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

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Abstract

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.

Authors

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