β-arrestin-1 participates in thrombosis and regulates integrin α_IIbβ₃ signalling without affecting P2Y receptors desensitisation and function

Summary

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 α_IIbβ₃. β-arr1 appeared to be located downstream of Src family kinases and to regulate α_IIbβ₃ signalling by increasing Akt phosphorylation. Overall, this study supports a role for β-arr1 in promoting thrombus formation, in part through its participation in α_IIbβ₃ signalling, and no role of β-arr1 and β-arr2 in agonist-induced platelet activation and P2Y receptors desensitisation.

Keywords

β-arrestins - platelets - thrombosis - α_IIbβ₃ - Akt

• References

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