Background: Arrestin3 and arrestin2 function in G protein-coupled receptor (GPCR) desensitization and its signaling in concert with the GPCR kinases (GRKs) in various cells. Despite the importance of GPCR-mediated signaling in platelets, little is known regarding the mechanism of GPCR desensitization by arrestins in platelets.

Aims: Therefore, we determined the functional differences of arrestin3 versus arrestin2 in the regulation of GPCR signaling and the mechanism of GPCR desensitization by arrestin3 in platelets.

Methods: We used mice lacking arrestin3 and arrestin2 to evaluate their functional role in platelet activation.

Results: Platelet aggregation and dense-granule secretion induced by 2-MeSADP, thrombin, and AYPGKF were significantly potentiated in arrestin3-deficient platelets compared to wild-type (WT) platelets. However, platelet aggregation and secretion induced by AYPGKF and thrombin were significantly inhibited while 2-MeSADP was minimally affected in arrestin2-deficient platelets compared to WT platelets. Moreover, deficiency of arrestin2 and arrestin3 showed no effect on CRP-induced platelet aggregation and secretion. Recently, we have shown that GRK6 plays a role in platelet function through selective GPCR desensitization as it was not involved in the regulation of serotonin- and epinephrine-induced platelet aggregation. Surprisingly, in contrast to GRK6, platelet aggregation induced by co-stimulation of serotonin and epinephrine was significantly potentiated in arrestin3-deficient platelets suggesting the central role of arrestin3 in general GPCR desensitization in platelets. In addition, the second challenge of ADP and AYPGKF restored platelet aggregation in arrestin3-deficient platelets but failed to do so in WT and arrestin2-deficient platelets, confirming that arrestin3 contributes to GPCR desensitization. Furthermore, 2-MeSADP- and AYPGKF-induced Akt and ERK phosphorylation were significantly increased in arrestin3-deficient platelets. Finally, arrestin3-deficient mice were not protected against FeCl₃-induced in vivo thrombosis model, indicating that arrestin3 is critical for thrombus formation in vivo. 

Conclusions: In conclusion, arrestin3, not arrestin2, plays a central role in the regulation of platelet functional responses and thrombus formation through general GPCR desensitization.

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ISTH Congress Abstracts - https://abstracts.isth.org/abstract/the-predominant-role-of-arrestin3-in-general-gpcr-desensitization-in-platelets/