The Predominant Role of Arrestin3 in General GPCR Desensitization in Platelets.
The Predominant Role of Arrestin3 in General GPCR Desensitization in Platelets.
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DOI：
10.3390/jcm10204743
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发表时间：
2021-10-15
影响因子：
3.9
通讯作者：
Kim S
中科院分区：
文献类型：
--
作者：
Chaudhary PK;Kim S;Kim S
抑制蛋白与GPCR激酶（GRKs）在各种细胞中的G蛋白偶联受体（GPCR）脱敏中起作用。因此，我们使用缺乏arrestin 3和arrestin 2的小鼠表征了arrestin 3与arrestin 2在GPCR信号转导调节及其在血小板中的脱敏中的功能差异。与arrestin 2相反，与野生型（WT）血小板相比，arrestin 3缺陷型血小板中由2-MeSADP、U46619、凝血酶和AYPGKF诱导的血小板聚集和致密颗粒分泌显著增强，而非GPCR激动剂CRP诱导的血小板聚集和分泌不受影响。令人惊讶的是，与GRK 6相反，由5-羟色胺和肾上腺素的共刺激诱导的血小板聚集在arrestin 3缺陷型血小板中显著增强，表明arrestin 3在血小板中的一般GPCR脱敏中的中心作用。此外，ADP和AYPGKF的第二次挑战恢复了arrestin 3缺陷型血小板中的血小板聚集，但在WT和arrestin 2缺陷型血小板中未能做到这一点，证实了arrestin 3有助于GPCR脱敏。此外，ADP-和AYPGKF-诱导Akt和ERK磷酸化显着增加arrestin 3缺陷血小板。最后，我们发现arrestin 3是体内血栓形成的关键。总之，arrestin 3，而不是arrestin 2，通过血小板中的一般GPCR脱敏在血小板功能反应和血栓形成的调节中起着核心作用。
Arrestins in concert with GPCR kinases (GRKs) function in G protein-coupled receptor (GPCR) desensitization in various cells. Therefore, we characterized the functional differences of arrestin3 versus arrestin2 in the regulation of GPCR signaling and its desensitization in platelets using mice lacking arrestin3 and arrestin2. In contrast to arrestin2, platelet aggregation and dense granule secretion induced by 2-MeSADP, U46619, thrombin, and AYPGKF were significantly potentiated in arrestin3-deficient platelets compared to wild-type (WT) platelets, while non-GPCR agonist CRP-induced platelet aggregation and secretion were not affected. Surprisingly, in contrast to GRK6, platelet aggregation induced by the 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, ADP- and AYPGKF-induced Akt and ERK phosphorylation were significantly increased in arrestin3-deficient platelets. Finally, we found that arrestin3 is critical for thrombus formation in vivo. In conclusion, arrestin3, not arrestin2, plays a central role in the regulation of platelet functional responses and thrombus formation through general GPCR desensitization in platelets.
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DOI：
10.1161/atvbaha.111.242388
发表时间：
2012-05
期刊：
Arteriosclerosis, thrombosis, and vascular biology
影响因子：
--
作者：
Bynagari-Settipalli YS;Lakhani P;Jin J;Bhavaraju K;Rico MC;Kim S;Woulfe D;Kunapuli SP
通讯作者：
Kunapuli SP
影响因子：
64.8
作者：
Goodman, OB;Krupnick, JG;Benovic, JL
通讯作者：
Benovic, JL
影响因子：
56.9
作者：
Bohn, LM;Lefkowitz, RJ;Lin, FT
通讯作者：
Lin, FT
影响因子：
64.8
作者：
Latorraca NR;Wang JK;Bauer B;Townshend RJL;Hollingsworth SA;Olivieri JE;Xu HE;Sommer ME;Dror RO
通讯作者：
Dror RO
影响因子：
3.2
作者：
Du, Xiaoping
通讯作者：
Du, Xiaoping