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

• Published in: The Journal of clinical investigation 2007-11, Vol.117 (11), p.3540-3550
• Main Authors: Grosse, Johannes, Braun, Attila, Varga-Szabo, David, Beyersdorf, Niklas, Schneider, Boris, Zeitlmann, Lutz, Hanke, Petra, Schropp, Patricia, Mühlstedt, Silke, Zorn, Carolin, Huber, Michael, Schmittwolf, Carolin, Jagla, Wolfgang, Yu, Philipp, Kerkau, Thomas, Schulze, Harald, Nehls, Michael, Nieswandt, Bernhard
• Format: Article
• Language: English
• Subjects: Activation; Animals; Biomedical research; Blood clots; Blood platelets; Bone marrow; Bone Marrow - pathology; Calcium - metabolism; Calcium Channels - metabolism; Care and treatment; Complications and side effects; EF Hand Motifs - genetics; Fibrosis - pathology; Gene expression; Health aspects; Hemorrhage; Hemorrhage - genetics; Hemorrhage - metabolism; Lymphocytes; Megakaryocytes - cytology; Megakaryocytes - metabolism; Membrane Glycoproteins - genetics; Membrane Glycoproteins - metabolism; Mice; Mice, Inbred Strains; Mutation; Physiology; Platelet Activation - genetics; Platelet Membrane Glycoproteins - metabolism; Risk factors; Signal Transduction - physiology; Splenomegaly - metabolism; Stromal Interaction Molecule 1; T-Lymphocytes - cytology; T-Lymphocytes - metabolism; Thrombocytopenia - genetics; Thrombocytopenia - metabolism
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/jci32312

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.