β-arrestin-1 participates in thrombosis and regulates integrin αIIbβ3 signalling without affecting P2Y receptors desensitisation and function

Abstract

<jats:title>Summary</jats:title><jats:p>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&lt;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.</jats:p>

Anti-thrombotic effects of α-linolenic acid isolated from Zanthoxylum bungeanum Maxim seeds

“…It has been evidenced that the process of platelet aggregation and thrombus formation was related to the P-selectin secretion and GP IIb/IIIa activation which was also cross-linked Akt activation [24, 25]. Our current results provided the certainly evidence that ALA can reduce P-selectin secretion and GP IIb/IIIa expression obviously.…”

Platelet function and microparticle levels in atrial fibrillation: Changes during the acute episode

“…Desensitization can be brought about by internalization of PAR-1 receptors, a process often seen in vascular cells, but limited in platelets as shown by electron microscopy and immunogold labeling of platelet sections of thrombin-stimulated platelets [24]. Alternatively, desensitization can be mediated through an arrestin-dependent pathway, again reported in nucleated cells but for platelets only reported for PAR-4 [25,26]. A third way of modulating PAR-1 activation has been shown for platelets incubated with TRAP peptide and consists of the desensitization of PAR-1 signaling, including a decrease in Ca 2+ mobilization, restricted protein kinase C substrate phosphorylation and reduced secretion but not associated with a modification of PAR-1 expression on platelet surface [27].…”

The platelet P2Y12 receptor under normal and pathological conditions. Assessment with the radiolabeled selective antagonist [3H]PSB-0413

“…For example, there is a debate on whether the platelet P2Y 12 receptor rapidly desensitizes and undergoes trafficking upon agonist activation [30][31][32][33][34][35][36]. Similarly, polymorphisms of the P2Y 12 receptor have been proposed to be associated with a gain of function in terms of platelet activation and an increased risk of cardiovascular disease [37][38][39][40][41], but the relative densities and binding properties of the platelet P2Y 12 receptor associated with these polymorphisms are not known.…”