GRK2 regulates ADP signaling in platelets via P2Y1 and P2Y12.
GRK2 regulates ADP signaling in platelets via P2Y1 and P2Y12.
复制标题
DOI：
10.1182/bloodadvances.2022007007
复制
发表时间：
2022-08-09
期刊：
影响因子：
7.5
通讯作者：
Ma, Peisong
中科院分区：
文献类型：
--
作者：
Zhao, Xuefei;Cooper, Matthew;Michael, James V.;Yarman, Yanki;Baltz, Aiden;Chuprun, J. Kurt;Koch, Walter J.;McKenzie, Steven E.;Tomaiuolo, Maurizio;Stalker, Timothy J.;Zhu, Li;Ma, Peisong
G蛋白偶联受体激酶2（GRK 2）在调节心脏功能中的关键作用已被充分记录超过30年。因此，靶向GRK 2作为治疗心血管疾病的新方法已被广泛研究。然而，关于其在止血和血栓形成中的作用知之甚少。我们在此提供了GRK 2限制血小板活化并调节对损伤的止血反应的第一个证据。小鼠血小板中GRK 2的缺失导致激光诱导的提睾肌小动脉损伤后血小板聚集增加，缩短尾部出血时间，并增强5′-二磷酸腺苷（ADP）诱导的肺血栓栓塞症和FeCl 3诱导的颈动脉损伤中的血栓形成。GRK 2 −/−血小板对ADP刺激的反应是增加整合素活化、P-选择素暴露和血小板聚集。此外，GRK 2 −/−血小板保留了对ADP再刺激的聚集能力，表明GRK 2有助于ADP受体脱敏。GRK 2 −/−血小板中这些变化的基础是ADP刺激的Ca 2+动员、RAS相关蛋白1激活和Akt磷酸化的增加，以及在前列腺素I2存在下ADP引起的环磷酸腺苷水平的减弱升高。P2 Y12拮抗剂治疗消除了野生型和GRK 2 −/−小鼠在损伤部位血小板聚集的表型差异。人血小板中GRK 2活性的药理学抑制增加血小板对ADP的响应活化。最后，我们发现GRK 2在血小板活化过程中与内源性Gβγ亚基结合。总的来说，这些结果表明GRK 2通过P2 Y1和P2 Y12调节ADP信号传导，与Gβγ相互作用，并作为血小板中的信号传导中心用于调节对损伤的止血反应。GRK 2通过限制ADP P2 Y1和P2 Y12介导的信号传导来调节止血反应。维持血小板中GRK 2活性可能有利于预防血栓性疾病。
The critical role of G protein–coupled receptor kinase 2 (GRK2) in regulating cardiac function has been well documented for >3 decades. Targeting GRK2 has therefore been extensively studied as a novel approach to treating cardiovascular disease. However, little is known about its role in hemostasis and thrombosis. We provide here the first evidence that GRK2 limits platelet activation and regulates the hemostatic response to injury. Deletion of GRK2 in mouse platelets causes increased platelet accumulation after laser-induced injury in the cremaster muscle arterioles, shortens tail bleeding time, and enhances thrombosis in adenosine 5′-diphosphate (ADP)-induced pulmonary thromboembolism and in FeCl3-induced carotid injury. GRK2−/− platelets have increased integrin activation, P-selectin exposure, and platelet aggregation in response to ADP stimulation. Furthermore, GRK2−/− platelets retain the ability to aggregate in response to ADP restimulation, indicating that GRK2 contributes to ADP receptor desensitization. Underlying these changes in GRK2−/− platelets is an increase in Ca2+ mobilization, RAS-related protein 1 activation, and Akt phosphorylation stimulated by ADP, as well as an attenuated rise of cyclic adenosine monophosphate levels in response to ADP in the presence of prostaglandin I2. P2Y12 antagonist treatment eliminates the phenotypic difference in platelet accumulation between wild-type and GRK2−/− mice at the site of injury. Pharmacologic inhibition of GRK2 activity in human platelets increases platelet activation in response to ADP. Finally, we show that GRK2 binds to endogenous Gβγ subunits during platelet activation. Collectively, these results show that GRK2 regulates ADP signaling via P2Y1 and P2Y12, interacts with Gβγ, and functions as a signaling hub in platelets for modulating the hemostatic response to injury. GRK2 regulates the hemostatic response by limiting ADP P2Y1- and P2Y12-mediated signaling. Maintaining GRK2 activity in platelets may be beneficial for prevention of thrombotic diseases.
登录
查看更多内容
DOI：
10.1074/jbc.m116.746867
发表时间：
2017-02-03
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Battram AM;Durrant TN;Agbani EO;Heesom KJ;Paul DS;Piatt R;Poole AW;Cullen PJ;Bergmeier W;Moore SF;Hers I
通讯作者：
Hers I
DOI：
10.1073/pnas.93.23.12974
发表时间：
1996-11-12
影响因子：
11.1
作者：
Jaber, M;Koch, WJ;Giros, B
通讯作者：
Giros, B
影响因子：
5.6
作者：
Chaudhary, Preeti Kumari;Kim, Sanggu;Kim, Soochong
通讯作者：
Kim, Soochong
影响因子：
7.5
作者：
Chen, Xi;Gupta, Shuchi;Ma, Peisong
通讯作者：
Ma, Peisong
影响因子：
3.9
作者：
Chaudhary PK;Kim S;Kim S
通讯作者：
Kim S