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J. Exp. Med. 205 (7): 1583-1591

Copyright © 2008 by the Rockefeller University Press.


The calcium sensor STIM1 is an essential mediator of arterial thrombosis and ischemic brain infarction

David Varga-Szabo1, Attila Braun1, Christoph Kleinschnitz2, Markus Bender1, Irina Pleines1, Mirko Pham3,5, Thomas Renné4, Guido Stoll2, , and Bernhard Nieswandt1,4

1 Rudolf Virchow Center, DFG Research Center for Experimental Biomedicine, 2 Department of Neurology, 3 Department of Neuroradiology, and 4 Institute of Clinical Biochemistry and Pathobiochemistry, University of Würzburg, 97078 Würzburg, Germany
5 Department of Neuroradiology, University of Heidelberg, 69120 Heidelberg, Germany

CORRESPONDENCE Bernhard Nieswandt: bernhard.nieswandt{at}

Abstract: Platelet activation and aggregation are essential to limit posttraumatic blood loss at sites of vascular injury but also contributes to arterial thrombosis, leading to myocardial infarction and stroke. Agonist-induced elevation of [Ca2+]i is a central step in platelet activation, but the underlying mechanisms are not fully understood. A major pathway for Ca2+ entry in nonexcitable cells involves receptor-mediated release of intracellular Ca2+ stores, followed by activation of store-operated calcium (SOC) channels in the plasma membrane. Stromal interaction molecule 1 (STIM1) has been identified as the Ca2+ sensor in the endoplasmic reticulum (ER) that activates Ca2+ release–activated channels in T cells, but its role in mammalian physiology is unknown. Platelets express high levels of STIM1, but its exact function has been elusive, because these cells lack a normal ER and Ca2+ is stored in a tubular system referred to as the sarcoplasmatic reticulum. We report that mice lacking STIM1 display early postnatal lethality and growth retardation. STIM1-deficient platelets have a marked defect in agonist-induced Ca2+ responses, and impaired activation and thrombus formation under flow in vitro. Importantly, mice with STIM1-deficient platelets are significantly protected from arterial thrombosis and ischemic brain infarction but have only a mild bleeding time prolongation. These results establish STIM1 as an important mediator in the pathogenesis of ischemic cardio- and cerebrovascular events.

D. Varga-Szabo and A. Braun contributed equally to this paper.

© 2008 Varga-Szabo et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at

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