磷脂双分子层的修饰对电压门控钠通道的门控特性和药理学特性的影响（英文）

发布时间：2018-11-04 17:21

【摘要】：电压门控钠通道广泛分布于各类细胞和组织中,参与许多生理功能的调节。作为位于脂质双分子层的膜蛋白,周围的质膜成分对于其门控特性和药理学特性是否存在影响仍然未知。本研究采用全细胞膜片钳技术,以两种钠通道的特异性调制剂BmK I和BmK AS为研究工具,在鞘磷脂酶D作用于细胞膜后,观察ND7-23细胞系上内源表达的电压门控钠通道的门控特性和药理学特性是否发生改变。结果显示,鞘磷脂酶D作用后,电压门控钠通道的门控特性并未发生变化,但其药理学特性发生了一定程度的改变。在低浓度30 nmol/L BmK I作用后,鞘磷脂酶D的修饰使得激活曲线的斜率因子k值发生改变,且30和100 nmol/L BmK I作用后,电压依赖性的慢失活和稳态失活发生超极化偏移。同样在低浓度0.1和10 nmol/L BmK AS作用后,鞘磷脂酶D的修饰使得电压依赖性的慢失活发生超极化偏移或斜率因子k值的改变。以上结果表明,通道毒理学依赖于周围的质膜环境。证明细胞膜可以调节钠通道的药理学特性。这不仅有助于对钠通道结构与周围膜蛋白相互作用关系的进一步理解,同时也为针对钠通道相关疾病的药物研发提供有益的参考思路。
[Abstract]:Voltage-gated sodium channels are widely distributed in all kinds of cells and tissues and participate in the regulation of many physiological functions. As a membrane protein located in lipid bilayer, the influence of plasma membrane composition on its gated and pharmacological properties is still unknown. In this study, whole-cell patch clamp technique was used to investigate the effects of sphingolipase D on cell membrane with two specific sodium channel modulators, BmK I and BmK AS. To observe whether the gated and pharmacological characteristics of voltage-gated sodium channel expressed in ND7-23 cell line changed. The results showed that the gated characteristics of voltage-gated sodium channels did not change after the action of sphingomyelinase D, but the pharmacological characteristics of the voltage-gated sodium channels changed to a certain extent. At low concentration of 30 nmol/L BmK I, the slope factor k of the activation curve changed with the modification of sphingolipase D, and the voltage dependent slow inactivation and steady-state inactivation occurred hyperpolarization shift after 30 and 100 nmol/L BmK I treatment. At low concentrations of 0. 1 and 10 nmol/L BmK AS, the modification of sphingomyelinase D resulted in the hyperpolarization shift or the change of slope factor k value in voltage dependent slow inactivation. These results indicate that channel toxicology depends on the surrounding plasma membrane environment. It is proved that cell membrane can regulate the pharmacological characteristics of sodium channel. This will not only help to further understand the interaction between sodium channel structure and peripheral membrane proteins, but also provide a useful reference for drug research and development of sodium channel related diseases.
【作者单位】：上海大学神经药理学与毒理学实验室;上海中医药大学附属普陀医院肾内科;复旦大学药学院药理学实验室;
【基金】：supported by the National Basic Research Development Program of China(No.2010CB529806) National Natural Science Foundation of China(No.31171064 and 30772554) Leading Academic Discipline Project of Shanghai Municipal Education Commission“Molecular Physiology”(No.J50108) Innovation Program of Shanghai Municipal Education Commission(No.15ZZ063) Research Project of Putuo Hospital,Shanghai University of Traditional Chinese Medicine,China(No.2014YJ002)
【分类号】：R96

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