A molecularly identified P2Y receptor simultaneously activates phospholipase C and inhibits adenylyl cyclase and is nonselectively activated by all nucleoside triphosphates

Citation
Jl. Boyer et al., A molecularly identified P2Y receptor simultaneously activates phospholipase C and inhibits adenylyl cyclase and is nonselectively activated by all nucleoside triphosphates, MOLEC PHARM, 57(4), 2000, pp. 805-810
Citations number
31
Categorie Soggetti
Pharmacology & Toxicology
Journal title
MOLECULAR PHARMACOLOGY
ISSN journal
0026895X → ACNP
Volume
57
Issue
4
Year of publication
2000
Pages
805 - 810
Database
ISI
SICI code
0026-895X(200004)57:4<805:AMIPRS>2.0.ZU;2-1
Abstract
We recently cloned and expressed a novel P2Y receptor (tp2y receptor) from a turkey cDNA library. Expression of this receptor in 1321N1 human astrocyt oma cells confers nucleotide-dependent stimulation of phospholipase C activ ity; however, as we demonstrate here, it also confers nucleotide-dependent inhibition of adenylyl cyclase. Both the phospholipase C and adenylyl cycla se responses were promoted by receptor agonists over a similar range of con centrations. Moreover, not only did UTP and ATP activate the avian receptor but ITP, GTP, xanthosine 5'-triphosphate, and CTP were also agonists, with EC50 values ranging between 0.1 and 1 mu M. Similar potencies, rank-order, and selectivity of nucleotide agonists were also demonstrated for intracel lular Ca2+ mobilization measured during a 30-s stimulation under constant s uperfusion conditions. This observation indicates that receptor activation by nucleoside 5'-triphosphates is not produced by interconversion of these nucleotides into ATP or UTP. Pretreatment of cells with pertussis toxin com pletely abolished the inhibitory effect of nucleotide agonists on adenylyl cyclase, whereas the activation of phospholipase C was only partially inhib ited. These results demonstrate that the avian P2Y receptor is a nucleoside triphosphate receptor of broad agonist selectivity that interacts with bot h pertussis toxin-insensitive and -sensitive G proteins to activate phospho lipase C and to inhibit adenylyl cyclase. This is the first cloned P2Y rece ptor that is clearly Gi/adenylyl cyclase-linked.