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 generation
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 malesConditional Astrocyte Rac1KO Attenuates Hyperreflexia after Spinal Cord Injury
Benson C, Olson K, Patwa S, Kauer S, King J, Waxman S, Tan A. Conditional Astrocyte Rac1KO Attenuates Hyperreflexia after Spinal Cord Injury. Journal Of Neuroscience 2023, 44: e1670222023. PMID: 37963762, PMCID: PMC10851682, DOI: 10.1523/jneurosci.1670-22.2023.Peer-Reviewed Original ResearchConceptsSpinal cord injuryRate-dependent depressionΑ-motor neuronsGlutamate transporter 1Dendritic spine dysgenesisCord injurySpine dysgenesisDevelopment of SCIMild contusion spinal cord injuryAstrocytic glutamate transporter 1Glial-specific glutamate transporterContusion spinal cord injuryTransporter 1Development of hyperreflexiaMonosynaptic H-reflexDendritic spine densityPre-injury levelSpinal reflex circuitsVentral spinal cordReflex hyperexcitabilityHyperexcitability disordersFunctional recoveryGlutamate clearanceH-reflexVentral hornNav1.7 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 ResearchConceptsParoxysmal 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 insensitivityMice
2018
Nonmuscle 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 channelsTherapeutic potential of Pak1 inhibition for pain associated with cutaneous burn injury
Guo Y, Benson C, Hill M, Henry S, Effraim P, Waxman S, Dib-Hajj S, Tan AM. Therapeutic potential of Pak1 inhibition for pain associated with cutaneous burn injury. Molecular Pain 2018, 14: 1744806918788648. PMID: 29956587, PMCID: PMC6053256, DOI: 10.1177/1744806918788648.Peer-Reviewed Original ResearchConceptsDendritic spine dysgenesisNeuropathic painSpine dysgenesisBurn injurySignificant tactile allodyniaDorsal horn neuronsChronic disease burdenActivity-dependent expressionCutaneous burn injurySecond-degree burn injuryBurn injury modelC-fos expressionPotential molecular targetsDrug discontinuationHeat hyperalgesiaTactile allodyniaDorsal hornPain outcomesChronic painNociceptive activityLower painDisease burdenInjury modelCognitive dysfunctionPain
2014
Physiological and genetic analysis of multiple sodium channel variants in a model of genetic absence epilepsy
Oliva MK, McGarr TC, Beyer BJ, Gazina E, Kaplan DI, Cordeiro L, Thomas E, Dib-Hajj SD, Waxman SG, Frankel WN, Petrou S. Physiological and genetic analysis of multiple sodium channel variants in a model of genetic absence epilepsy. Neurobiology Of Disease 2014, 67: 180-190. PMID: 24657915, PMCID: PMC4298829, DOI: 10.1016/j.nbd.2014.03.007.Peer-Reviewed Original Research
2012
Gain-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
2009
The ataxia3 Mutation in the N-Terminal Cytoplasmic Domain of Sodium Channel Nav1.6 Disrupts Intracellular Trafficking
Sharkey LM, Cheng X, Drews V, Buchner DA, Jones JM, Justice MJ, Waxman SG, Dib-Hajj SD, Meisler MH. The ataxia3 Mutation in the N-Terminal Cytoplasmic Domain of Sodium Channel Nav1.6 Disrupts Intracellular Trafficking. Journal Of Neuroscience 2009, 29: 2733-2741. PMID: 19261867, PMCID: PMC2679640, DOI: 10.1523/jneurosci.6026-08.2009.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBlotting, WesternCell LineChromosome MappingCytoplasmData Interpretation, StatisticalDNA, ComplementaryElectrophysiologyEthylnitrosoureaImmunohistochemistryMachado-Joseph DiseaseMiceMice, Inbred C57BLMutagensMutationMutation, MissenseNAV1.6 Voltage-Gated Sodium ChannelNerve Tissue ProteinsPatch-Clamp TechniquesSciatic NerveSodium ChannelsSubcellular FractionsTransfectionConceptsMutant channelsCytoplasmic N-terminal regionN-terminal cytoplasmic domainCytoplasmic N-terminal domainMouse chromosome 15N-terminal domainN-terminal regionAmino acid substitution p.Primary cerebellar granule cellsVoltage-dependent inward sodium currentMutant proteinsCytoplasmic domainJuvenile lethalityCis-GolgiTrafficking defectsPlasma membraneSodium channelsIntracellular traffickingProtein abundanceWild typeN-terminusGolgi complexMutant transcriptsChromosome 15Whole-cell patch-clamp studies
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
2001
Flanking regulatory sequences of the locus encoding the murine GDNF receptor, c‐ret, directs lac Z (β‐galactosidase) expression in developing somatosensory system
Sukumaran M, Waxman S, Wood J, Pachnis V. Flanking regulatory sequences of the locus encoding the murine GDNF receptor, c‐ret, directs lac Z (β‐galactosidase) expression in developing somatosensory system. Developmental Dynamics 2001, 222: 389-402. PMID: 11747074, DOI: 10.1002/dvdy.1192.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAnimals, NewbornBase SequenceChromosome MappingCloning, MolecularConsensus SequenceDrosophila ProteinsEmbryo, MammalianGanglia, SensoryGene ExpressionGene Expression Regulation, DevelopmentalGenes, RegulatorGlial Cell Line-Derived Neurotrophic Factor ReceptorsLac OperonLectinsMiceMice, TransgenicNeurons, AfferentNociceptorsPromoter Regions, GeneticProtein Structure, TertiaryProto-Oncogene ProteinsProto-Oncogene Proteins c-retReceptor Protein-Tyrosine KinasesSpinal CordTranscription Initiation SiteConceptsRegulatory domainLac Z expressionZ expressionCell type-specific expressionDistal regulatory domainEndogenous gene expressionCis-regulatory domainsTranscription initiation siteEntire structural geneSpecific regulatory domainsLac Z reporter geneStructural geneMouse genomeLateral mesodermRegulatory sequencesCpG islandsDNA sequencesPrimitive streakReporter geneFlanking sequencesCosmid contigGene expressionSpecific expressionTransgenic mouse lineInitiation siteContribution of Nav1.8 Sodium Channels to Action Potential Electrogenesis in DRG Neurons
Renganathan M, Cummins T, Waxman S. Contribution of Nav1.8 Sodium Channels to Action Potential Electrogenesis in DRG Neurons. Journal Of Neurophysiology 2001, 86: 629-640. PMID: 11495938, DOI: 10.1152/jn.2001.86.2.629.Peer-Reviewed Original ResearchConceptsAction potential electrogenesisDRG neuronsSodium channelsAction potentialsTTX-R sodium channelsSodium-dependent action potentialsDorsal root ganglion neuronsMultiple sodium channelsSmall DRG neuronsCurrent-clamp recordingsNav1.8 sodium channelsSignificant differencesSteady-state inactivationAction potential overshootMaximum rise slopeMV/msAction potential productionFast TTXGanglion neuronsModest depolarizationNeuronsInput resistanceMembrane depolarizationInward membraneElectrogenesisFibroblast Growth Factor Homologous Factor 1B Binds to the C Terminus of the Tetrodotoxin-resistant Sodium Channel rNav1.9a (NaN)*
Liu C, Dib-Hajj S, Waxman S. Fibroblast Growth Factor Homologous Factor 1B Binds to the C Terminus of the Tetrodotoxin-resistant Sodium Channel rNav1.9a (NaN)*. Journal Of Biological Chemistry 2001, 276: 18925-18933. PMID: 11376006, DOI: 10.1074/jbc.m101606200.Peer-Reviewed Original ResearchMeSH Keywords3T3 CellsAmino Acid SequenceAnimalsBlotting, WesternCell LineConserved SequenceCytoplasmDNA, ComplementaryDrug ResistanceFibroblast Growth FactorsGene LibraryGlutathione TransferaseGrowth SubstancesHumansMiceModels, BiologicalMolecular Sequence DataNAV1.9 Voltage-Gated Sodium ChannelNeuropeptidesPlasmidsProtein BindingProtein Structure, TertiaryRatsReverse Transcriptase Polymerase Chain ReactionRNASequence Analysis, DNASequence Homology, Amino AcidSodium ChannelsTetrodotoxinTissue DistributionTwo-Hybrid System TechniquesConceptsC-terminusTerminal polypeptideTwo-hybrid screenMammalian cell linesC-terminal regionN-terminal 5Fibroblast growth factor family membersFibroblast growth factor (FGF) familySodium channelsAmino acid residuesFactor family membersGrowth factor family membersCytoplasmic domainFirst growth factorGrowth factor familyFactor familyIntracellular segmentAcid residuesCell membraneFunctional significanceChannel complexDirect interactionCell linesTerminusPolypeptide
2000
Sensory neuron-specific sodium channel SNS is abnormally expressed in the brains of mice with experimental allergic encephalomyelitis and humans with multiple sclerosis
Black J, Dib-Hajj S, Baker D, Newcombe J, Cuzner M, Waxman S. Sensory neuron-specific sodium channel SNS is abnormally expressed in the brains of mice with experimental allergic encephalomyelitis and humans with multiple sclerosis. Proceedings Of The National Academy Of Sciences Of The United States Of America 2000, 97: 11598-11602. PMID: 11027357, PMCID: PMC17246, DOI: 10.1073/pnas.97.21.11598.Peer-Reviewed Original ResearchConceptsExperimental allergic encephalomyelitisMultiple sclerosisAllergic encephalomyelitisClinical abnormalitiesChannel expressionPurkinje cellsTrigeminal ganglion neuronsBrains of micePeripheral nervous systemSodium channel expressionIon channel expressionCerebellar Purkinje cellsAbnormal repertoiresAxonal degenerationControl miceGanglion neuronsControl subjectsMouse modelNormal brainAnimal modelsNervous systemNeurological diseasesSodium channelsProtein expressionAbnormal patterns
1999
Coding Sequence, Genomic Organization, and Conserved Chromosomal Localization of the Mouse Gene Scn11a Encoding the Sodium Channel NaN
Dib-Hajj S, Tyrrell L, Escayg A, Wood P, Meisler M, Waxman S. Coding Sequence, Genomic Organization, and Conserved Chromosomal Localization of the Mouse Gene Scn11a Encoding the Sodium Channel NaN. Genomics 1999, 59: 309-318. PMID: 10444332, DOI: 10.1006/geno.1999.5890.Peer-Reviewed Original ResearchConceptsSodium channel geneChannel genesConserved linkage groupMouse chromosome 9Sodium channel alphaAlternative exon 5Amino acid levelsGenomic organizationChromosomal localizationLinkage groupsHuman genesHuman SCN5ACoding sequenceCommon lineageChannel alphaChromosome 9TTX-R sodium channelsGenesSmall-diameter sensory neuronsTransduction of painDorsal root gangliaHigh-threshold nociceptorsExon 5SCN11A geneSodium channelsSodium channel expression in NGF‐overexpressing transgenic mice
Fjell J, Cummins T, Davis B, Albers K, Fried K, Waxman S, Black J. Sodium channel expression in NGF‐overexpressing transgenic mice. Journal Of Neuroscience Research 1999, 57: 39-47. PMID: 10397634, DOI: 10.1002/(sici)1097-4547(19990701)57:1<39::aid-jnr5>3.0.co;2-m.Peer-Reviewed Original ResearchConceptsNerve growth factorSodium channel expressionWild-type miceDRG neuronsTransgenic miceChannel expressionLevels of NGFDorsal root ganglion neuronsSNS/PN3Whole-cell patch-clamp studiesSmall DRG neuronsPeripheral nervous systemSodium channel mRNAFunctional sodium channelsPeak sodium current densityRegulation of expressionSodium current densityPatch-clamp studiesMechanical hyperalgesiaEmbryonic day 11Ganglion neuronsMouse DRGWild-type DRGsNervous systemLong-term overexpression
1996
Orphan nuclear receptor RORα gene: isoform-specific spatiotemporal expression during postnatal development of brain
Sashihara S, Felts P, Waxman S, Matsui T. Orphan nuclear receptor RORα gene: isoform-specific spatiotemporal expression during postnatal development of brain. Brain Research 1996, 42: 109-117. PMID: 8915586, DOI: 10.1016/s0169-328x(96)00118-0.Peer-Reviewed Original ResearchConceptsROR alphaAlpha cDNAOrphan nuclear receptor ROR alphaSpatiotemporal expressionN-terminal regionIsoform-specific regulationAlpha expressionSpecific transcriptsCell typesHybridization signalsPurkinje cellsCDNAExpressionPostnatal developmentRelative levelsRegulationCellsAlphaPostnatal maturationTranscriptsOlfactory bulbRodent brainIsoformsBrain regionsMaturation
1995
An orphan nuclear receptor, mROR α, and its spatial expression in adult mouse brain
Matsui T, Sashihara S, Oh Y, Waxman S. An orphan nuclear receptor, mROR α, and its spatial expression in adult mouse brain. Brain Research 1995, 33: 217-226. PMID: 8750880, DOI: 10.1016/0169-328x(95)00126-d.Peer-Reviewed Original ResearchMeSH KeywordsAmino Acid SequenceAnimalsBase SequenceBinding SitesBlotting, NorthernBrainCell DifferentiationCell LineGene ExpressionHumansIn Situ HybridizationMiceMolecular Sequence DataNeuronsNuclear Receptor Subfamily 1, Group F, Member 1Olfactory BulbOrgan SpecificityReceptors, Cytoplasmic and NuclearReceptors, Retinoic AcidSequence Homology, Amino AcidThalamusTrans-ActivatorsTransfectionTumor Cells, CulturedConceptsResponsive elementActivation of transcriptionThyroid hormone responsive elementRetinoic acid responsive elementNeural cell lineagesAcid-responsive elementLaminin B1 geneOrphan nuclear receptorHormone-responsive elementsRAR beta geneSitu hybridization analysisRetinoic acid receptor-related orphan receptorTranscription factorsAdult mouse brainCotransfection experimentsP19 cellsCell lineagesReceptor-related orphan receptorNorthern hybridizationAcid receptor-related orphan receptorHybridization analysisSpatial expressionOrphan receptorBeta geneNuclear receptors
1983
Long-term regenerated nerve fibres retain sensitivity to potassium channel blocking agents
Kocsis J, Waxman S. Long-term regenerated nerve fibres retain sensitivity to potassium channel blocking agents. Nature 1983, 304: 640-642. PMID: 6308475, DOI: 10.1038/304640a0.Peer-Reviewed Original ResearchConceptsNerve fibersPotassium channelsMyelinated peripheral nerve fibresAxon segmentsPeripheral nerve fibersAxon sproutsEndoneurial tubesNerve crushFunctional recoveryFunctional organizationMyelinated fibersAxon cylindersSchwann cellsBurst activityMyelinated axonsMammalian axonsAxonsPeripheral connectionsMembrane depolarizationBasement membraneK channelsRegenerated fibersAxon maturation
1981
Plasticity in the ontogeny and pathophysiology of myelinated fibers.
Waxman S. Plasticity in the ontogeny and pathophysiology of myelinated fibers. Advances In Neurology 1981, 31: 69-92. PMID: 7325049.Peer-Reviewed Original Research