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 ResearchMeSH KeywordsAction PotentialsAnimalsGanglia, SpinalHumansMiceNAV1.7 Voltage-Gated Sodium ChannelNAV1.8 Voltage-Gated Sodium ChannelNeuralgiaNeuronsRatsConceptsDorsal 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
Ih 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 ResearchMeSH KeywordsAction PotentialsAnimalsErythromelalgiaGanglia, SpinalHumansNAV1.7 Voltage-Gated Sodium ChannelNeuralgiaNeuronsNociceptorsRodentiaConceptsFunction 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 firingGenetic, electrophysiological, and pathological studies on patients with SCN9A‐related pain disorders
Yuan J, Cheng X, Matsuura E, Higuchi Y, Ando M, Hashiguchi A, Yoshimura A, Nakachi R, Mine J, Taketani T, Maeda K, Kawakami S, Kira R, Tanaka S, Kanai K, Dib‐Hajj F, Dib‐Hajj S, Waxman S, Takashima H. Genetic, electrophysiological, and pathological studies on patients with SCN9A‐related pain disorders. Journal Of The Peripheral Nervous System 2023, 28: 597-607. PMID: 37555797, DOI: 10.1111/jns.12590.Peer-Reviewed Original ResearchMeSH KeywordsErythromelalgiaHEK293 CellsHumansMutationNAV1.7 Voltage-Gated Sodium ChannelPainPeripheral Nervous System DiseasesConceptsParoxysmal extreme pain disorderPainful peripheral neuropathyPain disordersSCN9A mutationsPeripheral neuropathyNovel SCN9A mutationsVoltage-gated sodium channel Nav1.7Sodium channel Nav1.7Steady-state fast inactivationGene panel sequencingPatch-clamp analysisAutonomic neuropathyNeuropathic painSCN9A geneClinical featuresUnderlying pathogenesisPathological studiesPatientsChannel Nav1.7EM phenotypePhenotypic spectrumNeuropathyNav1.7 channelsPatch-clamp systemElectrophysiological analysisTargeting a Peripheral Sodium Channel to Treat Pain
Waxman S. Targeting a Peripheral Sodium Channel to Treat Pain. New England Journal Of Medicine 2023, 389: 466-469. PMID: 37530829, DOI: 10.1056/nejme2305708.Peer-Reviewed Original ResearchGenetic Profiling of Sodium Channels in Diabetic Painful and Painless and Idiopathic Painful and Painless Neuropathies
Almomani R, Sopacua M, Marchi M, Ślęczkowska M, Lindsey P, de Greef B, Hoeijmakers J, Salvi E, Merkies I, Ferdousi M, Malik R, Ziegler D, Derks K, Boenhof G, Martinelli-Boneschi F, Cazzato D, Lombardi R, Dib-Hajj S, Waxman S, Smeets H, Gerrits M, Faber C, Lauria G, Group O. Genetic Profiling of Sodium Channels in Diabetic Painful and Painless and Idiopathic Painful and Painless Neuropathies. International Journal Of Molecular Sciences 2023, 24: 8278. PMID: 37175987, PMCID: PMC10179245, DOI: 10.3390/ijms24098278.Peer-Reviewed Original ResearchMeSH KeywordsDiabetes MellitusDiabetic NeuropathiesHumansNAV1.7 Voltage-Gated Sodium ChannelNeuralgiaSmall Fiber NeuropathySodium ChannelsConceptsDiabetic peripheral neuropathySmall fiber neuropathyPainless neuropathySFN patientsPainful neuropathyPeripheral neuropathyNeuropathy patientsPainless diabetic peripheral neuropathyPathogenic variantsPersonalized pain treatmentPainful peripheral neuropathyDifferent pathogenic variantsGenetic profilingSodium channel genePotential pathogenic variantsDPN patientsNeuropathic painNociceptive pathwaysPain treatmentNeuropathyPatientsSodium channelsFrequent featureDifferent centersSCN7APain-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 ResearchMeSH KeywordsAustraliaNAV1.7 Voltage-Gated Sodium ChannelPainPeptidesToxins, BiologicalUrtica dioicaConceptsSensory neuronsVoltage-sensing domainNav channelsTransmembrane proteinAccessory proteinsVoltage-gated sodium channelsCritical regulatorPore domainChannel gatingExtracellular loopToxin-mediated effectsNeuronal excitabilityPeptide toxinsProteinSodium channelsPharmacological activitiesNav1.7 functionKnottin peptidesNeuronsImportant insightsToxinSubunitsRegulatorDomainExcelsaNav1.7 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 insensitivityMiceIntegrative miRNA–mRNA profiling of human epidermis: unique signature of SCN9A painful neuropathy
Andelic M, Salvi E, Marcuzzo S, Marchi M, Lombardi R, Cartelli D, Cazzato D, Mehmeti E, Gelemanovic A, Paolini M, Pardo C, D'Amato I, Hoeijmakers J, Dib-Hajj S, Waxman S, Faber C, Lauria G. Integrative miRNA–mRNA profiling of human epidermis: unique signature of SCN9A painful neuropathy. Brain 2023, 146: 3049-3062. PMID: 36730021, PMCID: PMC10316770, DOI: 10.1093/brain/awad025.Peer-Reviewed Original ResearchMeSH KeywordsEpidermal CellsEpidermisHumansMicroRNAsNAV1.7 Voltage-Gated Sodium ChannelNeuralgiaRNA, MessengerConceptsNeuropathic painPain-related mechanismsCohort of patientsSmall nerve fibersUnmet clinical needPainful neuropathyTargeted molecular profilingNeuropathy painPathophysiological mechanismsAvailable therapiesPreclinical modelsNerve fibersLimited efficacyHealthy individualsPersonalized managementPotential drug candidatesTranslational gapPainClinical needGene targetsPatientsImmunofluorescence assaysMolecular profilingMiR-30 familyProtein expressionNav1.7 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 transection
2022
The fates of internalized NaV1.7 channels in sensory neurons: Retrograde cotransport with other ion channels, axon-specific recycling, and degradation
Higerd-Rusli G, Tyagi S, Liu S, Dib-Hajj F, Waxman S, Dib-Hajj S. The fates of internalized NaV1.7 channels in sensory neurons: Retrograde cotransport with other ion channels, axon-specific recycling, and degradation. Journal Of Biological Chemistry 2022, 299: 102816. PMID: 36539035, PMCID: PMC9843449, DOI: 10.1016/j.jbc.2022.102816.Peer-Reviewed Original ResearchMeSH KeywordsAction PotentialsAxonsHumansIon ChannelsMembrane ProteinsNAV1.7 Voltage-Gated Sodium ChannelSensory Receptor CellsConceptsMembrane proteinsIon channelsNeuronal functionDistinct neuronal compartmentsAxonal membrane proteinsRetrograde traffickingNeuronal polarityRecycling pathwayLate endosomesPlasma membraneSpecific proteinsAxonal traffickingNovel mechanismCell membraneSodium channel NaNeuronal compartmentsMultiple pathwaysLive neuronsVoltage-gated sodium channel NaProteinEndocytosisMembrane specializationsTraffickingMembraneChannel Na
2019
Rat NaV1.7 loss-of-function genetic model: Deficient nociceptive and neuropathic pain behavior with retained olfactory function and intra-epidermal nerve fibers
Grubinska B, Chen L, Alsaloum M, Rampal N, Matson D, Yang C, Taborn K, Zhang M, Youngblood B, Liu D, Galbreath E, Allred S, Lepherd M, Ferrando R, Kornecook T, Lehto S, Waxman S, Moyer B, Dib-Hajj S, Gingras J. Rat NaV1.7 loss-of-function genetic model: Deficient nociceptive and neuropathic pain behavior with retained olfactory function and intra-epidermal nerve fibers. Molecular Pain 2019, 15: 1744806919881846. PMID: 31550995, PMCID: PMC6831982, DOI: 10.1177/1744806919881846.Peer-Reviewed Original ResearchMeSH KeywordsAllelesAnimalsBinding SitesFemaleGenotypeHumansMaleNAV1.7 Voltage-Gated Sodium ChannelNerve FibersNeuralgiaPhenotypeRatsSciatic NerveConceptsOlfactory functionNav1.7 proteinPain behaviorPain responseRat modelSmall-diameter dorsal root ganglion neuronsNormal intraepidermal nerve fibre densityIntraepidermal nerve fiber densityIntra-epidermal nerve fibersDorsal root ganglion neuronsNeuropathic pain behaviorsNeuropathic pain responsesSpinal nerve ligationNerve fiber densityDorsal root gangliaAction potential firingPeripheral nervous systemEarly postnatal developmentGenetic animal modelsNav1.7 lossNerve ligationPain targetsNeuropathic conditionsGanglion neuronsRoot ganglia
2018
Nav1.7 is phosphorylated by Fyn tyrosine kinase which modulates channel expression and gating in a cell type-dependent manner
Li Y, Zhu T, Yang H, Dib-Hajj S, Waxman S, Yu Y, Xu TL, Cheng X. Nav1.7 is phosphorylated by Fyn tyrosine kinase which modulates channel expression and gating in a cell type-dependent manner. Molecular Pain 2018, 14: 1744806918782229. PMID: 29790812, PMCID: PMC6024516, DOI: 10.1177/1744806918782229.Peer-Reviewed Original ResearchMeSH KeywordsAmino Acid SequenceCell MembraneHEK293 CellsHumansIon Channel GatingMutant ProteinsNAV1.7 Voltage-Gated Sodium ChannelNeuronsPhosphorylationPhosphotyrosineProtein BindingProto-Oncogene Proteins c-fynConceptsND7/23 cellsDRG neuron excitabilityModulation of Nav1.7New pain therapeuticsVoltage-gated sodium channel Nav1.7Fyn kinaseWhole-cell recordingsSodium channel Nav1.7Elevated protein expressionCell type-specific modulationHuman embryonic kidney 293 cellsTyrosine kinasePain disordersEmbryonic kidney 293 cellsPain therapeuticsNeuron excitabilityPain perceptionMutant channelsChannel Nav1.7Kidney 293 cellsNav1.7HEK-293 cellsNav1.7 channelsCell type-dependent mannerType-dependent mannerA 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 ResearchMeSH KeywordsCarbamazepineGain of Function MutationGanglia, SpinalHumansMembrane PotentialsMiddle AgedMutationNAV1.7 Voltage-Gated Sodium ChannelNeuralgiaNeuronsPainPeripheral Nervous System DiseasesConceptsPainful 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 variantsNeurons
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 awakeningsPlaceboPharmacological reversal of a pain phenotype in iPSC-derived sensory neurons and patients with inherited erythromelalgia
Cao L, McDonnell A, Nitzsche A, Alexandrou A, Saintot PP, Loucif AJ, Brown AR, Young G, Mis M, Randall A, Waxman SG, Stanley P, Kirby S, Tarabar S, Gutteridge A, Butt R, McKernan RM, Whiting P, Ali Z, Bilsland J, Stevens EB. Pharmacological reversal of a pain phenotype in iPSC-derived sensory neurons and patients with inherited erythromelalgia. Science Translational Medicine 2016, 8: 335ra56. PMID: 27099175, DOI: 10.1126/scitranslmed.aad7653.Peer-Reviewed Original ResearchMeSH KeywordsAdultErythromelalgiaFemaleHumansInduced Pluripotent Stem CellsMaleMutationNAV1.7 Voltage-Gated Sodium ChannelPainPhenyl EthersSensory Receptor CellsSulfonamidesConceptsSensory neuronsPain conditionsSodium channelsClinical phenotypeSensory neuronal activityChronic pain conditionsHeat-induced painPeripheral nervous systemUnmet clinical needSodium channel Nav1.7Nav1.7 sodium channelNav1.7 blockersPharmacological reversalPain phenotypesExtreme painNeuronal activityHeat stimuliNervous systemChannel Nav1.7PainClinical needPatientsAberrant responsesSensory conditionsInduced pluripotent stem cell line
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 ResearchGanglia, SpinalHumansNAV1.7 Voltage-Gated Sodium ChannelNAV1.9 Voltage-Gated Sodium ChannelPain Insensitivity, CongenitalSensory Receptor CellsVoltage-Gated Sodium Channels
2014
Paroxysmal itch caused by gain-of-function Nav1.7 mutation
Devigili G, Eleopra R, Pierro T, Lombardi R, Rinaldo S, Lettieri C, Faber C, Merkies I, Waxman S, Lauria G. Paroxysmal itch caused by gain-of-function Nav1.7 mutation. Pain 2014, 155: 1702-1707. PMID: 24820863, DOI: 10.1016/j.pain.2014.05.006.Peer-Reviewed Original ResearchMeSH KeywordsAdultAntipruriticsChild, PreschoolDNA Mutational AnalysisFemaleGamma-Aminobutyric AcidHumansMaleMutationNAV1.7 Voltage-Gated Sodium ChannelPainPain ThresholdPhysical StimulationPregabalinPruritusTreatment OutcomeConceptsIntraepidermal nerve fiber densityNerve fiber densityFiber densityAutonomic cardiovascular reflexesFunction Nav1.7 mutationsNerve conduction studiesManifestations of allergyQuantitative sensory testingParadoxical heat sensationProfile assessmentConsequence of diseaseNav1.7 sodium channelCardiovascular reflexesPregabalin treatmentAutonomic testsConduction studiesNav1.7 mutationPain thresholdClinical pictureSystemic diseaseSomatosensory pathwaysSkin biopsiesIndex patientsSensory testingSpicy foods
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 ResearchMeSH KeywordsAlanineAmino Acid SequenceChildErythromelalgiaExonsFemaleGanglia, SpinalHEK293 CellsHumansMolecular Sequence DataMutation, MissenseNAV1.7 Voltage-Gated Sodium ChannelValineConceptsMutations 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
The NaV1.7 sodium channel: from molecule to man
Dib-Hajj SD, Yang Y, Black JA, Waxman SG. The NaV1.7 sodium channel: from molecule to man. Nature Reviews Neuroscience 2012, 14: 49-62. PMID: 23232607, DOI: 10.1038/nrn3404.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBiophysicsHumansModels, MolecularMutationNAV1.7 Voltage-Gated Sodium ChannelPainPeripheral NervesSignal TransductionSodium Channel BlockersTetrodotoxinConceptsDorsal hornPain disordersNerve endingsNociceptive dorsal root ganglion (DRG) neuronsPainful small fiber neuropathyDorsal root ganglion neuronsVoltage-gated sodium channel Nav1.7Small fiber neuropathyTreatment of painFree nerve endingsSecond-order neuronsSmall molecule blockersSodium channel Nav1.7Function mutationsOlfactory sensory neuronsProbability of neuronsNav1.7 sodium channelSuperficial laminaeGanglion neuronsRisk factorsSympathetic neuronsSlow depolarizationSpinal cordCardiac deficitsSensory neuronsStructural 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 Research