Journal
THROMBOSIS AND HAEMOSTASIS
Volume 107, Issue 4, Pages 735-748Publisher
SCHATTAUER GMBH-VERLAG MEDIZIN NATURWISSENSCHAFTEN
DOI: 10.1160/TH11-06-0430
Keywords
beta-arrestins; platelets; thrombosis; alpha(IIb)beta(3); Akt
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Funding
- ARMESA (Association de Recherche et Developpement en Medecine et Sante Publique)
- Bourse Grenelle from the French government
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beta-arrestin-1 (beta-arr1) and beta-arrestin-2 (beta-arr2) are cytosolic proteins well-known to participate in G protein-coupled receptor desensitisation and signalling. We used genetically-inactivated mice to evaluate the role of beta-arr1 or beta-arr2 in platelet function, P2Y receptor desensitisation, haemostasis and thrombosis. Platelet aggregation, soluble fibrinogen binding and P-selectin exposure induced by various agonists were near normal in beta-arr1(-/-) and beta-arr2(-/-) platelets. In addition, deficiency in beta-arr1 or beta-arr2 was not critical for P2Y receptors desensitisation. A functional redundancy between beta-arr1 and beta-arr2 may explain these unchanged platelet responses. Interestingly, beta-arr1(-/-) but not beta-arr2(-/-) mice were protected against laser- and FeCl3-induced thrombosis. The tail bleeding times, number of rebleeds and volume of blood loss were unchanged in beta-arr1(-/-) and beta-arr2(-/-) mice, suggesting no defect in haemostasis. beta-arr1(-/-) platelet activation upon adhesion to immobilised fibrinogen was inhibited, as attested by a 37 +/- 5% (n = 3, p<0.0001) decrease in filopodia extension, suggesting defective signalling through integrin alpha(IIb)beta(3). beta-arr1 appeared to be located downstream of Src family kinases and to regulate alpha(IIb)beta(3) signalling by increasing Akt phosphorylation. Overall, this study supports a role for beta-arr1 in promoting thrombus formation, in part through its participation in alpha(IIb)beta(3) signalling, and no role of beta-arr1 and beta-arr2 in agonist-induced platelet activation and P2Y receptors desensitisation.
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