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-N6-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.

Involvement of vasodilator-stimulated phosphoprotein in UDP-induced microglial actin aggregation via PKC- and Rho-dependent pathways

“…We did not detect any phosphorylation at Ser239 after UDP stimulation (data not shown), and phosphorylation at Thr278 could not be assessed because of lack of commercially available antibodies. There was only one report indicating that the P2Y 6 receptor couples with PLA activity [28], but it is known as a canonical pathway that P2Y 6 receptor activation leads to PKC activation [17]. Our results indicate that phosphorylation at Ser157 of VASP is mediated by PKC.…”

“…Stimulation of the P2Y 6 receptor also leads to PKC activation by PLC signaling [17]. We investigated the effects of three PKC inhibitors, Bisindolylmaleimide I (Bis), Gö6976 (Gö76) and Gö6983 (Gö83), on both UDP-stimulated reactions, each with different selectivity for the PKC subtypes.…”

Cardiomyogenesis of embryonic stem cells upon purinergic receptor activation by ADP and ATP

“…Moreover, in presence of PPADS, a non-selective P2 receptor antagonist, intracellular [Ca 2+ ] i mobilization was completely blocked. Of note, it is reported that the P2Y1 subtype has a widespread expression and is involved in blood platelet aggregation, vasodilatation and neuromodulation [23,28]. RT-PCR evaluation of P2Y receptors revealed P2Y1, P2Y2, P2Y4, and P2Y6 receptor expression during the time course of ES cell differentiation.…”

“…The P2Y1 receptor is a major subtype expressed generally in all cell types, and it mainly involves in regulating cell proliferation and differentiation. Interestingly, the principal physiological agonist for P2Y1 is ADP rather than ATP [25,28].…”

Design and synthesis of new bicyclic diketopiperazines as scaffolds for receptor probes of structurally diverse functionality

“…Several of the derivatives were found to inhibit the activity of extracellular nucleotides through G protein-coupled P2Y receptors and subsequent biochemical steps. Eight mammalian subtypes of [18][19][20][21] such receptors (P2Y 1,2,4,6,[11][12][13][14] are currently sequence-defined. The P2Y receptors are present in the cardiovascular, immune, and nervous systems, as well as in other systems.…”