P2 RECEPTOR-MEDIATED INHIBITION OF ADENYLYL-CYCLASE IN PC12 CELLS

PC12 pheochromocytoma cells have P2 receptors which are coupled to Ca2 + influx and catecholamine release. Previously we reported that ATP st imulated cyclic AMP accumulation at low concentrations up to 100 mu M but showed inhibitory effects above this concentration [Yakushi, Y., W atanabe, A., Murayama, T., Nomura, Y., 1996. Eur. J. Pharmacol. (314) 243-248]. In this study we investigated the characteristics of the inh ibitory effects of ATP analogs. In the presence of 10 mu M forskolin, an activator of adenylyl cyclase, ATP, adenosine 5'-O-(3-thiotriphosph ate) (ATP gamma S), 2',3'-O-(4-benzoyl) benzoyl ATP, 2-methylthio ATP and adenosine 5'-O-(2-thiodiphosphate) inhibited cyclic AMP accumulati on in a dose-dependent manner from 100 mu M. UTP, alpha beta and beta gamma-methylene ATP had no or very limited effects. The relative order of ATP analogs suggests that the ATP receptor appears to be P2Y-like. However, suramin, an antagonist of P2X and P2Y receptors, and reactiv e blue-2, which inhibited beta gamma-methylene ATP-induced cyclic AMP accumulation, did not modify the inhibitory effect of ATP gamma S. Tre atment with pertussis toxin, which completely abolished the effect of carbachol, had no effect on the action of ATP over 300 mu M. The exist ence of a new type of ATP receptor-mediated inhibition of adenylyl cyc lase is proposed in PC12 cells. (C) 1998 Elsevier Science B.V.