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The calcium sensor ...
The calcium sensor STIM1 is an essential mediator of arterial thrombosis and ischemic brain infarction
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Varga-Szabo, D (author)
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Braun, A (author)
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Kleinschnitz, C (author)
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Bender, M (author)
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Pleines, I (author)
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Pham, M (author)
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- Renne, T (author)
- Karolinska Institutet
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Stoll, G (author)
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Nieswandt, B (author)
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(creator_code:org_t)
- 2008-06-16
- 2008
- English.
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In: The Journal of experimental medicine. - : Rockefeller University Press. - 1540-9538 .- 0022-1007. ; 205:7, s. 1583-1591
- Related links:
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http://jem.rupress.o...
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http://kipublication...
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https://doi.org/10.1...
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Abstract
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- Platelet activation and aggregation are essential to limit posttraumatic blood loss at sites of vascular injury but also contributes to arterial thrombosis, leading to myocardial infarction and stroke. Agonist-induced elevation of [Ca2+]i is a central step in platelet activation, but the underlying mechanisms are not fully understood. A major pathway for Ca2+ entry in nonexcitable cells involves receptor-mediated release of intracellular Ca2+ stores, followed by activation of store-operated calcium (SOC) channels in the plasma membrane. Stromal interaction molecule 1 (STIM1) has been identified as the Ca2+ sensor in the endoplasmic reticulum (ER) that activates Ca2+ release–activated channels in T cells, but its role in mammalian physiology is unknown. Platelets express high levels of STIM1, but its exact function has been elusive, because these cells lack a normal ER and Ca2+ is stored in a tubular system referred to as the sarcoplasmatic reticulum. We report that mice lacking STIM1 display early postnatal lethality and growth retardation. STIM1-deficient platelets have a marked defect in agonist-induced Ca2+ responses, and impaired activation and thrombus formation under flow in vitro. Importantly, mice with STIM1-deficient platelets are significantly protected from arterial thrombosis and ischemic brain infarction but have only a mild bleeding time prolongation. These results establish STIM1 as an important mediator in the pathogenesis of ischemic cardio- and cerebrovascular events.
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