2024
Interplay of Nav1.8 and Nav1.7 channels drives neuronal hyperexcitability in neuropathic pain
Vasylyev D, Zhao P, Schulman B, Waxman S. Interplay of Nav1.8 and Nav1.7 channels drives neuronal hyperexcitability in neuropathic pain. The Journal Of General Physiology 2024, 156: e202413596. PMID: 39378238, PMCID: PMC11465073, DOI: 10.1085/jgp.202413596.Peer-Reviewed Original ResearchConceptsDorsal root ganglionGain-of-function Nav1.7 mutationsDorsal root ganglion neuronsSodium channel Nav1.7Inherited erythromelalgiaNav1.7 mutationsNeuropathic painNeuronal hyperexcitabilityOpen-probabilityVoltage-gated sodium channel Nav1.7Hyperexcitability of DRG neuronsModel of neuropathic painSubthreshold membrane potential oscillationsResting membrane potentialMembrane potential oscillationsReduced firing probabilityIncreased rheobaseNav1.8 channelsDRG neuronsHuman genetic modelsNav1.8Root ganglionNav1.7 channelsNav1.7AP generationFunctionally-selective inhibition of threshold sodium currents and excitability in dorsal root ganglion neurons by cannabinol
Ghovanloo M, Effraim P, Tyagi S, Zhao P, Dib-Hajj S, Waxman S. Functionally-selective inhibition of threshold sodium currents and excitability in dorsal root ganglion neurons by cannabinol. Communications Biology 2024, 7: 120. PMID: 38263462, PMCID: PMC10805714, DOI: 10.1038/s42003-024-05781-x.Peer-Reviewed Original ResearchConceptsDorsal root ganglionDorsal root ganglion neuronal excitabilityDorsal root ganglion neuronsNeuronal excitabilityCurrent-clamp analysisSteady-state inactivationVoltage-dependent sodiumSlow inactivated stateAutomated patch clamp platformMultielectrode array recordingsNav currentsNeuropathic painSodium currentRoot ganglionGanglion neuronsSlow inactivationInactivated stateCurrent inhibitorsIon channelsNeuronsInhibitory effectCannabinolArray recordingsEndocannabinoidCannabinoidCompartment-specific regulation of NaV1.7 in sensory neurons after acute exposure to TNF-α
Tyagi S, Higerd-Rusli G, Ghovanloo M, Dib-Hajj F, Zhao P, Liu S, Kim D, Shim J, Park K, Waxman S, Choi J, Dib-Hajj S. Compartment-specific regulation of NaV1.7 in sensory neurons after acute exposure to TNF-α. Cell Reports 2024, 43: 113685. PMID: 38261513, PMCID: PMC10947185, DOI: 10.1016/j.celrep.2024.113685.Peer-Reviewed Original ResearchTNF-aSensory neuronsEffect of TNF-aSensory neuron excitabilityTumor necrosis factor-aRegulation of NaV1.7Voltage-gated sodiumPro-inflammatory cytokinesCompartment-specific effectsNeuronal plasma membraneSensitize nociceptorsNeuronal excitabilitySomatic membraneChannel N terminusElectrophysiological recordingsP38 MAPKIon channelsFactor AAcute exposureMolecular determinantsNeuronsAxonal endingsPhospho-acceptor sitesPlasma membraneCompartment-specific regulation
2023
Sodium currents in naïve mouse dorsal root ganglion neurons: No major differences between sexes
Ghovanloo M, Tyagi S, Zhao P, Effraim P, Dib-Hajj S, Waxman S. Sodium currents in naïve mouse dorsal root ganglion neurons: No major differences between sexes. Channels 2023, 18: 2289256. PMID: 38055732, PMCID: PMC10761158, DOI: 10.1080/19336950.2023.2289256.Peer-Reviewed Original ResearchConceptsSexual dimorphismRodent dorsal root ganglion neuronsBiophysical propertiesDorsal root ganglion neuronsExpression patternsSex-dependent regulationVoltage-gated sodiumFunctional analysisGanglion neuronsRodent sensory neuronsMouse dorsal root ganglion neuronsNaïve WT miceNumber of cellsMixed populationDimorphismUniform experimental conditionsSex-dependent differencesSensory neuronsNative DRG neuronsPain pathwaysDRG neuronsWT miceClinical studiesNav currentsAdult malesPain-causing stinging nettle toxins target TMEM233 to modulate NaV1.7 function
Jami S, Deuis J, Klasfauseweh T, Cheng X, Kurdyukov S, Chung F, Okorokov A, Li S, Zhang J, Cristofori-Armstrong B, Israel M, Ju R, Robinson S, Zhao P, Ragnarsson L, Andersson Å, Tran P, Schendel V, McMahon K, Tran H, Chin Y, Zhu Y, Liu J, Crawford T, Purushothamvasan S, Habib A, Andersson D, Rash L, Wood J, Zhao J, Stehbens S, Mobli M, Leffler A, Jiang D, Cox J, Waxman S, Dib-Hajj S, Neely G, Durek T, Vetter I. Pain-causing stinging nettle toxins target TMEM233 to modulate NaV1.7 function. Nature Communications 2023, 14: 2442. PMID: 37117223, PMCID: PMC10147923, DOI: 10.1038/s41467-023-37963-2.Peer-Reviewed Original ResearchConceptsSensory neuronsVoltage-sensing domainNav channelsTransmembrane proteinAccessory proteinsVoltage-gated sodium channelsCritical regulatorPore domainChannel gatingExtracellular loopToxin-mediated effectsNeuronal excitabilityPeptide toxinsProteinSodium channelsPharmacological activitiesNav1.7 functionKnottin peptidesNeuronsImportant insightsToxinSubunitsRegulatorDomainExcelsaPaclitaxel effects on axonal localization and vesicular trafficking of NaV1.8
Baker C, Tyagi S, Higerd-Rusli G, Liu S, Zhao P, Dib-Hajj F, Waxman S, Dib-Hajj S. Paclitaxel effects on axonal localization and vesicular trafficking of NaV1.8. Frontiers In Molecular Neuroscience 2023, 16: 1130123. PMID: 36860665, PMCID: PMC9970094, DOI: 10.3389/fnmol.2023.1130123.Peer-Reviewed Original ResearchChemotherapy-induced peripheral neuropathyDorsal root gangliaPTX treatmentDRG axonsEffect of paclitaxelVoltage-gated sodium channel NaPain syndromePeripheral neuropathyDRG neuronsSodium channel NaRoot gangliaCell cycle arrestNeuronal somataSensory neuronsSide effectsTherapeutic targetingTumor growthPaclitaxel effectAntineoplastic agentsAxonal localizationPaclitaxelNumber of NaAxonal compartmentAxonsChannel NaA novel high throughput combined voltage-clamp/current-clamp analysis of single primary neurons
Ghovanloo M, Tyagi S, Zhao P, Kiziltug E, Estacion M, Dib-Hajj S, Waxman S. A novel high throughput combined voltage-clamp/current-clamp analysis of single primary neurons. Biophysical Journal 2023, 122: 101a. DOI: 10.1016/j.bpj.2022.11.734.Peer-Reviewed Original ResearchHigh-throughput combined voltage-clamp/current-clamp analysis of freshly isolated neurons
Ghovanloo M, Tyagi S, Zhao P, Kiziltug E, Estacion M, Dib-Hajj S, Waxman S. High-throughput combined voltage-clamp/current-clamp analysis of freshly isolated neurons. Cell Reports Methods 2023, 3: 100385. PMID: 36814833, PMCID: PMC9939380, DOI: 10.1016/j.crmeth.2022.100385.Peer-Reviewed Original ResearchConceptsDorsal root ganglion neuronsCurrent-clamp recordingsCurrent-clamp analysisVoltage-gated sodium channelsPatch-clamp techniqueExcitable cellsGanglion neuronsElectrophysiological recordingsNeuronal cellsNeuronsGold standard methodologySodium channelsCellular levelRobotic instrumentsCellsDrug screeningSame cellsIntact tissueRecordings
2022
Fibroblast growth factor homologous factor 2 attenuates excitability of DRG neurons
Effraim PR, Estacion M, Zhao P, Sosniak D, Waxman SG, Dib-Hajj SD. Fibroblast growth factor homologous factor 2 attenuates excitability of DRG neurons. Journal Of Neurophysiology 2022, 128: 1258-1266. PMID: 36222860, PMCID: PMC9909838, DOI: 10.1152/jn.00361.2022.Peer-Reviewed Original ResearchConceptsDRG neuron excitabilityDRG neuronal excitabilityNeuronal excitabilityFibroblast growth factor homologous factorsNerve injuryDRG neuronsInflammatory mediatorsNeuron excitabilityDorsal root ganglion neuronsFunction of Nav1.7Peripheral nerve axotomyMultiple neurological disordersVoltage-gated sodium channelsDRG excitabilityFibroblast growth factor homologous factor 2Inflammatory painNerve axotomyGanglion neuronsIsoform-dependent mannerNeurological disordersBasal conditionsExcitabilityGating propertiesNeuron firingInjuryDepolarizing NaV and Hyperpolarizing KV Channels Are Co-Trafficked in Sensory Neurons
Higerd-Rusli GP, Alsaloum M, Tyagi S, Sarveswaran N, Estacion M, Akin EJ, Dib-Hajj FB, Liu S, Sosniak D, Zhao P, Dib-Hajj SD, Waxman SG. Depolarizing NaV and Hyperpolarizing KV Channels Are Co-Trafficked in Sensory Neurons. Journal Of Neuroscience 2022, 42: 4794-4811. PMID: 35589395, PMCID: PMC9188389, DOI: 10.1523/jneurosci.0058-22.2022.Peer-Reviewed Original ResearchIon channel traffickingMembrane proteinsChannel traffickingAxonal membrane proteinsTransport vesiclesPhysiological functionsSame vesiclesAxonal proteinsSpecific transport vesiclesIon channelsTrafficking of NaDiverse physiological functionsExcitability disordersDifferent physiological functionsDistinct ion channelsSensory neuron membraneSensory neuronsDistinct functional classesDistinct functional rolesNormal neuronal excitabilityTrafficking mechanismsNeuronal excitabilityPlasma membraneTherapeutic strategiesPrecise regulationInhibition of sodium conductance by cannabigerol contributes to a reduction of dorsal root ganglion neuron excitability
Ghovanloo M, Estacion M, Higerd‐Rusli G, Zhao P, Dib‐Hajj S, Waxman SG. Inhibition of sodium conductance by cannabigerol contributes to a reduction of dorsal root ganglion neuron excitability. British Journal Of Pharmacology 2022, 179: 4010-4030. PMID: 35297036, DOI: 10.1111/bph.15833.Peer-Reviewed Original ResearchConceptsEffect of cannabigerolDRG neuronsDorsal root ganglion neuron excitabilityVoltage-gated sodium currentDorsal root ganglion neuronsLower CBG concentrationPrimary dorsal root ganglion neuronsAnalgesic drug developmentNon-psychotropic phytocannabinoidMultielectrode array recordingsAction potential modellingInhibition of NaDRG excitabilityGanglion neuronsNeuron excitabilityAnalgesic propertiesCNS neuronsNeuronal hypoexcitabilityCBG concentrationsChannel inhibitorsSodium currentNeuronsFunctional selectivityDrug developmentUnderlying mechanism
2021
Contributions of NaV1.8 and NaV1.9 to excitability in human induced pluripotent stem-cell derived somatosensory neurons
Alsaloum M, Labau JIR, Liu S, Estacion M, Zhao P, Dib-Hajj F, Waxman SG. Contributions of NaV1.8 and NaV1.9 to excitability in human induced pluripotent stem-cell derived somatosensory neurons. Scientific Reports 2021, 11: 24283. PMID: 34930944, PMCID: PMC8688473, DOI: 10.1038/s41598-021-03608-x.Peer-Reviewed Original ResearchMeSH KeywordsAction PotentialsAutopsyCell DifferentiationElectrophysiologyHumansImmunohistochemistryInduced Pluripotent Stem CellsMembrane PotentialsMutationNAV1.8 Voltage-Gated Sodium ChannelNAV1.9 Voltage-Gated Sodium ChannelNeuronsNeurosciencesPainPatch-Clamp TechniquesProtein IsoformsSensory Receptor CellsSomatosensory CortexConceptsNeuronal excitabilitySomatosensory neuronsPluripotent stem cell-derived sensory neuronsDynamic clamp electrophysiologyTreatment of painPromising novel modalityVoltage-gated sodium channelsSodium channel isoformsNeuronal membrane potentialGenetic knockout modelsNav1.9 currentsPharmacologic blockSensory neuronsNav1.8Cellular correlatesRepetitive firingClamp electrophysiologyExcitabilityNeuronal backgroundNovel modalityChannel isoformsSodium channelsNeuronsNav1.9Knockout models
2018
Dynamic-Clamp Analysis of Wild-Type Human NaV1.7 and Erythromelalgia Mutant Channel L858H
Vasylyev D, Han C, Zhao P, Dib-Hajj S, Waxman S. Dynamic-Clamp Analysis of Wild-Type Human NaV1.7 and Erythromelalgia Mutant Channel L858H. 2018, 109-132. DOI: 10.7551/mitpress/10310.003.0016.Peer-Reviewed Original Research
2016
A Gain-of-Function Mutation in Nav1.6 in a Case of Trigeminal Neuralgia
Tanaka BS, Zhao P, Dib-Hajj FB, Morisset V, Tate S, Waxman SG, Dib-Hajj SD. A Gain-of-Function Mutation in Nav1.6 in a Case of Trigeminal Neuralgia. Molecular Medicine 2016, 22: 338-348. PMID: 27496104, PMCID: PMC5023517, DOI: 10.2119/molmed.2016.00131.Peer-Reviewed Original ResearchUnilateral facial painTrigeminal neuralgiaCentral nervous systemFacial painPain disordersTrigeminal nervePeripheral voltage-gated sodium channelsPhase 2 clinical studyWhole-cell voltage-clamp recordingsPeripheral nervous system neuronsDiagnosis of TNFunction mutationsIdiopathic trigeminal neuralgiaTrigeminal ganglion neuronsCurrent-clamp studiesResurgent sodium currentsHuman pain disordersHigh-frequency firingVoltage-clamp recordingsDe novo missense mutationsVoltage-gated sodium channelsMagnetic resonance imagingHigh-firing neuronsNovo missense mutationVascular compression
2014
Dynamic-clamp analysis of wild-type human Nav1.7 and erythromelalgia mutant channel L858H
Vasylyev DV, Han C, Zhao P, Dib-Hajj S, Waxman SG. Dynamic-clamp analysis of wild-type human Nav1.7 and erythromelalgia mutant channel L858H. Journal Of Neurophysiology 2014, 111: 1429-1443. PMID: 24401712, DOI: 10.1152/jn.00763.2013.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBiophysicsCells, CulturedElectric StimulationErythromelalgiaGanglia, SpinalHEK293 CellsHumansMembrane PotentialsMiceMice, KnockoutModels, BiologicalMutationNAV1.7 Voltage-Gated Sodium ChannelNeural ConductionNeuronsPatch-Clamp TechniquesSodium Channel BlockersTetrodotoxinTransfectionConceptsDRG neuronsMutant Nav1.7 channelsNav1.7 channelsDorsal root ganglion neuronsSodium influxPrimary nociceptive neuronsSmall DRG neuronsNet sodium influxSodium channel Nav1.7Current thresholdMechanistic linkAction potential generationNeuropathic painNociceptive neuronsNociceptor functionGanglion neuronsNociceptor hyperexcitabilityPain phenotypesChannel expressionChannel Nav1.7Subthreshold depolarizationHuman Nav1.7Electrophysiological recordingsDynamic-Clamp AnalysisIdentification of gain
2013
Sodium Channels Contribute to Degeneration of Dorsal Root Ganglion Neurites Induced by Mitochondrial Dysfunction in an In Vitro Model of Axonal Injury
Persson AK, Kim I, Zhao P, Estacion M, Black JA, Waxman SG. Sodium Channels Contribute to Degeneration of Dorsal Root Ganglion Neurites Induced by Mitochondrial Dysfunction in an In Vitro Model of Axonal Injury. Journal Of Neuroscience 2013, 33: 19250-19261. PMID: 24305821, PMCID: PMC6618782, DOI: 10.1523/jneurosci.2148-13.2013.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAxonsAxotomyCell DeathCells, CulturedGanglia, SpinalHumansHydrogen PeroxideImmunohistochemistryMiceMice, TransgenicMicrotubulesMitochondrial DiseasesNerve DegenerationNeuritesOxidantsRotenoneSodium Channel BlockersSodium ChannelsSodium-Calcium ExchangerSodium-Potassium-Exchanging ATPaseTetrodotoxinThioureaUncoupling AgentsConceptsAxonal degenerationNeurite degenerationSodium channelsKB-R7943Mouse peripheral sensory neuronsRotenone-induced mitochondrial dysfunctionOxidative stressMitochondrial dysfunctionPeripheral sensory neuronsDorsal root gangliaPeripheral nervous systemDegeneration of neuritesMitochondrial functionVoltage-gated sodium channelsMultiple neurodegenerative disordersSodium-calcium exchangerImpaired mitochondrial functionInjurious cascadeAxonal injuryActivity blockadeRoot gangliaAxonal neuropathySensory neuronsNCX activityDysfunctional intracellularSmall-Fiber Neuropathy Nav1.8 Mutation Shifts Activation to Hyperpolarized Potentials and Increases Excitability of Dorsal Root Ganglion Neurons
Huang J, Yang Y, Zhao P, Gerrits MM, Hoeijmakers JG, Bekelaar K, Merkies IS, Faber CG, Dib-Hajj SD, Waxman SG. Small-Fiber Neuropathy Nav1.8 Mutation Shifts Activation to Hyperpolarized Potentials and Increases Excitability of Dorsal Root Ganglion Neurons. Journal Of Neuroscience 2013, 33: 14087-14097. PMID: 23986244, PMCID: PMC6618513, DOI: 10.1523/jneurosci.2710-13.2013.Peer-Reviewed Original ResearchMeSH KeywordsAction PotentialsAmino Acid SequenceAnimalsCells, CulturedGanglia, SpinalHumansIon Channel GatingMaleMembrane PotentialsMiceMice, TransgenicMiddle AgedMolecular Sequence DataMutation, MissenseNAV1.8 Voltage-Gated Sodium ChannelNeuronsPeripheral Nervous System DiseasesRatsRats, Sprague-DawleyConceptsDorsal root ganglion neuronsSmall DRG neuronsDRG neuronsGanglion neuronsAction potentialsIdiopathic small fiber neuropathySmall-diameter DRG neuronsWhole-cell voltage-clamp recordingsSmall-caliber nerve fibersVoltage-gated sodium channel Nav1.7Peripheral sensory neuronsCurrent-clamp studiesLimited treatment optionsSmall fiber neuropathySodium channel Nav1.8Voltage-clamp recordingsSodium channel Nav1.7Autonomic dysfunctionIncreases excitabilityTreatment optionsUnknown etiologyFunctional variantsNerve fibersSensory neuronsRamp depolarizationBurn injury-induced mechanical allodynia is maintained by Rac1-regulated dendritic spine dysgenesis
Tan AM, Samad OA, Liu S, Bandaru S, Zhao P, Waxman SG. Burn injury-induced mechanical allodynia is maintained by Rac1-regulated dendritic spine dysgenesis. Experimental Neurology 2013, 248: 509-519. PMID: 23933578, DOI: 10.1016/j.expneurol.2013.07.017.Peer-Reviewed Original ResearchConceptsDendritic spine dysgenesisWDR neuronsNeuropathic painBurn injurySpine dysgenesisMechanical allodyniaInjury-induced chronic painInjury-induced mechanical allodyniaSpinal cord dorsal hornBurn-injured animalsHindpaw receptive fieldsInjury-induced painNeuropathic pain phenotypesSecond-degree burn injurySecond-degree burn modelDendritic spine morphologyDendritic spine shapeDorsal hornIntractable painMechanical painPain managementChronic painPain phenotypesElectrophysiological signsPreclinical models
2012
Maladaptive Dendritic Spine Remodeling Contributes to Diabetic Neuropathic Pain
Tan AM, Samad OA, Fischer TZ, Zhao P, Persson AK, Waxman SG. Maladaptive Dendritic Spine Remodeling Contributes to Diabetic Neuropathic Pain. Journal Of Neuroscience 2012, 32: 6795-6807. PMID: 22593049, PMCID: PMC6622192, DOI: 10.1523/jneurosci.1017-12.2012.Peer-Reviewed Original ResearchConceptsDiabetic neuropathic painNeuropathic painDendritic spinesSpine plasticitySpine morphologyMajor public health problemDiabetes-induced changesDevelopment of painDendritic spine remodelingDendritic spine plasticitySpontaneous firing activityPublic health problemAvailable clinical treatmentsEvidence of painDendritic spine morphologyDendritic spine shapeNeuronal hyperresponsivenessRange neuronsWDR neuronsNeuron hyperexcitabilitySTZ injectionDorsal hornMechanical painChronic painDiabetic ratsNav1.7-related small fiber neuropathy
Han C, Hoeijmakers JG, Ahn H, Zhao P, Shah P, Lauria G, Gerrits MM, te Morsche R, Dib-Hajj SD, Drenth JP, Faber CG, Merkies IS, Waxman SG. Nav1.7-related small fiber neuropathy. Neurology 2012, 78: 1635-1643. PMID: 22539570, DOI: 10.1212/wnl.0b013e3182574f12.Peer-Reviewed Original ResearchConceptsSmall fiber neuropathyDorsal root gangliaDRG neuronsIdiopathic small fiber neuropathySmall-diameter peripheral axonsDRG neuron hyperexcitabilityIdentifiable underlying causeNerve conduction studiesQuantitative sensory testingSympathetic ganglion neuronsSFN symptomsNeuron hyperexcitabilityConduction studiesGanglion neuronsRoot gangliaSkin biopsiesDifferential diagnosisPeripheral axonsSensory testingVoltage-clamp analysisApparent causePatientsNoninactivating componentUnderlying causeSuprathreshold stimuli