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.