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Neuroscience Bulletin 2008年第5期24卷 283-287页

作者：徐清程慧雯何慧琼刘志睿贺明杨宏天周智磊吉永华上海大学生命科学学院上海200444 中国科学院上海生命科学研究院上海200031

Objective To examine the effect of deglycosylation on gating properties of rNav1.3. Methods rNav1.3 was expressed in Xenopus oocyte, with glycosylation inhibition by using tunicamycin. Two-electrode voltage clamp was employed to record the whole-cell sodium current and data were analyzed by Origin software. Those of glycosylated rNav1.3 were kept as control. Results Compared with glycosylated ones, the steady-state activation curve of deglycosylated rNav1.3 was positively shifted by about 10 mV, while inactivation curve was negatively shifted by about 8 mV. Conclusion Glycosylation altered the gating properties of rNav 1.3 and contributed to the functional diversity.

关键词： rNav1.3 voltage-gated sodium channel glycosylation two-electrode voltage clamp Xenopus oocyte

Identification of a third promoter in human voltage-gated sodium channel SCNIA gene and repression of the promoter activity by a transcriptional repressor calsenilin/KChIP3/DREAM

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Identification of a third promoter in human voltage-gated so...

Distribution and Functional Characteristics of voltage-gated sodium channels in Immature Cochlear Hair Cells

中国神经科学学会第九届全国学术会议暨第五次会员代表大会

作者： Yue-Sheng LONG~*,Guang-Fei DENG,Jia-Ming QIN,Qi-Hua ZHAO,Yong-Hong YI,Wei-Ping LIAO Key Laboratory of Neurogenetics and channelopathies of Guangdong Province and the Ministry of Education of China,Institute of Neuroscience and the Second Affiliated Hospital of Guangzhou Medical University,Guangzhou 510260,China

Objective voltage-gated sodium channel a subunit type I(Na1.1) is mainly expressed in the central nervous *** expression of SCN1A(encoding Na1.1) is associated with *** SCN1A promoters have been identified in human *** present study is to identify a third promoter of SCN1A and then to explore the functions of potential transcriptional elements in this *** The minimal functional promoter and potential transcriptional elements were identified by 5’ truncating or 3’ extending *** promoter activity was measured using the Dual-Luciferase Reporter Assay System(Promega).Transcription factor and DNA flagment binding assay in vitro was performed using Electrophoretic mobility shift assay(EMSA).Results(1) The third promoter fragment(P1c,nt -1023 to +52) showed a high activity in NGF-induced PC12 cells,but very low in SHSY5Y cells and HEK-293 cells.(2) The minimal functional promoter located within the region between nt -73 and nt +52.(3) The region nt +53 to nt +90 decreased the luciferase activity by～75%that of the minimal functional promoter. (4) EMSA assay using a transcriptional repressor DREAM and the DNA fragment ranging from nt +53 to nt +90 showed that the DNA fragment was retarded after overexpression of DREAM in HEK293 cells.(5) Further truncating analysis demonstrated that the region between nt +53 and nt +62 was the DREAM binding site and was responsible for repressing the promoter *** The Ca binding factor DREAM represses the third SCN1A promoter by binding the downstream repression element(DRE),which implicates a potential role of Ca in the regulation of SCN1A expression in normal and diseased human tissues.

关键词： voltage-gated sodium channel promoter transcriptional regulation SCNIA epilepsy

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Neuroscience Bulletin 2020年第1期36卷 49-65页

作者： You Zhou Chenchen Xia Manli Yi Xueling Wang Hao Wu Yonghua Ji Department of Otolaryngology-Head and Neck Surgery Ninth People’s HospitalShanghai Jiaotong University School of MedicineShanghai 200125China Ear Institute Shanghai Jiaotong University School of MedicineShanghai 200125China Shanghai Key Laboratory of Translational Medicine on Ear and Nose Diseases Shanghai 200125China Laboratory of Neuropharmacology and Neurotoxicology Shanghai UniversityShanghai 200444China Translational Institute for Cancer Pain Xinhua Hospital Chongming BranchShanghai 202150China

voltage-gated sodium channels(VGSCs)are transiently expressed in cochlear hair cells before hearing onset and play an indispensable role in shaping spontaneous *** this study,we showed that Na^+currents shaped the spontaneous action potentials in developing mouse inner hair cells(IHCs)by decreasing the time required for the membrane potential to reach the action-potential *** immature IHCs,we identified 9 known VGSC subtypes(***-l.9ot),among which Navl.7a was the most highly expressed subtype and the main contributor to Na+currents in developing hair *** recordings of two cochlea-specific Navi.7 variants(CbmNavl.7a and CbmNavl.7b)revealed a novel loss-of-function mutation(C934R)at the extracellular linker between segments 5 and 6 of domain *** addition,post-transcriptional modification events,such as alternative splicing and RNA editing,amended the gating properties and kinetic features of CbmNavl.7a(C934).These results provide molecular and functional characteristics of VGSCs in mammalian IHCs and their contributions to spontaneous physiological activity during cochlear maturation.

关键词： Cochlear hair cell Spontaneous action potential voltage-gated sodium channel Post-transcriptional modification Gating property Introduction

Exploring the obscure profiles of pharmacological binding sites on voltage-gated sodium channels by BmK neurotoxins

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Protein & Cell 2011年第6期2卷 437-444页

作者： Zhi-Rui Liu Pin Ye Yong-Hua Ji Laboratory of Neuropharmacology and Neurotoxicology Shanghai UniversityShanghai 200444China

Diverse subtypes of voltage-gated sodium channels(VGSCs)have been found throughout tissues of the brain,muscles and the *** extracted from the venom of the Asian scorpion Buthus martensi Karsch(BmK)act as sodium channel-specific modulators and have therefore been widely used to study VGSCs.α-type neurotoxins,named BmK I,BmKαIV and BmK abT,bind to receptor site-3 on VGSCs and can strongly prolong the inactivation phase of *** contrast,β-type neurotoxins,named BmK AS,BmK AS-1,BmK IT and BmK IT2,occupy receptor site-4 on VGSCs and can suppress peak currents and hyperpolarize the activation kinetics of sodium *** evidence from binding assays of scorpion neurotoxins on VGSCs,however,indicate that pharmacological sensitivity of VGSC subtypes to different modulators is much more complex than that suggested by the simpleα-type and β-type neurotoxin *** the mechanisms of possible dynamic interactions between site 3-/4-specific modulators and region-and/or speciesspecific subtypes of VGSCs would therefore greatly expand our understanding of the physiological and pharmacological properties of diverse *** this review,we discuss the pharmacological and structural diversity of VGSCs as revealed by studies exploring the binding properties and cross-competitive binding of site 3-or site 4-specific modulators in VGSC subtypes in synaptosomes from distinct tissues of diverse species.

关键词： voltage-gated sodium channel receptor sites scorpion neurotoxins

Targeting voltage-gated sodium channels for treatment for chronic visceral pain

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World Journal of Gastroenterology 2011年第19期17卷 2357-2364页

作者： Fei-Hu Qi You-Lang Zhou Guang-Yin Xu Jiangsu Key Laboratory of Neuroregeneration Nantong University Nantong22600 I Jian~su Province China Institute of Neuroscience Key laboratory of Pain Research and Therapy Soochow University Suzhou 215123Jiangsu Province China Division of Gastroenterology Department of Internal Medicine University of Texas Medical Branch Galve-ston TX 77555-0655 United States

voltage-gated sodium channels (VGSCs) play a fundamental role in controlling cellular excitability,and their abnormal activity is related to several pathological processes,including cardiac arrhythmias,epilepsy,neurodegenerative diseases,spasticity and chronic *** particular,chronic visceral pain,the central symptom of functional gastrointestinal disorders such as irritable bowel syndrome,is a serious clinical problem that affects a high percentage of the world *** spite of intense research efforts and after the dedicated decade of pain control and research,there are not many options to treat chronic pain ***,there is a wealth of evidence emerging to give hope that a more refined approach may be *** using electronic databases,available data on structural and functional properties of VGSCs in chronic pain,particularly functional gastrointestinal hypersensitivity,were *** summarize the involvement and molecular bases of action of VGSCs in the pathophysiology of several organic and functionalgastrointestinal *** also describe the efficacy of VGSC blockers in the treatment of these neurological diseases,and outline future developments that may extend the therapeutic use of compounds that target ***,clinical and experimental data indicate that isoform-specific blockers of these channels or targeting of their modulators may provide effective and novel approaches for visceral pain therapy.

关键词： voltage-gated sodium channel Dorsal root ganglion Visceral pain Functional gastrointestinal disorders Treatment

Modeling protein-protein interactions in axon initial segment to understand their potential impact on action potential initiation

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Neural Regeneration Research 2021年第4期16卷 700-706页

作者： Piyush Bhardwaj Don Kulasiri Sandhya Samarasinghe Centre of Advanced Computational Solutions(C-fACS) Lincoln UniversityChristchurchNew Zealand Department of Molecular Biosciences Lincoln UniversityChristchurchNew Zealand

The axon initial segment(AIS)region is crucial for action potential initiation due to the presence of high-density AIS protein voltage-gated sodium channels(Nav).Nav channels comprise several serine residues responsible for the recruitment of Nav channels into the structure of AIS through interactions with ankyrin-G(AnkG).In this study,a series of computational experiments are performed to understand the role of AIS proteins casein kinase 2 and AnkG on Nav channel recruitment into the *** computational simulation results using Virtual cell software indicate that Nav channels with all serine sites available for phosphorylation bind to AnkG with strong *** the low initial concentration of AnkG and casein kinase 2,the concentration of Nav channels reduces significantly,suggesting the importance of casein kinase 2 and AnkG in the recruitment of Nav channels.

关键词： Alzheimer’s disease ankyrin-G axon initial segment casein kinase-2 microtubules voltage-gated potassium channel voltage-gated sodium channel

SCN9A Epileptic Encephalopathy Mutations Display a Gain-offunction Phenotype and Distinct Sensitivity to Oxcarbazepine

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Neuroscience Bulletin 2020年第1期36卷 11-24页

作者： Shuzhang Zhang Zhiping Zhang Yuan Shen Yudan Zhu Kun Du Jingkang Guo Yonghua Ji Jie Tao Institute of Biomembrane and Biopharmaceutics Shanghai UniversityShanghai 200444China Central Laboratory and Department of Neurology Putuo HospitalShanghai University of Traditional Chinese MedicineShanghai 200062China Department of Clinical Laboratory Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of MedicineShanghai 202150China Xinhua Translational Institute for Cancer Pain Xinhua Hospital Chongming BranchShanghai 202150China Putuo Clinical Medical School Anhui Medical UniversityShanghai 200062China

Genetic mutants of voltage-gated sodium channels(VGSCs)are considered to be responsible for the increasing number of epilepsy *** research has indicated that mutations of one of the VGSC genes,SCN9A(Navl.7),result in febrile seizures and Dravet syndrome in *** these recent efforts,the electrophysiological basis of SCN9A mutations remains ***,we performed a genetic screen of patients with febrile seizures and identified a novel missense mutation of SCN9A(W1150R).Electrophysiological characterization of different SCN9A mutants in HEK293T cells,the previously-reported N641Y and K655R variants,as well as the newly-found W1150R variant,revealed that the current density of the W1150R and N641Y variants was significantly larger than that of the wild-type(WT)*** time constants of recovery from fast inactivation of the N641Y and K655R variants were markedly lower than in the WT *** W1150R variant caused a negative shift of the G-V curve in the voltage dependence of steady-state *** mutants displayed persistent currents larger than the WT *** addition,we found that oxcarbazepine(OXC),one of the antiepileptic drugs targeting VGSCs,caused a significant shift to more negative potential for the activation and inactivation in WT and mutant ***-induced inhibition of currents was weaker in the W1150R variant than in the ***,with administering OXC the time constant of the N641Y variant was longer than those of the other two SCN9A *** all,our results indicated that the point mutation W1150R resulted in a novel gain-of-function *** findings indicated that SCN9A mutants contribute to an increase in seizure,and show distinct sensitivity to OXC.

关键词： voltage-gated sodium channel SCN9A Epilepsy Electrophysiological function Oxcarbazepine Sensitivity Introduction

Negative cross-resistance of a pyrethroid-resistant Drosophila mutant to Phryma leptostachya-derived haedoxan A

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Insect Science 2022年第3期29卷 817-826页

作者： Xingtao Qie Yuzhe Du Ahmed A.A.Aioub Ke Dong Zhaonong Hu Institution of Pesticide Science College of Plant ProtectionNorthwest A&F UniversityYanglingShaanxi 712100China Key Laboratory of Botanical Pesticide R&D in Shaanxi Province YanglingShaanxi 712100China Southern Insect Management Research Unit Agriculture Research ServiceUnited States Department of Agriculture141 Experiment Station RoadStonevilleMS 38776USA Plant Protection Department Faculty of AgricultureZagazig UniversityZagazig44511 Egypt Department of Biology Duke UniversityDurhamNC 27708USA

voltage-gated sodium channels are the primary target of pyrethroid *** in sodium channel confer knockdown resistance(kdr)to pyrethroids in various arthropod *** A(HA)is the major insecticidal component from Phryma *** has been shown that HA alters electrical responses at the Drosophila neuromuscular junction and modifies the gating properties of cockroach sodium channels expressed in Xenopus ***,whether sodium channel mutations that confer pyrethroid resistance also affect the action of HA is *** this study,we conducted bioassays using HA and permethrin in two Drosophila melanogaster strains:w^(1118),an insecticide-susceptible strain,and para^(tsl),a pyrethroid-resistant strain due to a I265N mutation in the sodium channel,and identified a new case of negative cross-resistance(NCR)between permethrin and *** para^(tsl) larvae and adults were more resistant to permethrin,as ***,both para^(tsl) larvae and adults were more sensitive to HA compared to w^(1118).We confirmed that the I265N mutation reduced the sensitivity to permethrin of a Drosophila sodium channel variant,DmNa_(v)22,expressed in Xenopus ***,the I265N mutation also abolished the effect of HA on sodium *** characterization showed that I265 on the sodium channels is critical for the action of both pyrethroids and HA on sodium channels,pointing to an overlapping mode of action between pyrethroids and HA on the sodium ***,our results suggest an I265N-independnt mechanism(s)in para^(tsl) flies that is responsible for the NCR between permethrin and HA at the whole insect level.

关键词： botanical insecticide haedoxan A insecticidal mechanism negative crossresistance permethrin voltage-gated sodium channel

Scorpion toxin BmKI directly activates Nav1.8 in primary sensory neurons to induce neuronal hyperexcitability in rats

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Protein & Cell 2015年第6期6卷 443-452页

作者： Pin Ye Yunlu Jiao Zhenwei Li Liming Hua Jin Fu Feng Jiang Tong Liu Yonghua Ji Laboratory of Neuropharmacology and Neurotoxicology Shanghai University Shanghai 200436 China Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and the Second Affiliated Hospital of Soochow University Institute of Neuroscience Soochow University Suzhou 215021 China

voltage-gated sodium channels （VGSCs） in primary sensory neurons play a key role in transmitting pain signals to the central nervous system. BmK I, a site-3 sodium channel-specific toxin from scorpion Buthus martensi Karsch, induces pain behaviors in rats. How- ever, the subtypes of VGSCs targeted by BmK I were not entirely clear. We therefore investigated the effects of BmK I on the current amplitude, gating and kinetic properties of Nav1.8, which is associated with neuronal hyperexcitability in DRG neurons. It was found that BmK I dose-dependently increased Nav1.8 current in small- sized （〈25 μm） acutely dissociated DRG neurons, which correlated with its inhibition on both fast and slow in- activation. Moreover, voltage-dependent activation and steady-state inactivation curves of Nay1.8 were shifted in a hyperpolarized direction. Thus, BmK I reduced the threshold of neuronal excitability and increased action potential firing in DRG neurons. In conclusion, our data clearly demonstrated that BmK I modulated Nav1.8 re- markably, suggesting BmK I as a valuable probe for studying Nay1.8. And Navl.8 is an important target re- lated to BmK I-evoked pain.

关键词： voltage-gated sodium channel Nay1.8,primary sensory neurons BmK I

Electroacupuncture of Neiguan(PC 6) inhibits enhanced voltage-gated sodium currents in ischemic ventricular myocytes

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Journal of Traditional Chinese Medicine 2014年第6期34卷 710-715页

作者： Baoqiang Dong Chunri Li Xiaoqing Zhang Shudong Wang Zhedong Cheng Peijing Rong College of Acumox and Tuina Liaoning University of Traditional Chinese Medicine Institute of Acupuncture and Moxibustion China Academy of Chinese Medical Sciences

OBJECTIVE: To examine the effect of electroacupuncture(EA) at bilateral Neiguan(PC 6) on voltage-gated Na+currents(INa) and channels(Nav) in ischemic ventricular ***: EA serum was prepared from six male adult Sprague-Dawley rats that had received EA at bilateral Neiguan(PC 6). Eighteen ventricular myocytes were prepared from six SD rats using an enzymolysis approach. Myocardial ischemia was mimicked by perfusion of ischemic solution. Whole-cell patch-clamping was used to record three currents evoked from isolated cells. The first current was the control, and recorded in absence of ischemic solution current. The second was the ischemic current,and recorded after perfusion of ischemic solution for 5 min, while the EA current was last, and recorded after perfusion of EA serum for 5 min. Navkinetic curves were fitted using related ***: Compared with those in controls, in the presence of ischemic solution, peak amplitudes of INasignificantly increased from ﹣40 m V to +30 m V,and half-maximal inactivation potentials of Navincreased significantly, while half-maximal activation potentials, slope factors and the recovery time from inactivation to activation of Navwere unchanged. Compared with those in the ischemic solution, in the presence of EA serum, peak ischemic current amplitudes significantly reduced from ﹣40m V to + 40 m V, and half-maximal inactivation potentials were restored, while half-maximal activation potentials, slope factors and the recovery time from inactivation to activation of Navwere ***: EA at bilateral Neiguan(PC 6) can reduce enhanced INavia restoration of delayed Navinactivation in ischemic ventricular myocytes.

关键词： Electroacupuncture Point PC 6 (Nei-guan) Myocardial Ischemia voltage-gated sodiumCurrent voltage-gated sodium channel