Morello R, Begenisich T, Trzos W, Reed J K
Biophys J. 1980 Sep;31(3):435-40. doi: 10.1016/S0006-3495(80)85071-5.
Alkyl and aromatic guanidines interact strongly with the tetrodotoxin (TTX)- receptor site in eel electroplaque membranes, showing competition with TTX. That these guanidines could be useful as highly reversible small molecular weight blockers of Na+ currents is therefore suggested. We have investigated the mechanisms of interaction of one of these derivatives, nonylguanidine, by studying its effects on Na+ currents in squid giant axons using voltage clamp techniques. Although nonylguanidine competed with TTX for binding to eel electroplaque membrane fragments (Ki = 1.8 X 10(-5) M), it reversibly blocked both inward and outward Na+ currents in intact axons only if applied to the interior. In axons with the Na+ inactivation removed by papain nonylguanidine produced a time-dependent block very similar to that reported for strychnine and pancuronium. The reduction of steady-state currents in these axons was also voltage-dependent, with increasing block observed with increasing step depolarization. These results suggest that nonylguanidine binds to a site accessible from the axoplasmic side of the channel, simulating Na+ inactivation in papain-treated axons and competing with the normal inactivation process in untreated axons. The competition between internal nonylguanidine and external TTX may result from perturbation by the positively charged nonylguanidine of the TTX-binding site from within the channel itself.
烷基胍和芳基胍与鳗鱼电板膜中的河豚毒素（TTX）受体位点强烈相互作用，表现出与TTX的竞争关系。因此，有人提出这些胍类化合物可用作Na⁺电流的高度可逆性小分子阻滞剂。我们通过使用电压钳技术研究其对鱿鱼巨轴突中Na⁺电流的影响，来探究其中一种衍生物壬基胍的相互作用机制。尽管壬基胍与TTX竞争结合鳗鱼电板膜片段（Ki = 1.8×10⁻⁵ M），但只有将其施加到轴突内部时，它才能可逆地阻断完整轴突中的内向和外向Na⁺电流。在木瓜蛋白酶去除了Na⁺失活的轴突中，壬基胍产生的时间依赖性阻断与士的宁和泮库溴铵报道的非常相似。这些轴突中稳态电流的降低也是电压依赖性的，随着去极化步幅增加，阻断作用增强。这些结果表明，壬基胍结合到通道轴浆侧可及的位点，在木瓜蛋白酶处理的轴突中模拟Na⁺失活，并在未处理的轴突中与正常失活过程竞争。内部壬基胍和外部TTX之间的竞争可能是由于带正电荷的壬基胍对通道内TTX结合位点的干扰所致。
