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

J Clin Invest. 2007 Nov;117(11):3540-50. 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bone Marrow / pathology
  • Calcium / metabolism*
  • Calcium Channels / metabolism
  • EF Hand Motifs / genetics*
  • Fibrosis / pathology
  • Hemorrhage* / genetics
  • Hemorrhage* / metabolism
  • Megakaryocytes / cytology
  • Megakaryocytes / metabolism
  • Membrane Glycoproteins / genetics
  • Membrane Glycoproteins / metabolism*
  • Mice
  • Mice, Inbred Strains
  • Mutation*
  • Platelet Activation* / genetics
  • Platelet Membrane Glycoproteins / metabolism
  • Signal Transduction / physiology
  • Splenomegaly / metabolism
  • Stromal Interaction Molecule 1
  • T-Lymphocytes / cytology
  • T-Lymphocytes / metabolism
  • Thrombocytopenia* / genetics
  • Thrombocytopenia* / metabolism


  • Calcium Channels
  • Membrane Glycoproteins
  • Platelet Membrane Glycoproteins
  • Stim1 protein, mouse
  • Stromal Interaction Molecule 1
  • Calcium