Department of Physiology, College of Medicine, National Cheng Kung University, Tainan City 70101, Taiwan.
Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan City 70101, Taiwan.
Int J Mol Sci. 2022 Jan 21;23(3):1171. doi: 10.3390/ijms23031171.
Lacosamide (Vimpat, LCS) is widely known as a functionalized amino acid with promising anti-convulsant properties; however, adverse events during its use have gradually appeared. Despite its inhibitory effect on voltage-gated Na current (), the modifications on varying types of ionic currents caused by this drug remain largely unexplored. In pituitary tumor (GH) cells, we found that the presence of LCS concentration-dependently decreased the amplitude of A-type K current () elicited in response to membrane depolarization. The amplitude in these cells was sensitive to attenuation by the application of 4-aminopyridine, 4-aminopyridine-3-methanol, or capsaicin but not by that of tetraethylammonium chloride. The effective IC value required for its reduction in peak or sustained was calculated to be 102 or 42 µM, respectively, while the value of the dissociation constant () estimated from the slow component in inactivation at varying LCS concentrations was 52 µM. By use of two-step voltage protocol, the presence of this drug resulted in a rightward shift in the steady-state inactivation curve of as well as in a slowing in the recovery time course of the current block; however, no change in the gating charge of the inactivation curve was detected in its presence. Moreover, the LCS addition led to an attenuation in the degree of voltage-dependent hysteresis for elicitation by long-duration triangular ramp voltage commands. Likewise, the identified in mouse mHippoE-14 neurons was also sensitive to block by LCS, coincident with an elevation in the current inactivation rate. Collectively, apart from its canonical action on inhibition, LCS was effective at altering the amplitude, gating, and hysteresis of in excitable cells. The modulatory actions on , caused by LCS, could interfere with the functional activities of electrically excitable cells (e.g., pituitary tumor cells or hippocampal neurons).
拉科酰胺（Vimpat，LCS）是一种广泛应用的具有抗惊厥作用的功能性氨基酸，但在其使用过程中逐渐出现了不良反应。尽管它对电压门控钠电流（）具有抑制作用，但这种药物对不同类型离子电流的影响在很大程度上仍未得到探索。在垂体瘤（GH）细胞中，我们发现 LCS 的存在浓度依赖性地降低了膜去极化引起的 A 型钾电流（）的幅度。这些细胞中的电流幅度对 4-氨基吡啶、4-氨基吡啶-3-甲醇或辣椒素的应用敏感，但对四乙铵氯化物的应用不敏感。计算出其降低峰或持续电流幅度的有效 IC 值分别为 102 或 42µM，而从不同 LCS 浓度下失活的慢成分中估计的解离常数（）值为 52µM。通过两步电压方案，该药物的存在导致稳态失活曲线的右移，以及电流阻断的恢复时间过程的减慢；然而，在其存在下，失活曲线的门控电荷没有变化。此外，LCS 的加入导致长持续时间三角斜坡电压命令引起的电流激发的电压依赖性滞后程度降低。同样，在小鼠 mHippoE-14 神经元中鉴定的电流也对 LCS 的阻断敏感，同时电流失活速率升高。总的来说，除了对抑制的典型作用外，LCS 还能有效改变兴奋细胞中电流的幅度、门控和滞后。LCS 对电流的调节作用可能会干扰电兴奋细胞的功能活动（例如，垂体瘤细胞或海马神经元）。
