β-arrestin-1 participates in thrombosis and regulates integrin aIIbβ3 signalling without affecting P2Y receptors desensitisation and function.
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.
INSERM UMR-S949, Etablissement Français du Sang-Alsace (EFS-Alsace), 10, rue Spielmann, BP 36, F-67065 Strasbourg Cedex, France.
M
M
Schaff
N
N
Receveur
C
C
Bourdon
P
P
Ohlmann
F
F
Lanza
C
C
Gachet
P H
PH
Mangin
D000818:Animals; D019390:Arrestins / Q000096:biosynthesis*; D001792:Blood Platelets / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002339:Carotid Arteries / Q000473:pathology; D002448:Cell Adhesion; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005340:Fibrinogen / Q000378:metabolism; D006470:Hemorrhage; D008638:Mesenteric Arteries / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D008855:Microscopy, Electron, Scanning / Q000379:methods; D019007:P-Selectin / Q000378:metabolism; D010766:Phosphorylation; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000378:metabolism*; D058470:Receptors, Purinergic P2Y / Q000378:metabolism*; D015398:Signal Transduction; D013927:Thrombosis / Q000097:blood* / Q000378:metabolism; D000071559:beta-Arrestin 1; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins
C000605255:Arrb1 protein, mouse; C000605258:Arrb2 protein, mouse; D019390:Arrestins; D019007:P-Selectin; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D058470:Receptors, Purinergic P2Y; D000071559:beta-Arrestin 1; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins; D005340:Fibrinogen; D002118:Calcium