Aguayo L G, Witkop B, Albuquerque E X
Proc Natl Acad Sci U S A. 1986 May;83(10):3523-7. doi: 10.1073/pnas.83.10.3523.
The actions of phencyclidine [1-(1-phenylcyclohexyl)piperidine, PCP] and its morpholine analog [1-(1-phenylcyclohexyl)morpholine, PCM] on ionic currents of nicotinic acetylcholine receptors were studied at the neuromuscular junction of frog skeletal muscle and on embryonic rat muscle cells in tissue culture. PCP and PCM reduced the peak amplitude and the decay time constant of the endplate current (EPC). PCP produced a voltage-dependent curvature and a time-dependent hysteresis loop at negative potentials (at potentials from -50 to -150 mV). In contrast, PCM caused a depression of EPC peak amplitude, but the current-voltage relationship (+60 to -150 mV) remained linear. When PCP-modified EPCs were elicited in trains at hyperpolarized potentials the amplitudes of successive events were progressively decreased and the magnitude of the decrease was dependent on the level of hyperpolarization. At positive potentials the process was reversed; the amplitude increased with successive stimulations. The EPC decayed exponentially in the presence of PCP and PCM, with a shortened time constant of decay that was less dependent on membrane potential than control. PCP and PCM caused only a 20% decrease of the amplitude of the iontophoretically evoked acetylcholine potential, which was significantly different from that induced by the desensitizing alkaloid perhydrohistrionicotoxin. Both PCP and PCM reduced by 50% the mean channel open time obtained from rat myoballs, giving a potency ratio for PCP to PCM of 2.5. This relative potency was correlated with that obtained for the reduction in the decay time constant of the EPC (ratio = 2.2). The effects of PCP on the peak amplitude of the EPC seem to be related to a conformational change of the acetylcholine receptor occurring before channel activation and not to a receptor desensitization.
在青蛙骨骼肌神经肌肉接头处以及组织培养的胚胎大鼠肌肉细胞上，研究了苯环己哌啶[1-(1-苯基环己基)哌啶，PCP]及其吗啉类似物[1-(1-苯基环己基)吗啉，PCM]对烟碱型乙酰胆碱受体离子电流的作用。PCP和PCM降低了终板电流(EPC)的峰值幅度和衰减时间常数。PCP在负电位(-50至-150 mV)时产生电压依赖性曲率和时间依赖性滞后环。相比之下，PCM导致EPC峰值幅度降低，但电流-电压关系(+60至-150 mV)保持线性。当在超极化电位下以串刺激诱发PCP修饰的EPC时，连续事件的幅度逐渐降低，降低幅度取决于超极化水平。在正电位时，该过程逆转；幅度随连续刺激而增加。在PCP和PCM存在下，EPC呈指数衰减，衰减时间常数缩短，且比对照更不依赖于膜电位。PCP和PCM仅使离子电渗法诱发的乙酰胆碱电位幅度降低20%，这与脱敏生物碱全氢组胺毒素引起的降低有显著差异。PCP和PCM均使从大鼠肌球获得的平均通道开放时间减少50%，PCP与PCM的效价比为2.5。这种相对效价与EPC衰减时间常数降低的效价相关(比值=2.2)。PCP对EPC峰值幅度的影响似乎与通道激活前乙酰胆碱受体的构象变化有关，而不是与受体脱敏有关。
