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

Research output: Contribution to journalShort surveypeer-review

101 Scopus citations

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.

Original languageEnglish
Pages (from-to)449-457
Number of pages9
JournalArteriosclerosis, Thrombosis, and Vascular Biology
Volume29
Issue number4
DOIs
StatePublished - Apr 1 2009

Keywords

  • G proteins
  • Platelets
  • Receptors
  • Signaling
  • Thrombosis

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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