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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2009;29:449.)
© 2009 American Heart Association, Inc.

Brief Review

G-Protein–Coupled Receptors as Signaling Targets for Antiplatelet Therapy

Susan S. Smyth; Donna S. Woulfe; Jeffrey I. Weitz; Christian Gachet; Pamela B. Conley; Shaun G. Goodman; Matthew T. Roe; Athan Kuliopulos; David J. Moliterno; Patricia A. French; Steven R. Steinhubl; Richard C. Becker for the 2008 Platelet Colloquium Participants^*

From the Veterans Affairs Medical Center and the Department of Medicine, Physiology, and Pharmacology (S.S.S.) and Division of Cardiovascular Medicine (D.J.M.), University of Kentucky, Lexington; the Center for Translational Medicine (D.S.W.), Department of Medicine, Thomas Jefferson University, Philadelphia, Pa; Henderson Research Centre (J.I.W.) and McMaster University, Hamilton, Ontario, Canada; Institut National de la Santé et de la Recherché Médicale U311 (C.G.), Etablissement Français du Sang-Alsace and Université Louis Pasteur, Strasbourg, France; Portola Pharmaceuticals Inc (P.B.C.), South San Francisco, Calif; Terrence Donnelly Heart Centre (S.G.G.), Division of Cardiology, St Michael’s Hospital, University of Toronto, and the Canadian Heart Research Centre, Toronto, Ontario, Canada; the Department of Medicine, Duke University School of Medicine and Duke Clinical Research Institute (M.T.R., R.C.B.), Durham, NC; the Division of Hematology–Oncology (A.K.), Department of Medicine and Biochemistry, Tufts Medical Center, Boston, Mass; Left Lane Communications (P.A.F.), Chapel Hill, NC; and Geisinger Medical Center (S.R.S.) and The Medicines Company, Danville, Pennsylvania and Parsippany, New Jersey.

Correspondence to Susan S. Smyth, MD, PhD, Division of Cardiovascular Medicine, The Gill Heart Institute, 900 S Limestone Avenue, 326 Charles T. Wethington Building, Lexington, KY 40536. E-mail susansmyth{at}uky.edu

Platelet G protein–coupled receptors (GPCRs) initiate and reinforce platelet activation and thrombus formation. The clinical utility of antagonists of the P2Y₁₂ receptor for ADP suggests that other GPCRs and their intracellular signaling pathways may represent viable targets for novel antiplatelet agents. For example, thrombin stimulation of platelets is mediated by 2 protease-activated receptors (PARs), PAR-1 and PAR-4. Signaling downstream of PAR-1 or PAR-4 activates phospholipase C and protein kinase C and causes autoamplification by production of thromboxane A₂, release of ADP, and generation of more thrombin. In addition to ADP receptors, thrombin and thromboxane A₂ receptors and their downstream effectors—including phosphoinositol-3 kinase, Rap1b, talin, and kindlin—are promising targets for new antiplatelet agents. The mechanistic rationale and available clinical data for drugs targeting disruption of these signaling pathways are discussed. The identification and development of new agents directed against specific platelet signaling pathways may offer an advantage in preventing thrombotic events while minimizing bleeding risk.

The clinical utility of antagonists of the P2Y₁₂ receptor for ADP suggests that other G protein–coupled receptors and intracellular signaling pathways might be viable targets for novel antiplatelet agents. The mechanistic rationale and available clinical data for agents targeting disruption of ADP-, thrombin-, and thromboxane A₂–related signaling pathways are discussed.

Key Words: platelets • signaling • G proteins • receptors • thrombosis

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