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