Go to JCI Insight
Jci spelled out white on transparent.20160208
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Alerts
  • Advertising/recruitment
  • Subscribe
  • Contact
  • Current Issue
  • Past Issues
  • By specialty
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All...
  • Videos
    • Conversations with Giants in Medicine
    • Author's Takes
  • Reviews
    • View all reviews...
    • Biology of familial cancer predisposition syndromes (Feb 2019)
    • Mitochondrial dysfunction in disease (Aug 2018)
    • Lipid mediators of disease (Jul 2018)
    • Cellular senescence in human disease (Apr 2018)
    • Fibrosis (Jan 2018)
    • Glia and Neurodegeneration (Sep 2017)
    • Transplantation (Jun 2017)
    • View all review series...
  • Collections
    • Recently published
    • In-Press Preview
    • Commentaries
    • Concise Communication
    • Editorials
    • Viewpoint
    • Scientific Show Stoppers
    • Top read articles
  • Clinical Medicine
  • JCI This Month
    • Current issue
    • Past issues

Jci only white

  • About
  • Editors
  • Consulting Editors
  • For authors
  • Current issue
  • Past issues
  • By specialty
  • Subscribe
  • Alerts
  • Advertise
  • Contact
  • Conversations with Giants in Medicine
  • Author's Takes
  • Recently published
  • Brief Reports
  • Technical Advances
  • Commentaries
  • Editorials
  • Hindsight
  • Review series
  • Reviews
  • The Attending Physician
  • First Author Perspectives
  • Scientific Show Stoppers
  • Top read articles
  • Concise Communication
Molecular identification and characterization of the platelet ADP receptor targeted by thienopyridine antithrombotic drugs
Carolyn J. Foster, … , Sergio A. Lira, Madhu S. Chintala
Carolyn J. Foster, … , Sergio A. Lira, Madhu S. Chintala
Published June 15, 2001
Citation Information: J Clin Invest. 2001;107(12):1591-1598. https://doi.org/10.1172/JCI12242.
View: Text | PDF
Category: Article

Molecular identification and characterization of the platelet ADP receptor targeted by thienopyridine antithrombotic drugs

  • Text
  • PDF
Abstract

ADP plays a critical role in modulating thrombosis and hemostasis. ADP initiates platelet aggregation by simultaneous activation of two G protein–coupled receptors, P2Y1 and P2Y12. Activation of P2Y1 activates phospholipase C and triggers shape change, while P2Y12 couples to Gi to reduce adenylyl cyclase activity. P2Y12 has been shown to be the target of the thienopyridine drugs, ticlopidine and clopidogrel. Recently, we cloned a human orphan receptor, SP1999, highly expressed in brain and platelets, which responded to ADP and had a pharmacological profile similar to that of P2Y12. To determine whether SP1999 is P2Y12, we generated SP1999-null mice. These mice appear normal, but they exhibit highly prolonged bleeding times, and their platelets aggregate poorly in responses to ADP and display a reduced sensitivity to thrombin and collagen. These platelets retain normal shape change and calcium flux in response to ADP but fail to inhibit adenylyl cyclase. In addition, oral clopidogrel does not inhibit aggregation responses to ADP in these mice. These results demonstrate that SP1999 is indeed the elusive receptor, P2Y12. Identification of the target receptor of the thienopyridine drugs affords us a better understanding of platelet function and provides tools that may lead to the discovery of more effective antithrombotic therapies.

Authors

Carolyn J. Foster, Dina M. Prosser, Jacqueline M. Agans, Ying Zhai, Michelle D. Smith, Jean E. Lachowicz, Fang L. Zhang, Eric Gustafson, Frederick J. Monsma Jr., Maria T. Wiekowski, Susan J. Abbondanzo, Donald N. Cook, Marvin L. Bayne, Sergio A. Lira, Madhu S. Chintala

×

Figure 3

Options: View larger image (or click on image) Download as PowerPoint
Concentration response curves for platelet aggregation. Washed platelet ...
Concentration response curves for platelet aggregation. Washed platelet aggregation was tested using the Bednar technique (24). The extent of aggregation was determined after 2 minutes. Each data point represents the average of three determinations. The plots were derived from a single typical experiment that was repeated two to three times with similar results.
Follow JCI: Facebook logo white Twitter logo v2 Rss icon
Copyright © 2019 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts