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- Title
An EF hand mutation in Stim1 causes premature platelet activation and bleeding in mice.
- 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; Mühlstedt, Silke
- 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.
- Subjects
BLOOD platelet activation; PLATELET activating factor; CELL membranes; LABORATORY mice; CELL physiology
- Publication
Journal of Clinical Investigation, 2007, Vol 117, Issue 11, p3540
- ISSN
0021-9738
- Publication type
journal article
- DOI
10.1172/JCI32312