In addition to its well-known involvement in intracellular energy and intermediary metabolism, adenosine triphosphate (ATP), when present in extracellular domains, can elicit functional responses in a large number of types of tissue and cells. While exogenous ATP can be rapidly catabolized to adenosine by a number of ectophosphohydrolases, many of the observed actions of extracellular ATP can be distinguished from those triggered by occupation of the well characterized A1- and A2-receptors for extracellular adenosine. What is currently emerging is the view that extracellular ATP per se may be of physiological significance as a signaling agent in many biologic systems. Many of these functional effects of ATP, furthermore, can be observed at extracellular concentrations (nanomolar to low-micromolar) that are generally well below the Michaelis constant (Km) values for most intracellular adenosine triphosphatases (ATPases) and other ATP-utilizing enzymes. These observations have suggested that there exist specific cell surface receptors for extracellular ATE Until fairly recently, most studies involving the actions of extracellular ATP and adenine nucleotides were performed on preparations of smooth muscle. This work was prompted by Burnstock and colleagues who, in 1970, proposed that ATP is released as a excitatory neurotransmitter in smooth muscles, and that the nucleotide is the primary transmitter substance responsible for neurogenic inhibitory responses mediated by what has been referred to as "nonadrenergic, noncholinergic" inhibitory nerves. It has turned out that Burnstock's original hypothesis has been difficult to prove, but it nevertheless initiated many experiments to support or disprove it. The outcome of this work has been somewhat different than envisaged, in that ATP has been shown to be a cotransmitter from nerves in which it is stored. In these studies of Burnstock and colleagues, the use of the term P2-purinergic was introduced to designate the putative receptor(s) for ATP and to distinguish them from so-called P1-purinergic receptors for adenosine.