ADP and platelets: the end of the beginning

Along with thrombin and collagen, ADP has long been recognized for its contribution to the propagation of platelet activation at sites of vascular injury. However, recent studies have brought a new appreciation of the extent of that contribution and identified the two G protein–coupled receptors that appear to be largely responsible for platelet responses to ADP: P2Y1, which activates phospholipase C (1), and P2Y12, which suppresses cAMP formation so that activation can occur (Figure ​(Figure1)1) (2, 3). P2Y12 (also known as P2T, P2Yac, and SP1999) was identified last year by two teams of investigators using distinctly different strategies (2, 3). Now, in this issue of the JCI, Carolyn Foster and her colleagues at Schering-Plough Research Institute describe the consequences of deleting the gene encoding P2Y12 in mice (4). Their results help to validate parts of the current model for platelet activation by ADP. They also bring to a conclusion a phase of research in which platelet responses to ADP were initially characterized, the contribution of heterotrimeric G proteins was recognized, and the existence of more than one class of ADP receptor was established. Given the growing use of antiplatelet agents that target P2Y12 in patients with cardiovascular disease, this is a good opportunity to review the role of ADP in platelet activation and consider some of the questions that have yet to be answered. Figure 1 ADP and platelet activation. Platelet activation by potent agonists such as thrombin or collagen causes the release of secondary agonists such as thromboxane A2 (TxA2) and the secretion of ADP from platelet dense granules. Platelet responses to ADP require ...