دورية أكاديمية
أعرض في EDS

GRK2 regulates ADP signaling in platelets via P2Y1 and P2Y12.

التفاصيل البيبلوغرافية
العنوان: GRK2 regulates ADP signaling in platelets via P2Y1 and P2Y12.
المؤلفون: Zhao X; Cardeza Foundation for Hematologic Research, Department of Medicine, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA.; Cyrus Tang Hematology Center, Soochow University, Suzhou, China., Cooper M; Cardeza Foundation for Hematologic Research, Department of Medicine, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA., Michael JV; Cardeza Foundation for Hematologic Research, Department of Medicine, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA., Yarman Y; Cardeza Foundation for Hematologic Research, Department of Medicine, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA., Baltz A; Cardeza Foundation for Hematologic Research, Department of Medicine, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA., Chuprun JK; Center for Translational Medicine, Department of Pharmacology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA; and., Koch WJ; Center for Translational Medicine, Department of Pharmacology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA; and., McKenzie SE; Cardeza Foundation for Hematologic Research, Department of Medicine, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA., Tomaiuolo M; Vickie and Jack Farber Vision Research Center, Wills Eye Hospital, Philadelphia, PA., Stalker TJ; Cardeza Foundation for Hematologic Research, Department of Medicine, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA., Zhu L; Cyrus Tang Hematology Center, Soochow University, Suzhou, China., Ma P; Cardeza Foundation for Hematologic Research, Department of Medicine, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA.
المصدر: Blood advances [Blood Adv] 2022 Aug 09; Vol. 6 (15), pp. 4524-4536.
نوع المنشور: Journal Article; Research Support, N.I.H., Extramural
اللغة: English
بيانات الدورية: Publisher: American Society of Hematology Country of Publication: United States NLM ID: 101698425 Publication Model: Print Cited Medium: Internet ISSN: 2473-9537 (Electronic) Linking ISSN: 24739529 NLM ISO Abbreviation: Blood Adv Subsets: MEDLINE
أسماء مطبوعة: Original Publication: Washington, DC : American Society of Hematology, [2016]-
مواضيع طبية MeSH: Hemostatics* , Thrombosis*/metabolism, Adenosine Diphosphate/pharmacology ; Animals ; Blood Platelets/metabolism ; Humans ; Mice ; Platelet Aggregation
مستخلص: 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.
(© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)
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معلومات مُعتمدة: R01 HL144574 United States HL NHLBI NIH HHS
المشرفين على المادة: 0 (Hemostatics)
61D2G4IYVH (Adenosine Diphosphate)
تواريخ الأحداث: Date Created: 20220706 Date Completed: 20220808 Latest Revision: 20221109
رمز التحديث: 20221213
مُعرف محوري في PubMed: PMC9636328
DOI: 10.1182/bloodadvances.2022007007
PMID: 35793439
قاعدة البيانات: MEDLINE
الوصف
تدمد:2473-9537
DOI:10.1182/bloodadvances.2022007007