An EF hand mutation in Stim1 causes premature platelet activation and bleeding in mice

Johannes Grosse; Attila Braun; David Varga-Szabo; Niklas Beyersdorf; Boris Schneider; Lutz Zeitlmann; Petra Hanke; Patricia Schropp; Silke Mühlstedt; Carolin Zorn; Michael Huber; Carolin Schmittwolf; Wolfgang Jagla; Philipp Yu; Thomas Kerkau; Harald Schulze; Michael Nehls; Bernhard Nieswandt

doi:10.1172/JCI32312

¹Ingenium Pharmaceuticals AG, Munich, Germany. ²Rudolf Virchow Center, DFG Research Center for Experimental Biomedicine, and ³Institute for Virology and Immunobiology, University of Würzburg, Würzburg, Germany. ⁴Max Planck Institute for Immunobiology, Freiburg, Germany. ⁵Laboratory for Pediatric Molecular Biology, Charité, Berlin, Germany. ⁶Institute of Clinical Biochemistry and Pathobiochemistry, University of Würzburg, Würzburg, Germany.

Address correspondence to: Bernhard Nieswandt, Rudolf Virchow Center, DFG Research Center for Experimental Biomedicine, University of Würzburg, Zinklesweg 10, 97078 Würzburg, Germany. Phone: 49-931-201-44060; Fax: 49-931-201-44068; E-mail: bernhard.nieswandt@virchow.uni-wuerzburg.de.

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Published October 25, 2007 - Version history
Received: April 4, 2007; Accepted: August 15, 2007

Changes in cytoplasmic Ca²⁺ levels regulate a variety of fundamental cellular functions in virtually all cells. In nonexcitable cells, a major pathway of Ca²⁺ entry involves receptor-mediated depletion of intracellular Ca²⁺ stores followed by the activation of store-operated calcium channels in the plasma membrane. We have established a mouse line expressing an activating EF hand motif mutant of stromal interaction molecule 1 (Stim1), an ER receptor recently identified as the Ca²⁺ sensor responsible for activation of Ca²⁺ release–activated (CRAC) channels in T cells, whose function in mammalian physiology is not well understood. Mice expressing mutant Stim1 had macrothrombocytopenia and an associated bleeding disorder. Basal intracellular Ca²⁺ levels were increased in platelets, which resulted in a preactivation state, a selective unresponsiveness to immunoreceptor tyrosine activation motif–coupled agonists, and increased platelet consumption. In contrast, basal Ca²⁺ levels, but not receptor-mediated responses, were affected in mutant T cells. These findings identify Stim1 as a central regulator of platelet function and suggest a cell type–specific activation or composition of the CRAC complex.

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An EF hand mutation in Stim1 causes premature platelet activation and bleeding in mice

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