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Expression and Role of voltage-gated sodium channels in Human Dorsal Root Ganglion Neurons with Special Focus on Nav1.7,Species Differences, and Regulation by Paclitaxel

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Neuroscience Bulletin 2018年第1期34卷 4-12页

作者： Wonseok Chang Temugin Berta Yong Ho Kim Sanghoon Lee Seok-Yong Lee Ru-Rong Ji Department of Anesthesiology Duke University Medical Center Durham NC 27710 USA Department of Physiology and Biophysics College of Medicine Eulji University Daejeon Korea Pain Research Center Department of Anesthesiology University of Cincinnati Medical Center Cincinnati OH 45267 USA D epartment of Physiology College of Medicine Gachon University Incheon Korea Department of Biochemistry Duke University Medical Center Durham NC 27710 USA Department of Neurobiology Duke University Medical Center Durham NC 27710 USA

voltage-gated sodium channels （Navs） play an important role in human pain sensation. However, the expression and role of Nav subtypes in native human sensory neurons are unclear. To address this issue, we obtained human dorsal root ganglion （hDRG） tissues from healthy donors. PCR analysis of seven DRG-expressed Nav subtypes revealed that the hDRG has higher expression of Navl.7 （,-~ 50% of total Nav expression） and lower expres- sion of Navl.8 （~ 12%）, whereas the mouse DRG has higher expression of Nav 1.8 （- 45%） and lower expression of Navl.7 （- 18%）. To mimic Nav regulation in chronic pain, we treated hDRG neurons in primary cultures with paclitaxel （0.1-1 μmol/L） for 24 h. Paclitaxel increased the Navl.7 but not Navl.8 expression and also increased the transient Na＋ currents and action potential firing frequency in small-diameter （〈50 ~tm） hDRG neurons. Thus, the hDRG provides a translational model in which to study ＂human pain in a dish＂ and test new pain therapeutics.

关键词： Dorsal root ganglion Neuropathic pain Paclitaxel voltage-gated sodium channels

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voltage-gated sodium channels and Blockers:An Overview and Where Will They Go?

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Current Medical Science 2019年第6期39卷 863-873页

作者： Zhi-mei LI Li-xia CHEN Hua LI Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation School of PharmacyTongji Medical CollegeHuazhong University of Science and TechnologyWuhan 430030China Wuya College of Innovation Key Laboratory of Structure-Based Drug Design&DiscoveryMinistry of EducationShenyang Pharmaceutical UniversityShenyang 110016China

voltage-gated sodium(Nav)channels are critical players in the generation and propagation of action potentials by triggering membrane depolarization.Mutations in Nav channels are associated with a variety of channelopathies,which makes them relevant targets for pharmaceutical intervention.Sofar,the cryoelectron microscopic structure of the human Nav 1.2,Nav 1.4,and Nav 1.7 has been reported,which sheds light on the molecular basis of functional mechanism of Nav channels and provides a path toward structure-based drug discovery.In this review,we focus on the recent advances in the structure,molecular mechanism and modulation of Nav channels,and state updated sodium channel blockers for the treatment of pathophysiology disorders and briefly discuss where the blockers may be developed in the future.

关键词： voltage-gated sodium channels blockers Nav channel structures channelopathies

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Low Mg2+ treatment increases the sensitivity of voltage-gated sodium channels to the Ca2+/calmodulin-mediated modulation in the cultured hippocampal neurons

Low Mg2+ treatment increases the sensitivity of voltage-gate...

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中国生理学会第24届全国会员代表大会暨生理学学术大会

作者：郭凤 Qinghua Gao Liying Hao 中国医科大学药学院药物毒理学教研室

The purpose of this study was to investigate the effect of Ca2+/calmodulin（Ca M）on voltage-gated sodium channels（VGSCs）in cultured hippocampal neurons exposed to low Mg2+（low Mg2+neurons）.Our data showed that the VGSC activity,which is associated with a persistent,noninactivating Na+current（INa,P）,was modulated by Ca M in a concentration-dependent manner in both normal neurons and low Mg2+neurons,but the channel activity in low Mg2+neurons was more sensitive to Ca2+/Ca M regulation than that in normal neurons,as determined by patch–clamp.The increased sensitivity of VGSCs in low Mg2+neurons was remained partiallywhenusing Ca M12 and Ca M34,Ca M mutants with disabled binding sites in the N-lobe or C-lobe,but it was dismissed when using Ca M1234,Ca M mutants with all four Ca2+sites disabled,indicating that functional calcium（Ca2+）-binding sites from either lobes of Ca M are required for the modulation of VGSCs in low Mg2+neurons.Furthermore,the number of neurons exhibiting colocalization of Ca M with the VGSC subtypes NaV1.1,NaV1.2 and NaV1.3 was significantly higher in low Mg2+neurons than that in normal neurons,as shown by immunofluorescence.Our main finding is that low Mg2+treatment increases the sensitivity of VGSCs to the Ca2+/Ca M-mediated regulation.Our data revealsthat Ca M,as a core regulating factor,connects the functional roles of the three main intracellular ions:Na+,Ca2+and Mg2+together by modulating VGSCs and provides a possible explanation for the seizure discharge observed in low Mg2+neurons.

关键词： Mg2+ calmodulin calcium voltage-gated sodium channels

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U-shaped dose-dependent effects of BmK AS,a unique scorpion polypeptide toxin on the voltage-gated sodium channels

U-shaped dose-dependent effects of BmK AS,a unique scorpion ...

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中国神经科学学会第四次会员代表大会暨第八届全国学术会议

作者： Jie TAO~1 Mang-Mang ZHU~2 Miao TAN~2 Hong-Tian YANG~1 Yong-Hua JI~(1 *) 1 School of Life Sciences Shanghai University Shanghai 200444 China 2 Graduate School of Chinese Academy of Sciences Shanghai Institute of Physiology Shanghai Institute of Biological Sciences Chinese Academy of Sciences Shanghai 200031 China

＜正＞Objective BmK AS,a scorpion polypeptide toxin,suggested to target the voltage-gated sodium channels （VGSCs）.However,the way of BmK AS acting on the VGSCs has yet to be defined.Methods We examined the electrophysiological effects of BmK AS in a wide dose range on the rat brain-type VGSC a-subunit,rNav1.2a,heterologously expressed in Xenopus oocytes as well as on the VGSCs endogenously expressed in the DRG neuroblastoma ND7- 23 cell line.Results（1） In the Xenopus oocytes,BmK AS depolarized the voltage dependence of activation and inactivation of rNav1.2a at 0.1 and 500 nM whereas hyperpolarized them at 1 nM.（2） While in the ND7-23 cells,BmK AS hyperpolarized the voltage dependence of activation and inactivation at 0.1,1 and 100 nM but not 10 nM.BmK AS also hyperpolarized the voltage dependence of recovery from inactivation at 0.1 and 100 nM,and slowed the recovery kinetics at all the concentrations,but the effects of 1 and 10 nM were relatively smaller than that of 0.1 and 100 nM.（3） The inactivation of VGSCs was potentiated by 10 nM BmK AS in both systems,whereas it was inhibited by 0.1 or 100 nM BmK AS in the Xenopus oocytes or ND7-23 cells,respectively.Conclusion BmK AS could modulate the VGSCs in a unique Ushaped dose-dependent manner,which might be from an integration of the bidirectional effects via binding to two distinct receptor sites on the VGSCs.

关键词： U-shaped dose-dependence voltage-gated sodium channels polypeptide modulator scorpion toxin electrophysiology

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Inhibitory effects of bufalin, an active ingredient from toad venom on voltage-gated sodium channels

Inhibitory effects of bufalin, an active ingredient from toa...

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中国神经科学学会第十二届全国学术会议

作者： Jie TAO Pei-Hao YIN Department of Neurosurgery and Central Laboratory Putuo Hospital Shanghai University of Traditional Chinese Medicine

Objective Bufonis Venenum（toad venom） is always used for analgesia in China from ancient to modern times. Bufalin, a non-peptide toxin extracted from Bufonis Venenum, are considered as one of the analgesic components. However, the molecular mechanism underlying the anti-nociceptive effects of bufalin remains unclear. Methods In the present study, we investigated the pharmacological effects of bufalin on painrelated ion channels as well as animal models through patch clamp, calcium imaging and animal behavior observation. Results（1） Using the whole-cell recording, bufalin caused remarkable suppressive effect on the peak currents of voltage-gated sodium channels（VGSCs） of dorsal root ganglion neuroblastoma ND7-23 cell in a dose-dependent manner. Bufalin prompted the voltage-dependent activation and caused a negative shift on the fast inactivation of VGSCs. The recovery kinetics of VGSCs were significantly slowed and recovery proportion were reduced after administering bufalin.（2） But bufalin produced insignificant effect not only on voltage-dependent Kv4.2, Kv4.3 and BK channels heteroexpressed in HEK293 T cells, but also on the capsaicin and allyl isothiocyanate（AITC） induced Ca2+ influx.（3） What’s more, bufalin could observably relieve formalin-induced spontaneous flinching and licking response as well as carrageenan-induced mechanical and thermal hyperalgesia in dose-dependent manner, which was in agreement with the results of in vitro experiments. Conclusion The present results suggest that the remarkable anti-nociceptive effects produced by bufalin are probably ascribed to its specific modulation of voltage-gated Na+ channels. It inhibited the VGSCs in a dosedependent manner, which provide references for the optimal dose selection of analgesia drugs.

关键词： voltage-gated sodium channels bufalin dose dependent inhibition antinociceptive effects ND7-23 cell

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The Effect of Pulse Radiofrequency on Pain Behavior and Function of voltage-gated sodium channels in DRG Neurons of Normal Rats

The Effect of Pulse Radiofrequency on Pain Behavior and Func...

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中国生理学会第24届全国会员代表大会暨生理学学术大会

作者：崔秀玉张胜男岳剑宁徐志卿潘娜杨云廷首都医科大学疼痛生物医学研究所首都医科大学附属宣武医院疼痛科首都医科大学神经生物学系

Objective:To investigate the effect of pulse radiofrequency（PRF）on pain behavior,and current densities,kinetic properties of voltage-gated sodium channels（VGSC）in dorsal root ganglion（DRG）neurons in rats.Methods:63 male SD rats weighing 60-80g were randomly divided into 3 groups:control group,sham group,PRF group（each n=21）.The rats in control group received no treatment.The right sciatic nerves of rats in sham group and PRF group were exposed after intraperitoneal anesthesia,then the rats in PRF group received PRF treatment of 42℃,2Hz,2min.Paw withdrawal mechanical threshold（PWMT）and paw withdrawal thermal latency（PWTL）were measured 2h before and 1day,3day,5day,7day after the PRF operation.At 1 day after PRF treatment,L4-5 DRG neurons were collected,then whole-cell patch clamp was conducted to test the current densities and kinetic properties of VGSCs.Results:Compared with basic threshold before the operation,there was no significant difference of PWMT and PWTL at different time.There was no significant difference in PWMT and PWTL among each group at the same time,also,the current densities and kinetic properties in three groups were not changed in DRG neurons after PRF treatment.Conclusion:PRF treatment had produced no effects on PWMT and PWTL,and had no effects on the current densities and kinetic properties of VGSCs,which indicated that PRF treatment of this parameter may not influence nociceptive sensory conduction in normal rats.

关键词： pulse radiofrequency DRG voltage-gated sodium channels

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Therapeutic efficacy of voltage‑gated sodium channel inhibitors in epilepsy

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Acta Epileptologica 2023年第2期6卷 65-85页

作者： John Agbo Zainab G.Ibrahim Shehu Y.Magaji Yahkub Babatunde Mutalub Philemon Paul Mshelia Daniel H.Mhyha Department of Clinical Pharmacology and Therapeutics Faculty of Basic Clinical SciencesCollege of Medical SciencesAbubakar Tafawa Balewa UniversityBauchi 740272Nigeria Department of Physiology Faculty of Basic Medical ScienceCollege of Medical SciencesAbubakar Tafawa Balewa UniversityBauchi 740272Nigeria Department of Medical Biochemistry Faculty of Basic Medical ScienceCollege of Medical SciencesAbubakar Tafawa Balewa UniversityBauchi 740272Nigeria

Epilepsy is a neurological disease characterized by excessive and abnormal hyper-synchrony of electrical discharges of the brain and a predisposition to generate epileptic seizures resulting in a broad spectrum of neurobiological insults,imposing psychological,cognitive,social and also economic burdens to the sufferer.voltage-gated sodium channels(VGSCs)are essential for the generation and propagation of action potentials throughout the central nervous system.Dysfunction of these channels has been implicated in the pathogenesis of epilepsy.VGSC inhibitors have been demonstrated to act as anticonvulsants to suppress the abnormal neuronal firing underlying epileptic seizures,and are used for the management and treatment of both genetic-idiopathic and acquired epilepsies.We discuss the forms of idiopathic and acquired epilepsies caused by VGSC mutations and the therapeutic efficacy of VGSC blockers in idiopathic,acquired and pharmacoresistant forms of epilepsy in this review.We conclude that there is a need for better alternative therapies that can be used alone or in combination with VGSC inhibitors in the management of epilepsies.The current anti-seizure medications(ASMs)especially for pharmacoresistant epilepsies and some other types of epilepsy have not yielded expected therapeutic efficacy partly because they do not show subtype-selectivity in blocking sodium channels while also bringing side effects.Therefore,there is a need to develop novel drug cocktails with enhanced selectivity for specific VGSC isoforms,to achieve better treatment of pharmacoresistant epilepsies and other types of epileptic seizures.

关键词： Epilepsy voltage-gated sodium channels Idiopathic epilepsy Acquired epilepsy Anti-seizure medications Pharmacoresistant epilepsy

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sodium channel beta subunits and extracellular matrix modulating mirror image pain induced by scorpion sting

Sodium channel beta subunits and extracellular matrix modula...

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第12届生物毒素研究及医药应用学术大会

作者： Xia Liu Qing-Hu Yang Xiao-Xia Zhao Hong-Ni Zhu Yan-Yan Wu Xiang-Xiang Chen Lei Xi Cheng-Hui Cao Sui-Bin Ma Ke-Ke Ren Xu Wang Zhi-Hong Sun Zhan-Tao Bai College of Life Sciences& Research Center for Polypetide Drugs Yanan University Shaanxi Engineering & Technological Research Center for Conversation & Utilization of Regional Biological Resources Shaanxi Provincial Key Lab of Red Dates

voltage-gated sodium（Nav） channels play key roles in induction,transmission,transduction of pathological pain.Nav channels are composed of a pore-forming a subunit and associated β subunits.Each of β subunit（β1-β4）isa single membrane-spanning glycoprotein with one Ig-like motif in their extracellular domains,which may bind to Chondroitin sulfate proteoglycans（CSPGs）.Thus,β subunits appear to function as cell adhesion molecules,and CSPGs may be the important regulator oflocalization and function of a subunit.Based on our well-established mirror image pain model induced by sodium channel specific scorpion peptidergic activator,here,we found that after pretreated with Chondroitinase,scorpion sting-induced rat spontaneous pain behaviors,bilateral mechanical hypersensitivity and unilateral thermal hypersensitivity,were reducedsignificantly.The quantitative real-time PCR,immunoblotting,immunofluorescent and other techniques showed that Tenascins（major components of CSPGs in nervous system） andpsubunits co-localized together in neurons,and increased synergistically underlying mirror image pain;and vice versa,decreased when pretreated with Chondroitmase.The results indicated that the interaction of CSPGs and β subunits would be an endogenous modulation of sodium channel-involved in mirror image pain,and thus provide some novel strategies for pain therapy and especially advantageous for analgesic development.

关键词： Scorpion sting voltage-gated sodium channels Beta subunits Mirror image pain Chondroitin sulfate proteoglycans

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Inhibitory effects of bufalin,an analgesic ingredient from toad venom on voltagegated sodium channels

Inhibitory effects of bufalin,an analgesic ingredient from t...

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第十四届生物毒素毒理学术大会暨第一届生物毒素——从生存...

作者： Jie Tao Peihao Yin Central Laboratory Putuo HospitalShanghai University of Traditional Chinese Medicine

Bufonis Venenum（toad venom） is always used for analgesia in China from ancient to modern times.Bufalin,a non-peptide toxin extracted from Bufonis Venenum,are considered as one of the analgesic components.However,the molecular mechanism underlying the anti-nociceptive effects of bufalin remains unclear.In the present study,we investigated the pharmacological effects of bufalin on pain-related ion channels as well as animal models through patch clamp,calcium imaging and animal behavior observation.Using the whole-cell recording,bufalin caused remarkable suppressive effect on the peak currents of voltage-gated sodium channels（VGSCs） of dorsal root ganglion neuroblastoma ND7-23 cell in a dose-dependent manner.Bufalin prompted the voltage-dependent activation and caused a negative shift on the fast inactivation of VGSCs.The recovery kinetics of VGSCs were significantly slowed and recovery proportion were reduced after administering bufalin.But bufalin produced insignificant effect not only on voltage-dependent Kv4.2,Kv4.3 and BK channels hetero-expressed in HEK293 T cells,but also on the capsaicin and allyl isothiocyanate（AITC）induced Ca2+influx.What’s more,bufalin could observably relieve formalin-induced spontaneous flinching and licking response as well as carrageenan-induced mechanical and thermal hyperalgesia in dose-dependent manner,which was in agreement with the results of in vitro experiments.The present results suggest that the remarkable anti-nociceptive effects produced by bufalin are probably ascribed to its specific modulation of voltage-gated Na～+channels.It inhibited the VGSCs in a dose-dependent manner,which provide references for the optimal dose selection of analgesia drugs.

关键词： voltage-gated sodium channels bufalin dose dependent inhibition anti-nociceptive effects ND7-23 cell

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Sensitization of sodium channels by cystathionine β-synthetase activation in colon primary sensory neurons contributes to visceral hypersensitivity in adult rats with neonatal maternal deprivation

Sensitization of sodium channels by cystathionine β-synthet...

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中国神经科学学会第十届全国学术会议

作者： Shufen Hu Weiyuan Xu Xiuhua Miao Liyan Zhu Youlang Zhou Lin Li Ying Xiao Yanping Gao Guang-Yin Xu Institute of Neuroscience Laboratory for Translational Pain MedicineDepartment of NeurobiologySoochow University Departments of Orthopedics and Anesthesiology the Affiliated Zhangjiagang Hospital of Soochow University

Background Irritable bowel syndrome(IBS) is a common gastrointestinal disorder characterized by abdominal pain in association with altered bowel movements.The pathogenesis of pain in IBS is poorly understood and treatment remains difficult.This study was designed to determine roles for sodium channels and endogenous HS signaling in a previously validated rat model of chronic visceral hypersensitivity induced by neonatal maternal deprivation(NMD).Methods Neonatal male rats(postnatal day 2-15) were exposed to a 3 hour period of daily maternal separation with temperature maintained at 3℃.Abdominal withdrawal reflex(AWR) scores were performed on adult male rats(62 weeks).Colon-specific dorsal root ganglion(DRG) neurons were labeled with DiI and acutely dissociated for measuring excitability and sodium channel currents under whole-cell patch clamp configurations.Expressions of Nav1.8,Nav1.9,the endogenous HS producing enzyme cystathionine p-synthetase(CBS) were analyzed by western blot,quantitative real-time PCR or immunofluorescence approaches.The endogenous HS producing enzyme CBS antagonist was injected intraperitoneally.Results NMD significantly increased AWR scores,which lasted for weeks in an association with hyperexcitability of colon DRG neurons.TTX-resistant but not TTX-sensitive sodium current density was greatly enhanced in colon DRG neurons in NMD rats.Compared with controls,activation curves showed a leftward shift in NMD rats whereas inactivation curves did not differ significantly.NMD markedly accelerated the activation time of peak current amplitude without any changes in inactivation time.Furthermore,NMD remarkably enhanced expression of Navl.8 at protein levels but not at mRNA levels in colon DRGs.Expression of Nav1.9 was not altered after NMD.In addition,CBS was colocalized with Navl.8 in colon-specific DRG neurons that were labeled with DiI.Pretreatment of O-(Carboxymethyl) hydroxylamine hemihydrochloride(AOAA),an inhibitor of CBS,significantly suppressed the expression of Navl.8 in colon DRGs whi

关键词： neonatal maternal deprivation dorsal root ganglion visceral pain voltage-gated sodium channels hydrogen sulfide

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