on November 20, 2008
Published online before print November 20, 2008, doi: 10.1161/ATVBAHA.108.176388
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Submitted on August 23, 2008
Accepted on November 1, 2008
G-Protein–Coupled Receptors as Signaling Targets for Antiplatelet Therapy
Susan S. Smyth *;
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.
* To whom correspondence should be addressed. E-mail: susansmyth{at}uky.edu.
Abstract—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.
Key words: platelets • signaling • G proteins • receptors • thrombosis
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