P2 receptor subtypes in the cardiovascular system

Extracellular nucleotides have been implicated in a number of physiological functions. Nucleotides act on cell-surface receptors known as P-2 receptors, of which several subtypes have been cloned. Both ATP and ADP are stored in platelets and are released upon platelet activation. Furthermore, nucleotides are also released from damaged or broken cells. Thus during vascular injury nucleotides play an important role in haemostasis through activation of platelets, modulation of vascular tone, recruitment of neutrophils and monocytes to the site of injury, and facilitation of adhesion of leucocytes to the endothelium. Nucleotides also moderate these functions by generating nitric oxide and prostaglandin I-2 through activation of endothelial cells, and by activating different receptor subtypes on vascular smooth muscle cells. In the heart, P-2 receptors regulate contractility through modulation of L-type Ca2+ channels, although the molecular mechanisms involved are still under investigation. Classical pharmacological studies have identified several P-2 receptor subtypes in the cardiovascular system. Molecular pharmacological studies have clarified the nature of some of these receptors, but have complicated the picture with others. In platelets, the classical P-2T receptor has now been resolved into three P-2 receptor subtypes: the P-2Y1, P-2X1 and P-2TAC receptors (the last of these, which is coupled to the inhibition of adenylate cyclase, is yet to be cloned). In peripheral blood leucocytes, endothelial cells, vascular smooth muscle cells and cardiomyocytes, the effects of classical P-2X, P-2Y and P-2U receptors have been found to be mediated by more than one P-2 receptor subtype. However, the exact functions of these multiple receptor subtypes remain to be understood, as P-2-receptor-selective agonists and antagonists are still under development.