Pharmacological profiles of cloned mammalian P2Y-receptor subtypes

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 (GPCRs). So far, the P2Y family is composed out of 8 human subtypes that have been cloned and functionally defined; species orthologues have been found in many vertebrates. P2Y(1)-, P2Y(2)-, P2Y(4)-, P2Y(6)-, and P2Y(11)-receptors all couple to stimulation of phospholipase C. The P2Y(11)-receptor mediates in addition a stimulation of adenylate cyclase. In contrast, activation of the P2Y(12)-, P2Y(13)-, and P2Y(14)-receptors causes an inhibition of adenylate cyclase activity. The expression of P2Y-receptors is widespread. The receptor is involved in blood platelet aggregation, vasodilatation and neuromodulation. It is activated by ADP and ADP analogues including 2-methylthio-ADP (2-MeSADP). 2'-Deoxy-N-6-methyladenosine-3',5-bisphosphate (MRS2179) and 2-chloro-N-6-methyl-(N)-methanocarba-2'-deoxyadenosine 3',5'-bisphospbate (MRS2279) are potent and selective antagonists. P2Y2 transcripts are abundantly distributed. One important example for its functional role is the control of chloride ion fluxes in airway epithelia. The P2Y(2)-receptor is activated by UTP and ATP and blocked by suramin. The P2Y(2)-agonist diquafosol is used for the treatment of the dry eye disease. P2Y(4)-receptors are expressed in the placenta and in epithelia. The human P2Y(4)-receptor has a strong preference for UTP as agonist, whereas the rat P2Y(4)-receptor is activated about equally by UTP and ATR The P2Y(4)-receptor is not blocked by suramin. The P2Y(6)-receptor has a widespread distribution including heart, blood vessels, and brain. The receptor prefers UDP as agonist and is selectively blocked by 1,2-di-(4-isothiocyanatophenyl)ethane (MRS2567). The P2Y(11)-receptor may play a role in the differentiation of immunocytes. The human P2Y I I-receptor is activated by ATP as naturally occurring agonist and it is blocked by suramin and reactive blue 2(RB2). The P2Y(12)-receptor plays a crucial role in platelet aggregation as well as in inhibition of neuronal cells. It is activated by ADP and very potently by 2-methylthio-ADP. Nucleotide antagonists including N6-(2-methylthioethyl)-2-(3,3,3-trifluoropropylthio)-beta,gamma-dichloromethylene-ATP (=cangrelor; AR-C69931MX), the nucleoside analogue AZD6140, as well as active metabolites of the thienopyridine compounds clopidogrel and prasugrel block the receptor. These P2Y(12)-antagonists are used in pharmacotherapy to inhibit platelet aggregation. The P2Y(13)-receptor is expressed in immunocytes and neuronal cells and is again activated by ADP and 2-methylthio-ADP. The 2-chloro-5-nitro pyridoxal-phosphate analogue 6-(2'-chloro-5'-nitro-azophenyl)-pyridoxal-alpha 5-phosphate (MRS2211) is a selective antagonist. mRNA encoding for the human P2Y(14)-receptor is found in many tissues. However, a physiological role of the receptor has notyetbeen established. UDP-glucose and related analogues act as agonists; antagonists are not known. Finally, UDP has been reported to act on receptors for cysteinyl leukotrienes as an additional agonist-indicating a dual agonist specificity of these receptors. (c) 2005 Elsevier Inc. All rights reserved.