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β-arrestin-1 participates in thrombosis and regulates integrin aIIbβ3 signalling without affecting P2Y receptors desensitisation and function.: Role of β-arrestins in platelet function

Mathieu Schaff 1 Nicolas Receveur 2 Catherine Bourdon 2 Philippe Ohlmann 2 François Lanza 2 Christian Gachet 2 Pierre Henri Mangin 1, *
* Corresponding author
1 UMR_S949
http://www.u949.inserm.fr/ - Biologie et pharmacologie des plaquettes sanguines: hémostase, thrombose, transfusion
Abstract : β-arrestin-1 (β-arr1) and β-arrestin-2 (β-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 β-arr1 or β-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 β-arr1-/- and β-arr2-/- platelets. In addition, deficiency in β-arr1 or β-arr2 was not critical for P2Y receptors desensitisation. A functional redundancy between β-arr1 and β-arr2 may explain these unchanged platelet responses. Interestingly, β-arr1-/- but not β-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 β-arr1-/- and β-arr2-/- mice, suggesting no defect in haemostasis. β-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 αIIbβ3. β-arr1 appeared to be located downstream of Src family kinases and to regulate αIIbβ3 signalling by increasing Akt phosphorylation. Overall, this study supports a role for β-arr1 in promoting thrombus formation, in part through its participation in αIIbβ3 signalling, and no role of β-arr1 and β-arr2 in agonist-induced platelet activation and P2Y receptors desensitisation.
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Submitted on : Friday, February 8, 2013 - 7:00:03 AM
Last modification on : Thursday, March 15, 2018 - 1:36:44 AM

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Mathieu Schaff, Nicolas Receveur, Catherine Bourdon, Philippe Ohlmann, François Lanza, et al.. β-arrestin-1 participates in thrombosis and regulates integrin aIIbβ3 signalling without affecting P2Y receptors desensitisation and function.: Role of β-arrestins in platelet function. Thrombosis and Haemostasis, Schattauer, 2012, 107 (4), pp.735-48. ⟨10.1160/TH11-06-0430⟩. ⟨inserm-00678288⟩

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