Molecule 1; D013927:Thrombosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology
D015220:Calcium Channels; D008562:Membrane Glycoproteins; D000071740:ORAI1 Protein; C520430:Orai1 protein, mouse; C100757:Stim1 protein, mouse; D000071737:Stromal Interaction Molecule 1; D002118:Calcium