Identification of a P2Y-purinergic receptor that inhibits adenylyl cyclase.
Adenine nucleotides inhibited isoproterenol- and forskolin-stimulated cyclic AMP accumulation in C6-2B rat glioma cells. Inhibition occurred in the presence of a phosphodiesterase inhibitor, and no effect of adenine nucleotides was observed in direct measurements of phosphodiesterase activity in intact cells. Pretreatment of C6-2B glioma cells with pertussis toxin blocked the inhibitory effects of P2Y-purinergic receptor agonists. The pharmacological specificity for a series of ATP and ADP analogs (2-methylthioadenosine 5'-triphosphate > or = 2-methylthioadenosine 5'-diphosphate > adenosine 5'-O-(2-thiodiphosphate) > 2-chloro-adenosine 5'-triphosphate = ADP = adenosine 5'-O-(3-thiotriphosphate) > ATP > UTP) was similar to that expected of a P2Y-purinergic receptor; the P2X-purinergic receptor agonists, alpha,beta-methyleneadenosine 5'-triphosphate and beta,gamma-methylene-adenosine 5'-triphosphate, had no effect. Because activation of phospholipase C occurs in response to P2-purinergic receptor activation in many target tissues, the effects of P2Y-receptor agonists on inositol phosphate accumulation were measured in C6-2B cells. No evidence for P2Y-purinergic receptor-mediated regulation of inositol lipid metabolism was observed under conditions where muscarinic cholinergic receptor activation or AIF4-markedly increased inositol phosphate accumulation. These results suggest that a P2-purinergic receptor subtype with distinct signaling properties exists on C6-2B rat glioma cells. Although this receptor expresses the general pharmacological specificity of a phospholipase C-coupled P2Y-purinergic receptor, it may represent a unique receptor subtype since it inhibits adenylyl cyclase.
Boyer
J L
JL
Department of Pharmacology, University of North Carolina School of Medicine, Chapel Hill.
Lazarowski
E R
ER
Chen
X H
XH
Harden
T K
TK
D000067956:Adenylyl Cyclase Inhibitors; D000818:Animals; D000242:Cyclic AMP / Q000378:metabolism; D004789:Enzyme Activation; D005910:Glioma; D007545:Isoproterenol / Q000494:pharmacology; D007700:Kinetics; D051381:Rats; D018048:Receptors, Purinergic P2 / Q000187:drug effects / Q000502:physiology*; D015290:Second Messenger Systems / Q000502:physiology; D013268:Stimulation, Chemical; D014407:Tumor Cells, Cultured; D010738:Type C Phospholipases / Q000378:metabolism
D000067956:Adenylyl Cyclase Inhibitors; D018048:Receptors, Purinergic P2; D000242:Cyclic AMP; D010738:Type C Phospholipases; D007545:Isoproterenol