Huang C-W, Hung T-Y, Wu S-N
Department of Neurology, National Cheng Kung University Hospital, Tainan, Taiwan.
Department of Pediatrics, Chi-Mei Medical Center, Tainan, Taiwan.
Neuroscience. 2015 Feb 26;287:125-36. doi: 10.1016/j.neuroscience.2014.12.026. Epub 2014 Dec 19.
The effect of lacosamide (LCS), a functionalized molecule with anti-convulsant properties, on ion channels was investigated, with the aid of patch clamp technology and simulation modeling. In NSC-34 neuronal cells, LCS was found to block voltage-gated Na(+) current (INa) in a frequency- and concentration-dependent manner. With the two-step voltage protocol, a minimal change in the steady-state inactivation of INa was found in the presence of LCS. However, with repetitive stimulation, the pulse-to-pulse reduction in peak current was shown to be exponential, with a rate linearly related to both the inter-stimulus interval and the LCS concentration. In addition, the frequency-dependent blocking properties were modeled by considering the drug interaction with a voltage-dependent mixture of NaV channels harboring either an accessible or an inaccessible binding site. LCS also increased the dimension of inactivation space of NaV-channel states, thereby producing the adaptive response of neurons to previous firing. LCS (30 μM) had no effects on the non-inactivating component of INa, while it slightly decreased the amplitude of delayed-rectifier K(+) current. Moreover, LCS suppressed the peak amplitude of INa in embryonic cortical neurons. In human embryonic kidney (HEK293T) cells which expressed SCN5A, LCS attenuated the peak amplitude of INa, in a concentration-dependent fashion. The unique effects of LCS on NaV currents presented here may contribute to its in vivo modulation of cellular excitability.
借助膜片钳技术和模拟建模，研究了具有抗惊厥特性的功能化分子拉科酰胺（LCS）对离子通道的影响。在NSC - 34神经元细胞中，发现LCS以频率和浓度依赖性方式阻断电压门控钠电流（INa）。采用两步电压方案，发现在LCS存在下，INa的稳态失活变化极小。然而，在重复刺激时，峰值电流的逐脉冲降低呈指数形式，其速率与刺激间隔和LCS浓度均呈线性相关。此外，通过考虑药物与具有可及或不可及结合位点的电压依赖性NaV通道混合物的相互作用，对频率依赖性阻断特性进行了建模。LCS还增加了NaV通道状态失活空间的维度，从而产生神经元对先前放电的适应性反应。LCS（30 μM）对INa的非失活成分无影响，而它略微降低了延迟整流钾电流（K(+)电流）的幅度。此外，LCS抑制胚胎皮质神经元中INa的峰值幅度。在表达SCN5A的人胚肾（HEK293T）细胞中，LCS以浓度依赖性方式减弱INa的峰值幅度。本文所述LCS对NaV电流的独特作用可能有助于其在体内对细胞兴奋性的调节。
