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GRK2 regulates ADP signaling in platelets via P2Y1 and P2Y12.
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.
Afiliação
  • Zhao X; Cardeza Foundation for Hematologic Research, Department of Medicine, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA.
  • Cooper M; Cyrus Tang Hematology Center, Soochow University, Suzhou, China.
  • 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; Cardeza Foundation for Hematologic Research, Department of Medicine, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA.
  • Koch WJ; Center for Translational Medicine, Department of Pharmacology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA; and.
  • McKenzie SE; Center for Translational Medicine, Department of Pharmacology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA; and.
  • Tomaiuolo M; Cardeza Foundation for Hematologic Research, Department of Medicine, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA.
  • Stalker TJ; Vickie and Jack Farber Vision Research Center, Wills Eye Hospital, Philadelphia, PA.
  • Zhu L; Cardeza Foundation for Hematologic Research, Department of Medicine, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA.
  • Ma P; Cyrus Tang Hematology Center, Soochow University, Suzhou, China.
Blood Adv ; 6(15): 4524-4536, 2022 08 09.
Article em En | MEDLINE | ID: mdl-35793439
ABSTRACT
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 Gßγ subunits during platelet activation. Collectively, these results show that GRK2 regulates ADP signaling via P2Y1 and P2Y12, interacts with Gßγ, and functions as a signaling hub in platelets for modulating the hemostatic response to injury.
Assuntos

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Trombose / Hemostáticos Idioma: En Ano de publicação: 2022 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Trombose / Hemostáticos Idioma: En Ano de publicação: 2022 Tipo de documento: Article