| Autor: |
Mu, Jian, Zhuang, Shou-yuan, Kirby, M. Todd, Hampson, Robert E., Deadwyler, Sam A. |
| Zdroj: |
The Journal of Pharmacology and Experimental Therapeutics; November 1999, Vol. 291 Issue: 2 p893-902, 10p |
| Abstrakt: |
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 IAfrom Icompto reveal ID. The time constants of inactivation (τ) of IAand IDas determined in this manner were found to be quite different. The CB1agonist WIN 55,212-2 produced a 15- to 20-mV positive shift in voltage-dependent inactivation of IAand a simultaneous voltage-independent reduction in the amplitude of IDin the same neurons. The EC50value for the effect of WIN 55,212-2 on IDamplitude (13.9 nM) was slightly lower than the EC50value for its effect on IAvoltage dependence (20.6 nM). Pretreatment with either the CB1antagonist SR141716A or pertussis toxin completely blocked the differential effects of WIN 55,212-2 on IAand 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 IAand IDwere 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 IAand IDchannels and the contribution of each to composite voltage-gated potassium currents in these cells. |
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