title: Lipid bilayer modification alters the gating properties and pharmacological sensitivity of voltage-gated sodium channel.
abstract: Voltage-gated sodium channels (VGSCs) are widely distributed in most cells and tissues, performing many physiological functions. As one kind of membrane proteins in the lipid bilayer, whether lipid composition plays a role in the gating and pharmacological sensitivity of VGSCs still remains unknown. Through the application of sphingomyelinase D (SMaseD), the gating and pharmacological sensitivity of the endogenous VGSCs in neuroblastoma ND7-23 cell line to BmK I and BmK AS, two sodium channel-specific modulators from the venom of Buthus martensi Karsch (BmK), were assessed before and after lipid modification. The results showed that, in ND7-23 cells, SMaseD did not change the gating properties of VGSCs. However, SMaseD application altered the slope factor of activation with the treatment of 30 nmol/L BmK I, but caused no significant effects at 100 and 500 nmol/L BmK I. With low concentration of BmK I (30 and 100 nmol/L) treatment, the application of SMaseD exerted hyperpolarizing effects on both slow-inactivation and steady-state inactivation, and increased the recovery time constant, whereas total inactivation and recovery remained unaltered at 500 nmol/L BmK I. Meanwhile, SMaseD modulation hyperpolarized the voltage dependence of slow-inactivation at 0.1 nmol/L BmK AS and altered the slope factor of slow-inactivation at 10 nmol/L BmK AS, whereas other parameters remained unchanged. These results indicated a possibility that the lipid bilayer would disturb the pharmacological sensitivity of VGSCs for the first time, which might open a new way of developing new drugs for treating sodium channelopathies.
authors.affiliation: Laboratory of Neuropharmacology and Neurotoxicology, Shanghai University, Shanghai 200444, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: Laboratory of Neuropharmacology and Neurotoxicology, Shanghai University, Shanghai 200444, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Wu
authors.affiliation: Laboratory of Neuropharmacology and Neurotoxicology, Shanghai University, Shanghai 200444, China.
authors.forename: Yi-Jun
authors.initials: YJ
authors.lastname: Feng
authors.affiliation: Department of Nephrology, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, China. jietao_putuo@foxmail.com.|Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai 201203, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Tao
authors.affiliation: Laboratory of Neuropharmacology and Neurotoxicology, Shanghai University, Shanghai 200444, China. yhji@staff.shu.edu.cn.
authors.forename: Yong-Hua
authors.initials: YH
authors.lastname: Ji
mesh_terms: D045744:Cell Line, Tumor; D006801:Humans; D008051:Lipid Bilayers / Q000737:chemistry*; D009447:Neuroblastoma; D012604:Scorpion Venoms / Q000737:chemistry*; D026941:Sodium Channel Blockers / Q000737:chemistry*; D061566:Voltage-Gated Sodium Channels / Q000502:physiology*
chemical_list: D008051:Lipid Bilayers; D012604:Scorpion Venoms; D026941:Sodium Channel Blockers; D061566:Voltage-Gated Sodium Channels