Cannabinoids modulate voltage sensitive potassium A-current in hippocampal neurons via a cAMP-dependent process
Deadwyler, S.A.; Hampson, R.E.; Mu, J.; Whyte, A.; Childers, S.
Journal of Pharmacology and Experimental Therapeutics 273(2): 734-743
1995
ISSN/ISBN: 0022-3565 PMID: 7538581 Document Number: 453847
Previous studies have shown that cannabinoid receptor analogs increase voltage-dependent potassium A-current (I-A) in cultured hippocampal cells. Because cannabinoid receptors inhibit adenylate cyclase, the present study explored whether cAMP played a role in mediating this effect on I-A. The specific issue of whether cannabinoid receptor modulation of voltage-dependent I-A 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 I-A 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 I-A and increased the effect of forskolin on I-A. As shown in previous studies, the cannabinoid agonist WIN 55,212-2 increased I-A via a decrease in steady-state voltage-dependent inactivation of I-A. WIN 55,212-2 also reversed the effects of forskolin on I-A. 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 I-A were probably the result of inhibition of adenylate cyclase. The findings are discussed in terms of modulation of I-A conductance properties via cannabinoid receptor-mediated inhibition of cAMP levels within the cell.