Molecular pharmacology of P2Y-receptors

Abstract

Membrane-bound P2-receptors mediate the actions of extracellular nucleotides in cell-to-cell signalling. P2X-receptors are ligand-gated ion channels, whereas P2Y-receptors belong to the superfamily of G-protein-coupled receptors. So far, the P2Y family is composed of eight cloned and functionally defined subtypes. Five of them (P2Y₁, P2Y₂, P2Y₄, P2Y₆ and P2Y₁₁) are present in human tissues. The P2Y₃-, p2y₈- and tp2y-receptors may be species orthologues. The principal physiological agonists of the cloned human P2Y-receptors are ADP (P2Y₁), UTP/ATP (P2Y₂), UTP (P2Y₄), UDP (P2Y₆) and ATP (P2Y₁₁). The rat P2Y₄-receptor is activated by both UTP and ATP. Specific patterns of polar amino acid residues in the exofacial portions 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 P2Y₄- and tp2y-receptors. PPADS has been shown to block P2Y₁-, the human P2Y₄- and P2Y₆-receptors. The nucleotide analogue 2'-deoxy-N ⁶-methyladenosine-3',5'-bisphosphate (MRS 2179), in contrast, seems to be a potent and selective antagonist at the P2Y₁-receptor. All cloned and functionally expressed P2Y-receptors are able to couple to phospholipase C. The P2Y₁₁-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 platelets, are not yet cloned.

The distribution of P2Y₁ mRNA is widespread. The receptor plays a crucial role in blood platelet aggregation and mediates the adenine nucleotide-induced release of the endothelium-derived relaxing factor nitric oxide. P2Y₁-receptors may also be involved in the modulation of neuro-neural signalling transmission. P2Y₂ transcripts are abundantly distributed. One important example for its functional role is the control of chloride ion fluxes in airway epithelia. The P2Y₄-receptor is highly expressed in the placenta. The distribution of the P2Y₆-receptor is widespread including heart, blood vessels and brain. The P2Y₁₁-receptor may play a role in the differentiation of immunocytes.