9 - Platelet receptors: ADP

Summary

Introduction

Adenine nucleotides interact with P2 receptors, which are widely distributed in many different cell types including endothelial, smooth muscle, epithelial and blood cells, mastocytes and neurons and regulate a broad range of physiological processes. These receptors are divided into two main groups: the G protein coupled or ‘metabotropic’ superfamily termed P2Y and the ligand gated ion channel or ‘ionotropic’ superfamily termed P2X. ADP was identified 40 years ago as a factor derived from red blood cells which influenced platelet adhesiveness and induced platelet aggregation and it rapidly became recognized as one of the most important mediators of hemostasis and thrombosis. Evidence that ADP plays a crucial role in formation of the hemostatic plug and the pathogenesis of arterial thrombosis has accumulated during the last decades: ADP is present at near molar concentrations in platelet dense granules and is released when platelets are stimulated by other agents such as thrombin or collagen, thus reinforcing their aggregation; inhibitors of ADP-induced platelet aggregation are effective antithrombotic drugs; ADP removing enzymes display antithrombotic properties in animal models; patients with defects of ADP receptors or lacking ADP in their platelet granules suffer from a bleeding diathesis. Hence ADP receptors are potential pharmacological targets for antithrombotic drugs. Molecular identification of the platelet P2 receptors over the last 5 years has now made it possible to separately assign the known effects of ADP and ATP to the three cloned P2 receptors found on platelets, namely P2Y₁, P2Y₁₂ and P2X₁.