An EF hand mutation in Stim1 causes premature platelet activation and bleeding in mice.
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.
Grosse
Johannes
J
Ingenium Pharmaceuticals AG, Munich, Germany.
Braun
Attila
A
Varga-Szabo
David
D
Beyersdorf
Niklas
N
Schneider
Boris
B
Zeitlmann
Lutz
L
Hanke
Petra
P
Schropp
Patricia
P
Mühlstedt
Silke
S
Zorn
Carolin
C
Huber
Michael
M
Schmittwolf
Carolin
C
Jagla
Wolfgang
W
Yu
Philipp
P
Kerkau
Thomas
T
Schulze
Harald
H
Nehls
Michael
M
Nieswandt
Bernhard
B
D000818:Animals; D001853:Bone Marrow / Q000473:pathology; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000378:metabolism; D020832:EF Hand Motifs / Q000235:genetics*; D005355:Fibrosis / Q000473:pathology; D006470:Hemorrhage / Q000235:genetics / Q000378:metabolism; D008533:Megakaryocytes / Q000166:cytology / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008815:Mice, Inbred Strains; D009154:Mutation; D015539:Platelet Activation / Q000235:genetics; D010980:Platelet Membrane Glycoproteins / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D013163:Splenomegaly / Q000378:metabolism; D000071737:Stromal Interaction Molecule 1; D013601:T-Lymphocytes / Q000166:cytology / Q000378:metabolism; D013921:Thrombocytopenia / Q000235:genetics / Q000378:metabolism
D015220:Calcium Channels; D008562:Membrane Glycoproteins; D010980:Platelet Membrane Glycoproteins; C100757:Stim1 protein, mouse; D000071737:Stromal Interaction Molecule 1; D002118:Calcium