Pharmacological kinetics of BmK AS, a sodium channel site 4-specific modulator on Na_v1.3  

作　　者：Zhi-Rui Liu Jie Tao Bang-Qian Dong Gang Ding Zhi-Jun Cheng Hui-Qiong He Yong-Hua Ji 

机构地区：[1]Laboratory of Neuropharmacology and Neurotoxicology, Shanghai University, Shanghai 200444, China [2]Xinhua Translational Institute for Cancer Pain, Chongming, Shanghai 202151, China

出　　处：《Neuroscience Bulletin》2012年第3期209-221,共13页神经科学通报（英文版）

基　　金：supported by grants from the National Basic Research Development Program of China (2010CB529806);the National Natural Science Foundation of China (31171064);the Key Research Program of Science and Technology Commissions of Shanghai Municipality (11JC1404300);the Leading Academic Discipline Project of Shanghai Municipal Education Commission (J50108)

摘　　要：Objective In this study, the pharmacological kinetics of Buthus martensi Karsch （BmK） AS, a specific modulator of voltage-gated sodium channel site 4, was investigated on Nav1.3 expressed in Xenopus oocytes. Methods Two-electrode voltage clamp was used to record the whole-cell sodium current. Results The peak currents of Nav1.3 were depressed by BmK AS over a wide range of concentrations （10, 100, and 500 nmol/L）. Most remarkably, BmK AS at 100 nmol/L hyperpolarized the voltage-dependence and increased the voltage-sensitivity of steady-state activation/inactivation. In addition, BmK AS was capable of hyperpolarizing not only the fast inactivation but also the slow inactivation, with a greater preference for the latter. Moreover, BmK AS accelerated the time constant and increased the ratio of recovery in Nav1.3 at all concentrations. Conclusion This study provides direct evidence that BmK AS facilitates steady-state activation and inhibits slow inactivation by stabilizing both the closed and open states of the Nav1.3 channel, which might result from an integrative binding to two receptor sites on the voltage-gated sodium channels. These results may shed light on therapeutics against Nav1.3-targeted pathology.Objective In this study, the pharmacological kinetics of Buthus martensi Karsch （BmK） AS, a specific modulator of voltage-gated sodium channel site 4, was investigated on Nav1.3 expressed in Xenopus oocytes. Methods Two-electrode voltage clamp was used to record the whole-cell sodium current. Results The peak currents of Nav1.3 were depressed by BmK AS over a wide range of concentrations （10, 100, and 500 nmol/L）. Most remarkably, BmK AS at 100 nmol/L hyperpolarized the voltage-dependence and increased the voltage-sensitivity of steady-state activation/inactivation. In addition, BmK AS was capable of hyperpolarizing not only the fast inactivation but also the slow inactivation, with a greater preference for the latter. Moreover, BmK AS accelerated the time constant and increased the ratio of recovery in Nav1.3 at all concentrations. Conclusion This study provides direct evidence that BmK AS facilitates steady-state activation and inhibits slow inactivation by stabilizing both the closed and open states of the Nav1.3 channel, which might result from an integrative binding to two receptor sites on the voltage-gated sodium channels. These results may shed light on therapeutics against Nav1.3-targeted pathology.

关 键 词：VGSC subtype Nav1.3 VGSC site 4-specific modulator BmKAS 

分 类 号：Q424[生物学—神经生物学] TQ453.01[生物学—生理学]