title: G-protein-coupled receptors signaling pathways in new antiplatelet drug development.
abstract: Platelet G-protein-coupled receptors influence platelet function by mediating the response to various agonists, including ADP, thromboxane A2, and thrombin. Blockade of the ADP receptor, P2Y12, in combination with cyclooxygenase-1 inhibition by aspirin has been among the most widely used pharmacological strategies to reduce cardiovascular event occurrence in high-risk patients. The latter dual pathway blockade strategy is one of the greatest advances in the field of cardiovascular medicine. In addition to P2Y12, the platelet thrombin receptor, protease activated receptor-1, has also been recently targeted for inhibition. Blockade of protease activated receptor-1 has been associated with reduced thrombotic event occurrence when added to a strategy using P2Y12 and cyclooxygenase-1 inhibition. At this time, the relative contributions of these G-protein-coupled receptor signaling pathways to in vivo thrombosis remain incompletely defined. The observation of treatment failure in ≈10% of high-risk patients treated with aspirin and potent P2Y12 inhibitors provides the rationale for targeting novel pathways mediating platelet function. Targeting intracellular signaling downstream from G-protein-coupled receptor receptors with phosphotidylionisitol 3-kinase and Gq inhibitors are among the novel strategies under investigation to prevent arterial ischemic event occurrence. Greater understanding of the mechanisms of G-protein-coupled receptor-mediated signaling may allow the tailoring of antiplatelet therapy.
authors: From the Sinai Center for Thrombosis Research, Sinai Hospital of Baltimore, MD (P.A.G., U.S.T.); and Center for Hemostasis and Thrombosis Research, Tufts Medical Center, Boston, MA (A.K.). PGURBEL@LIFEBRIDGEHEALTH.ORG.
authors: Paul A
authors: PA
authors: Gurbel
authors: From the Sinai Center for Thrombosis Research, Sinai Hospital of Baltimore, MD (P.A.G., U.S.T.); and Center for Hemostasis and Thrombosis Research, Tufts Medical Center, Boston, MA (A.K.).
authors: Athan
authors: A
authors: Kuliopulos
authors: From the Sinai Center for Thrombosis Research, Sinai Hospital of Baltimore, MD (P.A.G., U.S.T.); and Center for Hemostasis and Thrombosis Research, Tufts Medical Center, Boston, MA (A.K.).
authors: Udaya S
authors: US
authors: Tantry
mesh_terms: D000818:Animals; D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism; D015195:Drug Design; D006801:Humans; D058990:Molecular Targeted Therapy; D010975:Platelet Aggregation Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D058921:Purinergic P2Y Receptor Antagonists / Q000494:pharmacology; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors* / Q000378:metabolism; D044462:Receptors, Proteinase-Activated / Q000037:antagonists & inhibitors / Q000378:metabolism; D058925:Receptors, Purinergic P2Y12 / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013927:Thrombosis / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism
chemical_list: C548576:P2RY12 protein, human; D010975:Platelet Aggregation Inhibitors; D058921:Purinergic P2Y Receptor Antagonists; D043562:Receptors, G-Protein-Coupled; D044462:Receptors, Proteinase-Activated; D058925:Receptors, Purinergic P2Y12
keywords: GTP-binding proteins; blood platelet; coronary disease; purinerginc 2Y12 receptor agoists; receptors, thrombin
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