PT - JOURNAL ARTICLE AU - Deadwyler, S A AU - Hampson, R E AU - Mu, J AU - Whyte, A AU - Childers, S TI - Cannabinoids modulate voltage sensitive potassium A-current in hippocampal neurons via a cAMP-dependent process. DP - 1995 May 01 TA - Journal of Pharmacology and Experimental Therapeutics PG - 734--743 VI - 273 IP - 2 4099 - http://jpet.aspetjournals.org/content/273/2/734.short 4100 - http://jpet.aspetjournals.org/content/273/2/734.full SO - J Pharmacol Exp Ther1995 May 01; 273 AB - Previous studies have shown that cannabinoid receptor analogs increase voltage-dependent potassium A-current (IA) in cultured hippocampal cells. Because cannabinoid receptors inhibit adenylate cyclase, the present study explored whether cAMP played a role in mediating this effect on IA. The specific issue of whether cannabinoid receptor modulation of voltage-dependent IA acts via a cAMP-dependent process was investigated. The cAMP analog, 8-bromo-cAMP, as well as the adenylate cyclase stimulant forskolin, produced concentration-dependent shifts in IA that were opposite those produced by cannabinoid receptor ligands. Moreover, the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine also produced a marked negative shift in the steady-state voltage dependence of IA and increased the effect of forskolin on IA. As shown in previous studies, the cannabinoid agonist WIN 55,212-2 increased IA via a decrease in steady-state voltage-dependent inactivation of IA. WIN 55,212-2 also reversed the effects of forskolin on IA. The electrophysiological studies were paralleled by direct assays of cAMP in these cells, where cannabinoids inhibited forskolin-stimulated cAMP by 50% in a pertussis toxin-sensitive manner. The results confirmed that pertussis toxin-sensitive cannabinoid receptor-mediated changes in IA were probably the result of inhibition of adenylate cyclase. The findings are discussed in terms of modulation of IA conductance properties via cannabinoid receptor-mediated inhibition of cAMP levels within the cell.