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P2Y12, a new platelet ADP receptor, target of clopidogrel

Jean-Marc Herbert1, Pierre Savi

  • 1Sanofi-Synthélabo Recherche, Toulouse, France. jean-marc.herbert@sanofi-synthelabo.com

Seminars in Vascular Medicine
|June 17, 2004
PubMed

Insights

Clopidogrel, an antithrombotic drug, prevents vascular events by irreversibly inhibiting the P2Y12 receptor, which mediates adenosine diphosphate (ADP)-induced platelet aggregation. This action explains clopidogrel

Area of Science:

  • Pharmacology
  • Cardiovascular Medicine
  • Molecular Biology

Background:

  • Clopidogrel is a widely used antithrombotic agent demonstrating superior efficacy over aspirin in preventing vascular ischemic events in patients with atherosclerotic disease.
  • Its antiplatelet effect stems from inhibiting adenosine diphosphate (ADP)-mediated platelet aggregation, though its precise molecular target was initially unclear.
  • Platelets express various purinergic receptors, including P2X, P2Y1, and the Gi-coupled P2Y12 receptor, with differing roles in platelet activation.

Purpose of the Study:

  • To identify the specific platelet purinergic receptor targeted by the active metabolite of clopidogrel.
  • To elucidate the mechanism by which clopidogrel's active metabolite exerts its antiplatelet effects.
  • To confirm the role of the P2Y12 receptor in ADP-induced platelet aggregation and clopidogrel's action.

Main Methods:

  • Cloning and stable expression of the human P2Y12 receptor in Chinese Hamster Ovary (CHO) cells.
  • Radioligand binding assays using (33)P-2-methylthio-ADP ((33)P-2MeS-ADP) to assess binding affinity and inhibition by clopidogrel's active metabolite.
  • Measurement of adenylyl cyclase activity in transfected CHO cells and human platelets following ADP stimulation and treatment with clopidogrel's active metabolite.

Main Results:

  • The cloned P2Y12 receptor in CHO cells exhibited binding characteristics for (33)P-2MeS-ADP consistent with the 'P2t' receptor on human platelets.
  • The active metabolite of clopidogrel potently inhibited (33)P-2MeS-ADP binding to P2Y12 receptors, correlating with its observed efficacy on platelets.
  • ADP-induced adenylyl cyclase downregulation in both transfected cells and platelets was effectively blocked by clopidogrel's active metabolite, indicating P2Y12 as the target.

Conclusions:

  • The study definitively identifies the P2Y12 receptor as the 'P2t' platelet receptor and the primary target of clopidogrel's active metabolite.
  • Clopidogrel's active metabolite acts via covalent binding to the P2Y12 receptor, thereby blocking ADP-induced platelet aggregation.
  • These findings provide a clear molecular mechanism for the antiplatelet action of clopidogrel, supporting its clinical use in preventing thrombotic events.

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