Molecular pharmacology of P2Y-receptors

Membrane-bound P2-receptors mediate the actions of extracellular nucleotide s in cell-to-cell signalling. P2X-receptors are ligand-gated ion channels, whereas P2Y-receptors belong to the superfamily of G-protein-coupled recept ors. So far, the P2Y family is composed of eight cloned and functionally de fined subtypes. Five of them (P2Y(1), P2Y(2), P2Y(4), P2Y(6) and P2Y(11)) a re present in human tissues. The P2Y(3)-, p2y(8)- and tp2y-receptors may be species orthologues. The principal physiological agonists of the cloned hu man P2Y-receptors are ADP (P2Y,), UTP/ATP (P2Y(2)), UTP (P2Y(4)), UDP (P2Y( 6)) and ATP (P2Y(11)). The rat P2Y(4)-receptor is activated by both UTP and ATP. Specific patterns of polar amino acid residues in the exofacial porti ons of transmembrane domains (TMs) 6 and 7 of the P2Y-receptors may account for the ligand specificity of the subtypes. Suramin acts as an antagonist at most P2Y-receptors with the exception of P2Y(4)- and tp2y-receptors. PPA DS has been shown to block P2Y(1)-, the human P2Y(4)- and P2Y(6)-receptors. The nucleotide analogue 2'-deoxy-N-6-methyladenosine-3',5'-bisphosphate (M RS 2179), in contrast, seems to be a potent and selective antagonist at the P2Y(1)-receptor. All cloned and functionally expressed P2Y-receptors are a ble to couple to phospholipase C. The P2Y(11)-receptor mediates in addition a stimulation of adenylate cyclase and the tp2y-receptor an inhibition of this signal transduction pathway. Other functionally defined subtypes, e.g. , the receptor mediating an inhibition of adenylate cyclase in blood platel ets, are not yet cloned. The distribution of P2Y(1) mRNA is widespread. The receptor plays a crucial role in blood platelet aggregation and mediates the adenine nucleotide-ind uced release of the endothelium-derived relaxing factor nitric oxide. P2Y(1 )-receptors may also be involved in the modulation of neuro-neural signalli ng transmission. P2Y2 transcripts are abundantly distributed. One important example for its functional role is the control of chloride ion fluxes in a irway epithelia. The P2Y(4)-receptor is highly expressed in the placenta. T he distribution of the P2Y(6)-receptor is widespread including heart, blood vessels and brain. The P2Y(11)-receptor may play a role in the differentia tion of immunocytes.