Preeti K Chaudhary, Sanggu Kim, Satya P Kunapuli, Soochong Kim
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引用次数: 0
Abstract
Background: Many platelet agonists mediate their cellular effects through G protein-coupled receptors (GPCRs) to induce platelet activation, and GPCR kinases (GRKs) have been demonstrated to have crucial roles in most GPCR functions in other cell types. Here, we investigated the functional role of GRK3 and the molecular basis for the regulation of GPCR desensitization by GRK3 in platelets.
Methods: We used mice lacking GRK3 as well as β-arrestin2, which has been shown to be important in GPCR function in platelets.
Results: Platelet aggregation and dense granule secretion induced by 2-MeSADP, U46619, thrombin, and AYPGKF were significantly potentiated in both GRK3 -/- and β-arrestin2 -/- platelets compared with wild-type (WT) platelets, whereas non-GPCR agonist collagen-induced platelet aggregation and secretion were not affected. We have previously shown that GRK6 is not involved in the regulation of Gq-coupled 5HT2A and Gz-coupled α2A adrenergic receptors. Interestingly, in contrast to GRK6, platelet aggregation induced by costimulation of serotonin and epinephrine, which activate 5-HT2A and α2A adrenergic receptors, respectively, was significantly potentiated in GRK3 -/- platelets, suggesting that GRK3 is involved in general GPCR regulation. In addition, platelet aggregation in response to the second challenge of adenosine diphosphate was restored in GRK3 -/- platelets, whereas restimulation of the agonist failed to induce aggregation in WT platelets, confirming that GRK3 contributes to general GPCR desensitization. Furthermore, 2-MeSADP- and AYPGKF-induced AKT and ERK phosphorylation were significantly potentiated in GRK3 -/- platelets. Finally, GRK3 -/- mice showed shorter tail bleeding times compared with WT, indicating that GRK3 -/- mice is more susceptible to hemostasis.
Conclusion: GRK3 plays a crucial role in the regulation of platelet activation through general GPCR desensitization in platelets.
期刊介绍：
Thrombosis and Haemostasis publishes reports on basic, translational and clinical research dedicated to novel results and highest quality in any area of thrombosis and haemostasis, vascular biology and medicine, inflammation and infection, platelet and leukocyte biology, from genetic, molecular & cellular studies, diagnostic, therapeutic & preventative studies to high-level translational and clinical research. The journal provides position and guideline papers, state-of-the-art papers, expert analysis and commentaries, and dedicated theme issues covering recent developments and key topics in the field.
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