G protein-coupled receptor kinase 5 regulates thrombin signaling in platelets via PAR-1.
G protein-coupled receptor kinase 5 regulates thrombin signaling in platelets via PAR-1.
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DOI：
10.1182/bloodadvances.2021005453
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发表时间：
2022-04-12
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：
Downes, Kate;Zhao, Xuefei;Gleadall, Nicholas S.;McKinney, Harriet;Kempster, Carly;Batista, Joana;Thomas, Patrick L.;Cooper, Matthew;Michael, James, V;Kreuzhuber, Roman;Wedderburn, Katherine;Waller, Kathryn;Varney, Bianca;Verdier, Hippolyte;Kriek, Neline;Ashford, Sofie E.;Stirrups, Kathleen E.;Dunster, Joanne L.;McKenzie, Steven E.;Ouwehand, Willem H.;Gibbins, Jonathan M.;Yang, Jing;Astle, William J.;Ma, Peisong
通过 PAR-1 凝血酶受体的血小板反应性由 GRK5 介导。血小板 GRK5 与人类和小鼠的血栓形成有关。血小板对激动剂激活的功能反应的个体差异是可遗传的。血小板功能定量测量的全基因组关联研究 (GWAS) 已识别出不到 20 个明显相关的变异，其中一些具有未知的机制。在这里，我们在 1562 名个体的子集中报告了对腺苷 5′-二磷酸（一种糖蛋白 VI 特异性胶原模拟物）和凝血酶受体激动剂肽（每种对 G 蛋白偶联受体 PAR-1 和 PAR-4 中的一种具有特异性）的激动作用的通路特异性功能反应的 GWAS。我们发现 G 蛋白偶联受体激酶 5 基因 (GRK5) 中常见的内含子变异 rs10886430 与血小板通过 PAR-1 激活的敏感性之间存在关联 (P = 2.75 × 10−40)。该变体存在于与转录因子 GATA1 和 MEIS1 结合的巨核细胞特异性增强子中。小等位基因 (G) 与血小板中较少的 GRK5 转录物以及血小板通过 PAR-1 激活的较高敏感性相关。我们发现，凝血酶介导的人血小板激活导致 GRK5 与 PAR-1 结合，并且小鼠同源物 Grk5 的缺失增强了凝血酶诱导的血小板激活敏感性，并增加了血管损伤部位的血小板积累。这证实了 rs10886430 的人类 G 等位基因与心血管疾病的更大风险相关的证据。总之，通过将人类途径特异性 GWAS 和表达数量性状位点研究的结果与 Grk5−/− 小鼠血小板功能研究的结果相结合，我们获得了 GRK5 通过 PAR-1 途径调节人类血小板对凝血酶反应的证据。
Platelet reactivity via the PAR-1 thrombin receptor is mediated by GRK5. Platelet GRK5 is associated with thrombus formation in humans and mice. The interindividual variation in the functional response of platelets to activation by agonists is heritable. Genome-wide association studies (GWASs) of quantitative measures of platelet function have identified fewer than 20 distinctly associated variants, some with unknown mechanisms. Here, we report GWASs of pathway-specific functional responses to agonism by adenosine 5′-diphosphate, a glycoprotein VI–specific collagen mimetic, and thrombin receptor-agonist peptides, each specific to 1 of the G protein–coupled receptors PAR-1 and PAR-4, in subsets of 1562 individuals. We identified an association (P = 2.75 × 10−40) between a common intronic variant, rs10886430, in the G protein–coupled receptor kinase 5 gene (GRK5) and the sensitivity of platelets to activate through PAR-1. The variant resides in a megakaryocyte-specific enhancer that is bound by the transcription factors GATA1 and MEIS1. The minor allele (G) is associated with fewer GRK5 transcripts in platelets and the greater sensitivity of platelets to activate through PAR-1. We show that thrombin-mediated activation of human platelets causes binding of GRK5 to PAR-1 and that deletion of the mouse homolog Grk5 enhances thrombin-induced platelet activation sensitivity and increases platelet accumulation at the site of vascular injury. This corroborates evidence that the human G allele of rs10886430 is associated with a greater risk for cardiovascular disease. In summary, by combining the results of pathway-specific GWASs and expression quantitative trait locus studies in humans with the results from platelet function studies in Grk5−/− mice, we obtain evidence that GRK5 regulates the human platelet response to thrombin via the PAR-1 pathway.
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影响因子：
64.5
作者：
Astle, William J.;Elding, Heather;Soranzo, Nicole
通讯作者：
Soranzo, Nicole
影响因子：
20.3
作者：
Edelstein, Leonard C.;Simon, Lukas M.;Bray, Paul F.
通讯作者：
Bray, Paul F.
影响因子：
3.3
作者：
Chen MH;Yanek LR;Backman JD;Eicher JD;Huffman JE;Ben-Shlomo Y;Beswick AD;Yerges-Armstrong LM;Shuldiner AR;O'Connell JR;Mathias RA;Becker DM;Becker LC;Lewis JP;Johnson AD;Faraday N
通讯作者：
Faraday N
影响因子：
64.8
作者：
Gieger, Christian;Radhakrishnan, Aparna;Cvejic, Ana;Tang, Weihong;Porcu, Eleonora;Pistis, Giorgio;Serbanovic-Canic, Jovana;Elling, Ulrich;Goodall, Alison H.;Labrune, Yann;Lopez, Lorna M.;Maegi, Reedik;Meacham, Stuart;Okada, Yukinori;Pirastu, Nicola;Sorice, Rossella;Teumer, Alexander;Voss, Katrin;Zhang, Weihua;Ramirez-Solis, Ramiro;Bis, Joshua C.;Ellinghaus, David;Goegele, Martin;Hottenga, Jouke-Jan;Langenberg, Claudia;Kovacs, Peter;O'Reilly, Paul F.;Shin, So-Youn;Esko, Toenu;Hartiala, Jaana;Kanoni, Stavroula;Murgia, Federico;Parsa, Afshin;Stephens, Jonathan;van der Harst, Pim;van der Schoot, C. Ellen;Allayee, Hooman;Attwood, Antony;Balkau, Beverley;Bastardot, Francois;Basu, Saonli;Baumeister, Sebastian E.;Biino, Ginevra;Bomba, Lorenzo;Bonnefond, Amelie;Cambien, Francois;Chambers, John C.;Cucca, Francesco;D'Adamo, Pio;Davies, Gail;de Boer, Rudolf A.;de Geus, Eco J. C.;Doering, Angela;Elliott, Paul;Erdmann, Jeanette;Evans, David M.;Falchi, Mario;Feng, Wei;Folsom, Aaron R.;Frazer, Ian H.;Gibson, Quince D.;Glazer, Nicole L.;Hammond, Chris;Hartikainen, Anna-Liisa;Heckbert, Susan R.;Hengstenberg, Christian;Hersch, Micha;Illig, Thomas;Loos, Ruth J. F.;Jolley, Jennifer;Khaw, Kay Tee;Kuehnel, Brigitte;Kyrtsonis, Marie-Christine;Lagou, Vasiliki;Lloyd-Jones, Heather;Lumley, Thomas;Mangino, Massimo;Maschio, Andrea;Leach, Irene Mateo;McKnight, Barbara;Memari, Yasin;Mitchell, Braxton D.;Montgomery, Grant W.;Nakamura, Yusuke;Nauck, Matthias;Navis, Gerjan;Noethlings, Ute;Nolte, Ilja M.;Porteous, David J.;Pouta, Anneli;Pramstaller, Peter P.;Pullat, Janne;Ring, Susan M.;Rotter, Jerome I.;Ruggiero, Daniela;Ruokonen, Aimo;Sala, Cinzia;Samani, Nilesh J.;Sambrook, Jennifer;Schlessinger, David;Schreiber, Stefan;Schunkert, Heribert;Scott, James;Smith, Nicholas L.;Snieder, Harold;Starr, John M.;Stumvoll, Michael;Takahashi, Atsushi;Tang, W. H. Wilson;Taylor, Kent;Tenesa, Albert;Thein, Swee Lay;Toenjes, Anke;Uda, Manuela;Ulivi, Sheila;van Veldhuisen, Dirk J.;Visscher, Peter M.;Voelker, Uwe;Wichmann, H-Erich;Wiggins, Kerri L.;Willemsen, Gonneke;Yang, Tsun-Po;Zhao, Jing Hua;Zitting, Paavo;Bradley, John R.;Dedoussis, George V.;Gasparini, Paolo;Hazen, Stanley L.;Metspalu, Andres;Pirastu, Mario;Shuldiner, Alan R.;van Pelt, L. Joost;Zwaginga, Jaap-Jan;Boomsma, Dorret I.;Deary, Ian J.;Franke, Andre;Froguel, Philippe;Ganesh, Santhi K.;Jarvelin, Marjo-Riitta;Martin, Nicholas G.;Meisinger, Christa;Psaty, Bruce M.;Spector, Timothy D.;Wareham, Nicholas J.;Akkerman, Jan-Willem N.;Ciullo, Marina;Deloukas, Panos;Greinacher, Andreas;Jupe, Steve;Kamatani, Naoyuki;Khadake, Jyoti;Kooner, Jaspal S.;Penninger, Josef;Prokopenko, Inga;Stemple, Derek;Toniolo, Daniela;Wernisch, Lorenz;Sanna, Serena;Hicks, Andrew A.;Rendon, Augusto;Ferreira, Manuel A.;Ouwehand, Willem H.;Soranzo, Nicole
通讯作者：
Soranzo, Nicole
影响因子：
7.5
作者：
Chen, Xi;Gupta, Shuchi;Ma, Peisong
通讯作者：
Ma, Peisong