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Roles of platelet STIM1 and Orai1 in glycoprotein VI- and thrombin-dependent procoagulant activity and thrombus formation.
- Source :
-
The Journal of biological chemistry [J Biol Chem] 2010 Jul 30; Vol. 285 (31), pp. 23629-38. Date of Electronic Publication: 2010 Jun 02. - Publication Year :
- 2010
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Abstract
- In platelets, STIM1 has been recognized as the key regulatory protein in store-operated Ca(2+) entry (SOCE) with Orai1 as principal Ca(2+) entry channel. Both proteins contribute to collagen-dependent arterial thrombosis in mice in vivo. It is unclear whether STIM2 is involved. A key platelet response relying on Ca(2+) entry is the surface exposure of phosphatidylserine (PS), which accomplishes platelet procoagulant activity. We studied this response in mouse platelets deficient in STIM1, STIM2, or Orai1. Upon high shear flow of blood over collagen, Stim1(-/-) and Orai1(-/-) platelets had greatly impaired glycoprotein (GP) VI-dependent Ca(2+) signals, and they were deficient in PS exposure and thrombus formation. In contrast, Stim2(-/-) platelets reacted normally. Upon blood flow in the presence of thrombin generation and coagulation, Ca(2+) signals of Stim1(-/-) and Orai1(-/-) platelets were partly reduced, whereas the PS exposure and formation of fibrin-rich thrombi were normalized. Washed Stim1(-/-) and Orai1(-/-) platelets were deficient in GPVI-induced PS exposure and prothrombinase activity, but not when thrombin was present as co-agonist. Markedly, SKF96365, a blocker of (receptor-operated) Ca(2+) entry, inhibited Ca(2+) and procoagulant responses even in Stim1(-/-) and Orai1(-/-) platelets. These data show for the first time that: (i) STIM1 and Orai1 jointly contribute to GPVI-induced SOCE, procoagulant activity, and thrombus formation; (ii) a compensating Ca(2+) entry pathway is effective in the additional presence of thrombin; (iii) platelets contain two mechanisms of Ca(2+) entry and PS exposure, only one relying on STIM1-Orai1 interaction.
- Subjects :
- Animals
Blood Platelets metabolism
Calcium chemistry
Calcium metabolism
Female
Mice
Mice, Inbred C57BL
Mice, Transgenic
Models, Biological
ORAI1 Protein
Stromal Interaction Molecule 1
Calcium Channels metabolism
Coagulants metabolism
Membrane Glycoproteins metabolism
Platelet Membrane Glycoproteins metabolism
Thrombin metabolism
Thrombosis metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1083-351X
- Volume :
- 285
- Issue :
- 31
- Database :
- MEDLINE
- Journal :
- The Journal of biological chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 20519511
- Full Text :
- https://doi.org/10.1074/jbc.M110.108696