Search

The P2Y receptors are a widely expressed group of eight nucleotide-activated G protein-coupled receptors (GPCRs). The P2Y(1)(ADP), P2Y(2)(ATP/UTP), P2Y(4)(UTP), P2Y(6)(UDP), and P2Y(11)(ATP) receptors activate G(q) and therefore robustly promote inositol lipid signaling responses. The P2Y(12)(ADP), P2Y(13)(ADP), and P2Y(14)(UDP/UDP-glucose) receptors activate G(i) leading to inhibition of adenylyl cyclase and to Gβγ-mediated activation of a range of effector proteins including phosphoinositide 3-kinase-γ, inward rectifying K(+) (GIRK) channels, phospholipase C-β2 and -β3, and G protein-receptor kinases 2 and 3. A broad range of physiological responses occur downstream of activation of these receptors ranging from Cl(-) secretion by epithelia to aggregation of platelets to neurotransmission. Useful structural models of the P2Y receptors have evolved from extensive genetic analyses coupled with molecular modeling based on three-dimensional structures obtained for rhodopsin and several other GPCRs. Selective ligands have been synthesized for most of the P2Y receptors with the most prominent successes attained with highly selective agonist and antagonist molecules for the ADP-activated P2Y(1) and P2Y(12) receptors. The widely prescribed drug, clopidogrel, which results in irreversible blockade of the platelet P2Y(12) receptor, is the most important therapeutic agent that targets a P2Y receptor.

Publisher Summary As molecular modeling of cloned G protein-coupled receptor (GPCR) sequences using a rhodopsin template has been refined, it has become possible to generate hypotheses for location of the binding sites that are consistent with mutagenesis results and ligand specificities. To obtain an energetically refined 3-D structure of the ligand–receptor complex, the chapter introduces a new computational approach, a “cross docking” procedure, which simulates the reorganization of the native receptor induced by the ligand. The molecular basis for recognition by human P2Y 1 receptors of the selective, competitive antagonist MRS 2179 is probed using site-directed mutagenesis and molecular modeling. The model was derived from primary sequence comparison, secondary structure predictions, and 3-D homology building, using rhodopsin as a template, and was consistent with data obtained from mutagenesis studies. A putative nucleotide binding site was localized, following a cross docking procedure to obtain energetically refined 3-D structures of the ligand–receptor complexes, and used to predict which residues are likely to be in proximity to agonists and antagonists. Molecular modeling using PowerFit has suggested a possible model of superimposition of two classes of antagonists, nucleotides related to MRS 2179, and non-nucleotides related to pyridoxal phosphate.

Publisher Summary This chapter discusses the properties and the functional roles of P2-receptors present on postganglionic sympathetic neurons. A physiological role is well established for release inhibiting P2-receptors located at the axon terminals of postganglionic sympathetic neurons. These presynaptic P2-receptors are activated by cotransmitter ATP and operate as a kind of autoreceptor mediating a feedback inhibition of ongoing action potential evoked sympathetic transmitter release. In addition to release-modulating P2-receptors, postganglionic sympathetic neurons possess P2-receptors, activation of which causes the generation of action potentials and subsequently transmitter release. Excitatory P2-receptors located at the nerve cell bodies or dendrites of postganglionic sympathetic neurons have been proposed to be involved in fast synaptic neuro-neural transmission in sympathetic ganglia. Sympathetic neurons cultured from rat paravertebral ganglia possess two different subtypes of excitatory P2-receptors. Activation of both receptors induced the generation of action potentials and transmitter release. One receptor is an adenine nucleotide sensitive P2X-receptor. The other receptor is activated by uracil nucleotides and belongs most likely to the group of G-protein-coupled P2Y-receptors.