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 recordingsEndocannabinoidCannabinoid
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 malesIh current stabilizes excitability in rodent DRG neurons and reverses hyperexcitability in a nociceptive neuron model of inherited neuropathic pain
Vasylyev D, Liu S, Waxman S. Ih current stabilizes excitability in rodent DRG neurons and reverses hyperexcitability in a nociceptive neuron model of inherited neuropathic pain. The Journal Of Physiology 2023, 601: 5341-5366. PMID: 37846879, PMCID: PMC10843455, DOI: 10.1113/jp284999.Peer-Reviewed Original ResearchConceptsFunction Nav1.7 mutationsDorsal root ganglion neuronsSmall DRG neuronsDRG neuronsNav1.7 mutationNeuropathic painGanglion neuronsHuman genetic modelsAction potentialsDRG neuron excitabilityDRG neuron hyperexcitabilityRodent DRG neuronsAP generationCardiac cellsPotential molecular targetsNeuron hyperexcitabilitySevere painPain therapeuticsCNS neuronsExcessive firingNeuron excitabilityCentral neuronsSubthreshold oscillationsHyperexcitabilityNeuronal firingNav1.7 gain-of-function mutation I228M triggers age-dependent nociceptive insensitivity and C-LTMR dysregulation
Wimalasena N, Taub D, Shim J, Hakim S, Kawaguchi R, Chen L, El-Rifai M, Geschwind D, Dib-Hajj S, Waxman S, Woolf C. Nav1.7 gain-of-function mutation I228M triggers age-dependent nociceptive insensitivity and C-LTMR dysregulation. Experimental Neurology 2023, 364: 114393. PMID: 37003485, PMCID: PMC10171359, DOI: 10.1016/j.expneurol.2023.114393.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsFemaleGain of Function MutationGanglia, SpinalMaleMiceMutationNAV1.7 Voltage-Gated Sodium ChannelNociceptionSodiumConceptsParoxysmal extreme pain disorderSmall fiber neuropathyFunction mutationsDRG neuron hyperexcitabilityYoung adult miceVoltage-gated sodium channel NaSodium conductanceAge-related changesNeuron hyperexcitabilityPain disordersCongenital insensitivitySodium channel NaExcitability changesFemale miceMouse DRGYoung miceNeuronal excitabilityNoxious heatSkin lesionsVoltage-gated channelsAdult miceNeuron subtypesNervous systemProfound insensitivityMiceNav1.7 P610T mutation in two siblings with persistent ocular pain after corneal axon transection: impaired slow inactivation and hyperexcitable trigeminal neurons
Ghovanloo M, Effraim P, Yuan J, Schulman B, Jacobs D, Dib-Hajj S, Waxman S. Nav1.7 P610T mutation in two siblings with persistent ocular pain after corneal axon transection: impaired slow inactivation and hyperexcitable trigeminal neurons. Journal Of Neurophysiology 2023, 129: 609-618. PMID: 36722722, PMCID: PMC9988530, DOI: 10.1152/jn.00457.2022.Peer-Reviewed Original ResearchConceptsPersistent ocular painTrigeminal ganglion neuronsOcular painCorneal refractive surgeryGanglion neuronsRefractive surgeryAxonal injurySlow inactivationHuman pain modelTrigeminal afferent nervesTrigeminal ganglion axonsSmall subgroupPain-related disordersEffects of injurySodium channel Nav1.7Channel slow inactivationEye painPostoperative painMost patientsPain modelAfferent nervesPersistent painTrigeminal neuronsNav1.7 mutationAxon transectionHigh-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
2019
A gain-of-function sodium channel β2-subunit mutation in painful diabetic neuropathy
Alsaloum M, Estacion M, Almomani R, Gerrits MM, Bönhof GJ, Ziegler D, Malik R, Ferdousi M, Lauria G, Merkies IS, Faber CG, Dib-Hajj S, Waxman S. A gain-of-function sodium channel β2-subunit mutation in painful diabetic neuropathy. Molecular Pain 2019, 15: 1744806919849802. PMID: 31041876, PMCID: PMC6510061, DOI: 10.1177/1744806919849802.Peer-Reviewed Original ResearchConceptsDiabetic peripheral neuropathyPeripheral neuropathyNeuropathic painDiabetic peripheral neuropathy patientsPainful diabetic peripheral neuropathyDorsal root ganglion neuronsPainful diabetic neuropathyPeripheral neuropathy patientsSodium channel β subunitsSpectrum of patientsUse-dependent inhibitionCardiac conducting systemSodium channel α subunitVoltage-gated sodium channelsChannel α-subunitsSCN11A geneDiabetic neuropathyDiabetes mellitusChronic painNeuropathy patientsGanglion neuronsNegative genetic screeningChannel β subunitHealth sequelaeRepetitive stimulation
2018
A novel gain-of-function Nav1.7 mutation in a carbamazepine-responsive patient with adult-onset painful peripheral neuropathy
Adi T, Estacion M, Schulman BR, Vernino S, Dib-Hajj S, Waxman S. A novel gain-of-function Nav1.7 mutation in a carbamazepine-responsive patient with adult-onset painful peripheral neuropathy. Molecular Pain 2018, 14: 1744806918815007. PMID: 30392441, PMCID: PMC6856981, DOI: 10.1177/1744806918815007.Peer-Reviewed Original ResearchConceptsPainful peripheral neuropathyDorsal root gangliaPeripheral neuropathyUse-dependent inhibitionDRG neuronsPain disordersM variantFunction Nav1.7 mutationsMulti-electrode array recordingsSympathetic ganglion neuronsCommon pain disordersVoltage-clamp recordingsVoltage-gated sodium channel NaRare MendelianNav1.7 mutationGanglion neuronsSodium channel NaTrigeminal ganglionRoot gangliaNeonatal ratsPatientsNeuropathyMutant channelsFunction variantsNeuronsNonmuscle myosin II isoforms interact with sodium channel alpha subunits
Dash B, Han C, Waxman S, Dib-Hajj S. Nonmuscle myosin II isoforms interact with sodium channel alpha subunits. Molecular Pain 2018, 14: 1744806918788638. PMID: 29956586, PMCID: PMC6052497, DOI: 10.1177/1744806918788638.Peer-Reviewed Original ResearchMeSH KeywordsAction PotentialsAnimalsAnkyrinsBrainCell Line, TransformedElectric StimulationGanglia, SpinalGene Expression RegulationGreen Fluorescent ProteinsHumansImmunoprecipitationMiceMice, Inbred C57BLMice, TransgenicMolecular Motor ProteinsMyosin Heavy ChainsNAV1.6 Voltage-Gated Sodium ChannelNonmuscle Myosin Type IIBPatch-Clamp TechniquesRatsTransfectionConceptsSodium channel alpha subunitND7/23 cellsChannel alpha subunitDorsal root ganglion tissueAlpha subunitMyosin II motor proteinsNonmuscle myosin II isoformsRodent nervous tissueRodent brain tissueSteady-state fast inactivationVoltage-sensitive channelsFast inactivationVoltage-dependent activationSodium channel alphaGanglion tissueIsoform-dependent mannerMyosin II isoformsNervous tissueRecombinant myosinBrain tissueCommon structural motifRamp currentsMotor proteinsCellular excitabilitySodium channels
2016
Pharmacotherapy for Pain in a Family With Inherited Erythromelalgia Guided by Genomic Analysis and Functional Profiling
Geha P, Yang Y, Estacion M, Schulman BR, Tokuno H, Apkarian AV, Dib-Hajj SD, Waxman SG. Pharmacotherapy for Pain in a Family With Inherited Erythromelalgia Guided by Genomic Analysis and Functional Profiling. JAMA Neurology 2016, 73: 659. PMID: 27088781, DOI: 10.1001/jamaneurol.2016.0389.Peer-Reviewed Original ResearchMeSH KeywordsAction PotentialsAdultAnalgesics, Non-NarcoticBrainCarbamazepineChronic PainDNA Mutational AnalysisDouble-Blind MethodElectric StimulationErythromelalgiaFemaleGanglia, SpinalHumansMagnetic Resonance ImagingMaleMutationNAV1.7 Voltage-Gated Sodium ChannelPain MeasurementRegression AnalysisSensory Receptor CellsConceptsMean episode durationDRG neuronsPatient 1Nav1.7 mutationEpisode durationDorsal root ganglion neuronsPlacebo-controlled studyMaintenance periodAttenuation of painEffects of carbamazepineBrain activityFunctional magnetic resonance imagingMagnetic resonance imagingT mutationMutant channelsFunctional magnetic resonanceNeuropathic painSecondary somatosensoryChronic painPain areaPatient 2Ganglion neuronsEffective pharmacotherapyNight awakeningsPlacebo
2015
Diversity of composition and function of sodium channels in peripheral sensory neurons
Dib-Hajj S, Waxman S. Diversity of composition and function of sodium channels in peripheral sensory neurons. Pain 2015, 156: 2406-2407. PMID: 26580678, DOI: 10.1097/j.pain.0000000000000353.Peer-Reviewed Original Research
2013
A new Nav1.7 mutation in an erythromelalgia patient
Estacion M, Yang Y, Dib-Hajj SD, Tyrrell L, Lin Z, Yang Y, Waxman SG. A new Nav1.7 mutation in an erythromelalgia patient. Biochemical And Biophysical Research Communications 2013, 432: 99-104. PMID: 23376079, DOI: 10.1016/j.bbrc.2013.01.079.Peer-Reviewed Original ResearchConceptsMutations of Nav1.7Voltage-gated sodium channel Nav1.7Year old patientSodium channel Nav1.7Voltage-clamp studiesErythromelalgia patientsOlder patientsDRG neuronsNav1.7 mutationPainful disordersFunction missense mutationsChannel Nav1.7Neuron firingPatientsRamp stimuliExon 20Channel biophysical propertiesControl allelesNav1.7Missense mutationsBiophysical propertiesMutations
2012
Structural modelling and mutant cycle analysis predict pharmacoresponsiveness of a Nav1.7 mutant channel
Yang Y, Dib-Hajj SD, Zhang J, Zhang Y, Tyrrell L, Estacion M, Waxman SG. Structural modelling and mutant cycle analysis predict pharmacoresponsiveness of a Nav1.7 mutant channel. Nature Communications 2012, 3: 1186. PMID: 23149731, PMCID: PMC3530897, DOI: 10.1038/ncomms2184.Peer-Reviewed Original ResearchGain-of-function Nav1.8 mutations in painful neuropathy
Faber CG, Lauria G, Merkies IS, Cheng X, Han C, Ahn HS, Persson AK, Hoeijmakers JG, Gerrits MM, Pierro T, Lombardi R, Kapetis D, Dib-Hajj SD, Waxman SG. Gain-of-function Nav1.8 mutations in painful neuropathy. Proceedings Of The National Academy Of Sciences Of The United States Of America 2012, 109: 19444-19449. PMID: 23115331, PMCID: PMC3511073, DOI: 10.1073/pnas.1216080109.Peer-Reviewed Original ResearchConceptsPainful peripheral neuropathySmall fiber neuropathyPainful neuropathyPeripheral neuropathyPainful small fiber neuropathyDorsal root ganglion neuronsSodium channelsApparent underlying causePeripheral nerve axonsDRG neuronsGanglion neuronsNeuropathyNerve axonsUnderlying causeFunction variantsCurrent clampPatientsPotential pathogenicityNeuronsMutationsHyperexcitabilityAxonsResponse
2008
Nav1.9, G‐proteins, and nociceptors
Waxman SG, Estacion M. Nav1.9, G‐proteins, and nociceptors. The Journal Of Physiology 2008, 586: 917-918. PMID: 18287383, PMCID: PMC2375642, DOI: 10.1113/jphysiol.2007.149922.Peer-Reviewed Original Research
2007
A case of inherited erythromelalgia
Novella SP, Hisama FM, Dib-Hajj SD, Waxman SG. A case of inherited erythromelalgia. Nature Reviews Neurology 2007, 3: 229-234. PMID: 17410110, DOI: 10.1038/ncpneuro0425.Peer-Reviewed Original ResearchConceptsLaboratory blood testingMRI brain scansNeuropathic painSymptomatic managementNeurological examinationRecurrent episodesBlood testingMedical historySkin biopsiesFamily historyDistal extremitiesBrain scansSimilar symptomsGenetic counselingEarly childhoodPainEpisodesErythromelalgiaBiopsyErythemaSymptomsExtremitiesDNA analysisMultiple sodium channels and their roles in electrogenesis within dorsal root ganglion neurons
Rush AM, Cummins TR, Waxman SG. Multiple sodium channels and their roles in electrogenesis within dorsal root ganglion neurons. The Journal Of Physiology 2007, 579: 1-14. PMID: 17158175, PMCID: PMC2075388, DOI: 10.1113/jphysiol.2006.121483.Peer-Reviewed Original ResearchConceptsSodium channel isoformsDorsal root ganglion neuronsChannel isoformsDRG neuronsGanglion neuronsSpecific sodium channel isoformsMultiple sodium channelsSodium channelsPattern of expressionModulatory moleculesDisease insultsModulation of channelsPlasticity of expressionNeuronsDifferent subclassesExcitabilityDistinct biophysical characteristicsIsoformsExpressionBody of literatureInsultImportant roleResponse
2002
Primary motor neurons fail to up‐regulate voltage‐gated sodium channel Nav1.3/brain type III following axotomy resulting from spinal cord injury
Hains B, Black J, Waxman S. Primary motor neurons fail to up‐regulate voltage‐gated sodium channel Nav1.3/brain type III following axotomy resulting from spinal cord injury. Journal Of Neuroscience Research 2002, 70: 546-552. PMID: 12404508, DOI: 10.1002/jnr.10402.Peer-Reviewed Original ResearchConceptsSpinal cord injuryUpper motor neuronsPrimary motor cortexDorsal root gangliaMotor neuronsCord injuryMotor cortexRat primary motor cortexDorsal column transectionIpsilateral DRG neuronsCortical motor neuronsSciatic nerve transectionTraumatic head injuryFacial motor neuronsSodium channel expressionPrimary motor neuronsVoltage-gated sodium channelsPeripheral axotomyDRG neuronsNerve transectionLayer VControl brainsHead injuryRoot gangliaSpinal cordAxotomy does not up-regulate expression of sodium channel Nav1.8 in Purkinje cells
Black J, Dusart I, Sotelo C, Waxman S. Axotomy does not up-regulate expression of sodium channel Nav1.8 in Purkinje cells. Brain Research 2002, 101: 126-131. PMID: 12007840, DOI: 10.1016/s0169-328x(02)00200-0.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAxonsAxotomyCerebellumDisease Models, AnimalFemaleGanglia, SpinalGene Expression RegulationImmunohistochemistryMultiple SclerosisNAV1.8 Voltage-Gated Sodium ChannelNeurons, AfferentNeuropeptidesPurkinje CellsRatsRats, WistarRNA, MessengerSodium ChannelsUp-RegulationZebrafish ProteinsConceptsMultiple sclerosisPurkinje cellsSensory neuron-specific sodium channelsDorsal root ganglion neuronsAberrant expressionSodium channelsHuman multiple sclerosisPrimary sensory neuronsSodium channel Nav1.8Specific sodium channelsCerebellar Purkinje cellsGanglion neuronsSensory neuronsAxotomySurgical modelSodium channel transcriptsExperimental modelCerebellar functionChannel transcriptsNeuronsSitu hybridizationCellsExpressionNav1.8Sclerosis