Deadwyler S A, Hampson R E, Mu J, Whyte A, Childers S
Department of Physiology and Pharmacology, Bowman Gray School of Medicine, Wake Forest University, Winston-Salem, North Carolina, USA.
J Pharmacol Exp Ther. 1995 May;273(2):734-43.
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.
先前的研究表明，大麻素受体类似物可增加培养的海马细胞中电压依赖性钾离子A电流（IA）。由于大麻素受体抑制腺苷酸环化酶，因此本研究探讨了cAMP是否在介导对IA的这种作用中发挥作用。研究了大麻素受体对电压依赖性IA的调节是否通过cAMP依赖性过程起作用这一具体问题。cAMP类似物8-溴-cAMP以及腺苷酸环化酶刺激剂福斯可林在IA中产生了浓度依赖性的变化，其变化方向与大麻素受体配体产生的变化相反。此外，磷酸二酯酶抑制剂3-异丁基-1-甲基黄嘌呤也使IA的稳态电压依赖性产生明显的负向变化，并增强了福斯可林对IA的作用。如先前研究所示，大麻素激动剂WIN 55,212-2通过降低IA的稳态电压依赖性失活来增加IA。WIN 55,212-2还逆转了福斯可林对IA的作用。这些电生理研究与对这些细胞中cAMP的直接测定结果相平行，在这些细胞中，大麻素以百日咳毒素敏感的方式将福斯可林刺激的cAMP抑制了50%。结果证实，百日咳毒素敏感的大麻素受体介导的IA变化可能是腺苷酸环化酶受到抑制的结果。本文根据通过大麻素受体介导的细胞内cAMP水平抑制对IA电导特性的调节来讨论这些发现。
