RT Journal Article SR Electronic T1 Cannabinoid Receptors Differentially Modulate Potassium A and D Currents in Hippocampal Neurons in Culture JF Journal of Pharmacology and Experimental Therapeutics JO J Pharmacol Exp Ther FD American Society for Pharmacology and Experimental Therapeutics SP 893 OP 902 VO 291 IS 2 A1 Jian Mu A1 Shou-yuan Zhuang A1 M. Todd Kirby A1 Robert E. Hampson A1 Sam A. Deadwyler YR 1999 UL http://jpet.aspetjournals.org/content/291/2/893.abstract AB Cannabinoid (CB1) receptor activation produced differential effects on voltage-gated outward potassium currents in whole-cell recordings from cultured (7–15 days) rat hippocampal neurons. Voltage-dependent potassium currents A (IA) and D (ID) were isolated from a composite tetraethylammonium-insensitive current (Icomp) by blockade with either 4-aminopyridine (500 μM) or dendrotoxin (2 μM) and subtraction of the residual IA from Icomp to reveal ID. The time constants of inactivation (τ) of IA and ID as determined in this manner were found to be quite different. The CB1 agonist WIN 55,212-2 produced a 15- to 20-mV positive shift in voltage-dependent inactivation of IA and a simultaneous voltage-independent reduction in the amplitude of ID in the same neurons. The EC50 value for the effect of WIN 55,212-2 on IDamplitude (13.9 nM) was slightly lower than the EC50 value for its effect on IA voltage dependence (20.6 nM). Pretreatment with either the CB1 antagonist SR141716A or pertussis toxin completely blocked the differential effects of WIN 55,212-2 on IA and ID, whereas cellular dialysis with guanosine-5′-O-(3-thio)triphosphate mimicked the action of cannabinoids but blocked the action of simultaneously administered cannabinoid receptor ligands. Finally, the differential effects of cannabinoids on IA and ID were both shown to be mediated via the well documented cannabinoid receptor inhibition of adenylyl cyclase and subsequent modulation of cAMP and protein kinase. These actions are considered in terms of cAMP-mediated phosphorylation of separate IA and ID channels and the contribution of each to composite voltage-gated potassium currents in these cells. The American Society for Pharmacology and Experimental Therapeutics