Häggblad J, Eriksson H, Hedlund B, Heilbronn E
Unit of Neurochemistry and Neurotoxicology, University of Stockholm, Sweden.
Naunyn Schmiedebergs Arch Pharmacol. 1987 Oct;336(4):381-6. doi: 10.1007/BF00164869.
Forskolin, a commonly used adenylate cyclase activator, was found to inhibit reversibly the carbachol-induced ion-translocating capacity of the nicotinic acetylcholine receptor (nAChR) on chick myotubes in a dose- (IC50 = 20 microM) and time-dependent manner. This effect was not correlated to increases in cellular cAMP. Forskolin, at a concentration (50 microM) that totally blocked the carbachol-induced 86Rb influx, caused no change in carbachol or alpha-bungarotoxin binding to chick myotube nAChR in situ. In contrast, in the presence of carbachol, forskolin inhibited (IC50 = 10 microM) the binding of 3H-phencyclidine, a putative nAChR ion-channel ligand, to Torpedo microsac nAChR. Inhibition of 3H-phencyclidine binding in the absence of carbachol was not complete. Membrane leakage studies on myotubes, measuring 3H-efflux from 2-deoxy-D(1-3H)-glucose loaded cells and electrophysiological measurements of membrane properties supported the interpretation that forskolin induced decreases in plasma membrane permeability. In conclusion, forskolin blocks the carbachol-mediated increase in permeability of the nAChR channel by (1) binding to the ion-channel (open state) and (2) generally perturbing the plasma membrane function possibly by interfering with the protein-lipid interface.
福司可林是一种常用的腺苷酸环化酶激活剂，研究发现它能以剂量依赖（IC50 = 20 microM）和时间依赖的方式可逆性抑制卡巴胆碱诱导的鸡肌管烟碱型乙酰胆碱受体（nAChR）的离子转运能力。这种效应与细胞内cAMP的增加无关。福司可林在完全阻断卡巴胆碱诱导的86Rb内流的浓度（50 microM）下，对卡巴胆碱或α-银环蛇毒素与鸡肌管nAChR的原位结合没有影响。相反，在卡巴胆碱存在的情况下，福司可林抑制（IC50 = 10 microM）了3H-苯环利定（一种假定的nAChR离子通道配体）与电鳐微囊nAChR的结合。在没有卡巴胆碱的情况下，对3H-苯环利定结合的抑制并不完全。对肌管进行的膜渗漏研究，测量从负载2-脱氧-D（1-3H）-葡萄糖的细胞中流出的3H以及对膜特性的电生理测量，支持了福司可林导致质膜通透性降低的解释。总之，福司可林通过（1）与离子通道（开放状态）结合以及（2）可能通过干扰蛋白质-脂质界面普遍扰乱质膜功能，来阻断卡巴胆碱介导的nAChR通道通透性增加。
