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

作者:Grosse Johannes*; Braun Attila; Varga Szabo David; Beyersdorf Niklas; Schneider Boris; Zeitlmann Lutz; Hanke Petra; Schropp Patricia; Muehlstedt Silke; Zorn Carolin; Huber Michael; Schmittwolf Carolin; Jagla Wolfgang; Yu Philipp; Kerkau Thomas; Schulze Harald; Nehls Michael; Nieswandt Bernhard
来源:Journal of Clinical Investigation, 2007, 117(11): 3540-3550.


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.

  • 出版日期2007-11