Enhancement of Cellular Adenosine Triphosphate Levels in PC12 Cells by 2,5-Dideoxyadenosine, a P-Site Inhibitor of Adenylate Cyclase

To elucidate the biological significance of the P-site inhibitor of adenylate cyclase, the effect of 2,5-dideoxyadenosine (DDA) on cellular levels of adenine compounds in PC12 cells was studied. The addition of DDA and deoxyadenosine (deoxyAdo), P-site inhibitors of adenylate cyclase, as well as the addition of adenosine (Ado) to the incubation medium containing glucose as the sole nutrient significantly enhanced cellular ATP levels in PC12 cells. N6-Methyladenosine and N6-cyclohexyladenosine did not augment the ATP levels. The ATP level-enhancing effect of DDA was further enhanced by Ado. After pretreatment of PC12 cells with theophylline, DDA-induced ATP enhancement was potentiated by theophylline but the effect of Ado was suppressed. cAMP levels in PC12 cells were markedly reduced by DDA but the levels were not changed by Ado. These results suggest for the first time that P-site inhibitors of adenylate cyclase may stimulate ATP synthesis via glycolysis by decreasing cAMP levels and the mode of action of the ATP level-enhancing effect of DDA may be different from that of Ado.