發(fā)布時間：2018-11-04 17:21

【摘要】：電壓門控鈉通道廣泛分布于各類細(xì)胞和組織中,參與許多生理功能的調(diào)節(jié)。作為位于脂質(zhì)雙分子層的膜蛋白,周圍的質(zhì)膜成分對于其門控特性和藥理學(xué)特性是否存在影響仍然未知。本研究采用全細(xì)胞膜片鉗技術(shù),以兩種鈉通道的特異性調(diào)制劑BmK I和BmK AS為研究工具,在鞘磷脂酶D作用于細(xì)胞膜后,觀察ND7-23細(xì)胞系上內(nèi)源表達(dá)的電壓門控鈉通道的門控特性和藥理學(xué)特性是否發(fā)生改變。結(jié)果顯示,鞘磷脂酶D作用后,電壓門控鈉通道的門控特性并未發(fā)生變化,但其藥理學(xué)特性發(fā)生了一定程度的改變。在低濃度30 nmol/L BmK I作用后,鞘磷脂酶D的修飾使得激活曲線的斜率因子k值發(fā)生改變,且30和100 nmol/L BmK I作用后,電壓依賴性的慢失活和穩(wěn)態(tài)失活發(fā)生超極化偏移。同樣在低濃度0.1和10 nmol/L BmK AS作用后,鞘磷脂酶D的修飾使得電壓依賴性的慢失活發(fā)生超極化偏移或斜率因子k值的改變。以上結(jié)果表明,通道毒理學(xué)依賴于周圍的質(zhì)膜環(huán)境。證明細(xì)胞膜可以調(diào)節(jié)鈉通道的藥理學(xué)特性。這不僅有助于對鈉通道結(jié)構(gòu)與周圍膜蛋白相互作用關(guān)系的進一步理解,同時也為針對鈉通道相關(guān)疾病的藥物研發(fā)提供有益的參考思路。
[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.
【作者單位】： 上海大學(xué)神經(jīng)藥理學(xué)與毒理學(xué)實驗室;上海中醫(yī)藥大學(xué)附屬普陀醫(yī)院腎內(nèi)科;復(fù)旦大學(xué)藥學(xué)院藥理學(xué)實驗室;
【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)
【分類號】：R96

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本文編號：2310602