Although biological actions of adenine nucleotides were described in 1929 by Drury and Szent-Gyorgi (1), and in 1950 by Green and Stoner (2), it was ADP that was the first nucleotide to be specifically identified as a humoral agent, when, in 1961, it was discovered that ADP could account for the action of an acidic extract of red blood cells which increased the ability of platelets to stick to glass (3, 4). Sub sequently a wide variety of pharmacological responses to nucleotides have been identified, and a comprehensive system for the classification of nucleotide receptors has been developed (5-8). Originally these receptors, classified by their preference for a variety of nucleotide analogues as agonists, were referred to as P2 purinergic receptors, to distinguish them from receptors that recognize adenosine, known as purinoceptors. As some of these receptors are equally reactive to ATP and UTP, a pyrimidine nucleotide, I will refer to them as P2nucleotide receptors. Several of these have now been cloned and their linear structures elucidated (9-23). So far the cloned receptors fall into two categories, designated P2x and P2y on the basis of structural criteria and numbered according to the order in which they were cloned. The P2y receptors have seven hydrophobic domains, and resemble the rhodopsin family of receptors that interact with G-proteins to activate phospholipases, or to stimulate or inhibit adenylyl cyclase. P2y receptors are further distinguished according to whether they recognize UTP as an agonist or not. The binding site on the cloned P2y2 receptor, formally known as P2u, which responds equally to UTP and ATP, but not to ADP or UDP (24), has been studied by site-directed mutagenesis (19); sever al positively charged amino acids have been identified in the sixth and seventh transmembrane helices that are necessary for high affinity binding. Substitution of Arg for Lys at position 289 in the seventh helix produced a mutant receptor with 100-fold greater preference for diphos phates over triphosphates. A novel P2y receptor (P2y3) which shows a preference for nucleoside diphosphates over triphosphates has been cloned from chicken brain (23), while P2y4responds less to ATP than to UTP and not to the diphosphates; P2y6responds to UDP in preference to UTP, ATP or ADP (24).

The P2x receptors, in contrast, have two hydrophobic domains and are homologous to the ligand-gated ion channel proteins (12, 13). So far no specific, competitive antagonists have been found that distinguish between the P2x and P2y receptors. A receptor for ATP4* on mast cells that causes a generalized increase in membrane permeability has been called P2z (25, 26), though recent evidence indicates that it belongs to