There is now wide acceptance that ATP and other nucleotides are ubiquitous extracellular chemical messengers. ATP and diadenosine polyphosphates can be released from synaptosomes. They act on a large and diverse family of P2 purinoceptors, four of which have been cloned. This receptor family can be divided into two distinct classes: ligand-gated ion channels for P2X receptors and G proteincoupled receptors for P2Y, P2U, P2T and P2D receptors. The P2Y, P2U and P2D receptors have a fairly wide tissue distribution, while the P2X receptor is mainly found in neurons and muscles and the P2T and P2Z receptors confined to platelets and immune cells, respectively. lnositol phosphate and calcium signalling appear to be the predominant mechanisms for transducing the G-protein linked P2 receptor signals. Multiple P2 receptors are expressed by neurons and glia in the CNS and also in neuroendocrine cells. ATP and other nucleotides may therefore have important roles not only as a neurotransmitter but also as a neuroendocrine regulatory messenger.In addition to the well established role of nucleotides in intracellular metabolism, it has recently become apparent that they also have important extracellular roles. In 1929 Drury & SzentGyorgyi (1) published the first report that adenylic acid and adenosine produced sinus bradycardia, complete atrioventricular block, a negative inotropic effect on the atrium and cessation of atrial fibrillation in the mammalian heart. In 1933 Gillespie (2) found that ATP had a positive inotropic effect in frogs and Drury ( 3 ) in 1936 suggested that ATP and adenosine might have different effects on cardiac contraction. Holton et al. in 1950s demonstrated that ATP was present in dry powders of spinal roots ( 4 ) and in the perfusate of the rabbit ear artery following nerve stimulation ( 5 ) , suggesting a possible neurotransmitter role for ATP. It was more than a decade, however, before Burnstock and his colleagues observed a non-adrenergic and non-cholinergic element in the autonomic nervous system, and made the landmark proposals that ATP acted as a neurotransmitter in the peripheral autonomic nervous system (6-9). This finding was confirmed and extended over the subsequent two decades, with ATP-evoked synaptic potentials being recorded in neurons in the central and peripheral systems (10-12). The very recent molecular cloning of P2 purinoceptors removed the last doubts about nucleotides being true extracellular mediators (13-16), and it is now clear that ATP is a ubiquitous extracellular mediator acting on a superfamily of P2 purinoceptors that play important physiological and pathophysiological roles in a variety of biological processes. These include neurotransmission, cardiac function, platelet aggregation, muscle contraction and relaxation, vascular tone, secretion of hormones, immune response and cell growth.There are a number of excellent review articles available in the literature (17-25) and therefore, this review will mainly focus on the most recent advancements in this fascinatin...

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