2023
Genetic 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 centersSCN7A
2012
An AnkyrinG-Binding Motif Is Necessary and Sufficient for Targeting Nav1.6 Sodium Channels to Axon Initial Segments and Nodes of Ranvier
Gasser A, Ho TS, Cheng X, Chang KJ, Waxman SG, Rasband MN, Dib-Hajj SD. An AnkyrinG-Binding Motif Is Necessary and Sufficient for Targeting Nav1.6 Sodium Channels to Axon Initial Segments and Nodes of Ranvier. Journal Of Neuroscience 2012, 32: 7232-7243. PMID: 22623668, PMCID: PMC3413458, DOI: 10.1523/jneurosci.5434-11.2012.Peer-Reviewed Original ResearchConceptsReporter proteinAxon initial segmentKinase phosphorylation siteSodium channelsIntracellular loop 2Nodes of RanvierFull-length channelGlutamic acid residuesPhosphorylation sitesMechanism of channelVoltage-gated sodium channelsAcid residuesLoop 2Functional mouseNav1.6 sodium channelsMotifProteinVivo analysisAnkyrinGSomatodendritic compartmentCultured neuronsInitial segmentVivoAction potentialsCellsA channelopathy contributes to cerebellar dysfunction in a model of multiple sclerosis
Shields SD, Cheng X, Gasser A, Saab CY, Tyrrell L, Eastman EM, Iwata M, Zwinger PJ, Black JA, Dib‐Hajj S, Waxman SG. A channelopathy contributes to cerebellar dysfunction in a model of multiple sclerosis. Annals Of Neurology 2012, 71: 186-194. PMID: 22367990, DOI: 10.1002/ana.22665.Peer-Reviewed Original ResearchConceptsMultiple sclerosisCerebellar dysfunctionMouse modelPurkinje neuronsNervous systemNew transgenic mouse modelPurkinje neuron firingDisease-modifying agentsSodium channel Nav1.8Healthy nervous systemPeripheral nervous systemTransgenic mouse modelCerebellar Purkinje neuronsWild-type littermatesNav1.8 expressionNeurons altersSymptom burdenSymptomatic therapySymptom progressionNav1.8Electrophysiological propertiesNeuron firingDysfunctionEAEMotor behavior
2011
Gain of function NaV1.7 mutations in idiopathic small fiber neuropathy
Faber CG, Hoeijmakers JG, Ahn H, Cheng X, Han C, Choi J, Estacion M, Lauria G, Vanhoutte EK, Gerrits MM, Dib‐Hajj S, Drenth JP, Waxman SG, Merkies IS. Gain of function NaV1.7 mutations in idiopathic small fiber neuropathy. Annals Of Neurology 2011, 71: 26-39. PMID: 21698661, DOI: 10.1002/ana.22485.Peer-Reviewed Original ResearchConceptsSmall nerve fibre neuropathyIntraepidermal nerve fiber densityQuantitative sensory testingSmall-diameter peripheral axonsDorsal root ganglion neuronsGanglion neuronsPeripheral axonsSodium channelsAbnormal intraepidermal nerve fibre densityAbnormal quantitative sensory testingIdiopathic small fiber neuropathyFunction Nav1.7 mutationsNerve conduction studiesNerve fiber densitySmall fiber neuropathyVoltage-gated sodium channelsRare genetic syndromeExpression of gainTendon reflexesConduction studiesNav1.7 mutationUnderlying etiologyVibration senseSensory testingPatients
2010
A new Nav1.7 sodium channel mutation I234T in a child with severe pain
Ahn H, Dib‐Hajj S, Cox JJ, Tyrrell L, Elmslie FV, Clarke AA, Drenth JP, Woods CG, Waxman SG. A new Nav1.7 sodium channel mutation I234T in a child with severe pain. European Journal Of Pain 2010, 14: 944-950. PMID: 20385509, DOI: 10.1016/j.ejpain.2010.03.007.Peer-Reviewed Original ResearchConceptsSevere painSevere pain symptomsYear old patientAvoidance of triggersWhole-cell voltage-clamp analysisPain episodesPain symptomsOlder patientsDrug treatmentVoltage-clamp analysisPainRamp depolarizationIEM patientsPatient's genomic DNAMild warmthPatientsSodium channelsFunction mutationsT mutationLimited reliefMonthsActivation shiftActivationRednessMutationsCan robots patch‐clamp as well as humans? Characterization of a novel sodium channel mutation
Estacion M, Choi JS, Eastman EM, Lin Z, Li Y, Tyrrell L, Yang Y, Dib‐Hajj S, Waxman SG. Can robots patch‐clamp as well as humans? Characterization of a novel sodium channel mutation. The Journal Of Physiology 2010, 588: 1915-1927. PMID: 20123784, PMCID: PMC2901980, DOI: 10.1113/jphysiol.2009.186114.Peer-Reviewed Original Research
2009
A sodium channel gene SCN9A polymorphism that increases nociceptor excitability
Estacion M, Harty TP, Choi J, Tyrrell L, Dib‐Hajj S, Waxman SG. A sodium channel gene SCN9A polymorphism that increases nociceptor excitability. Annals Of Neurology 2009, 66: 862-866. PMID: 20033988, DOI: 10.1002/ana.21895.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsArginineBiophysical PhenomenaCell Line, TransformedElectric StimulationGanglia, SpinalGreen Fluorescent ProteinsHumansMembrane PotentialsMiceNAV1.7 Voltage-Gated Sodium ChannelNociceptorsPatch-Clamp TechniquesPolymorphism, Single NucleotideSensory Receptor CellsSensory ThresholdsSodium ChannelsTransfectionTryptophanConceptsNonsynonymous single nucleotide polymorphismsNociceptive primary sensory neuronsDorsal root ganglion neuronsPrimary sensory neuronsCurrent-clamp analysisSingle nucleotide polymorphismsSCN9A geneDRG neuronsNociceptor excitabilityGanglion neuronsUnaffected family membersControl chromosomesSensory neuronsSmall depolarizationSodium channelsMembrane potentialNeuronsAffected probandPolymorphismFamily membersDepolarizationChromosomesGenesErythromelalgiaPainVoltage-Gated Sodium Channels: Therapeutic Targets for Pain
Dib-Hajj S, Black JA, Waxman SG. Voltage-Gated Sodium Channels: Therapeutic Targets for Pain. Pain Medicine 2009, 10: 1260-1269. PMID: 19818036, DOI: 10.1111/j.1526-4637.2009.00719.x.Peer-Reviewed Reviews, Practice Guidelines, Standards, and Consensus StatementsMeSH KeywordsAnimalsDrug Delivery SystemsHumansIon Channel GatingModels, NeurologicalNociceptorsPainSodium Channel BlockersSodium ChannelsConceptsDifferent pain statesPain statesVoltage-gated sodium channelsPain syndromeTherapeutic targetParoxysmal extreme pain disorderFunction mutationsIsoform-specific blockersSodium channelsInflammatory pain conditionsDifferent pain syndromesTreatment of painDorsal root gangliaSodium channel expressionMajor medical needsSodium channel blockersSodium channel isoformsAmeliorate painPain conditionsPain disordersChronic painTreatment optionsRoot gangliaNociceptor neuronsChannel blockersA novel Nav1.7 mutation producing carbamazepine‐responsive erythromelalgia
Fischer TZ, Gilmore ES, Estacion M, Eastman E, Taylor S, Melanson M, Dib‐Hajj S, Waxman SG. A novel Nav1.7 mutation producing carbamazepine‐responsive erythromelalgia. Annals Of Neurology 2009, 65: 733-741. PMID: 19557861, PMCID: PMC4103031, DOI: 10.1002/ana.21678.Peer-Reviewed Original ResearchConceptsSteady-state inactivationDorsal root ganglion neuron hyperexcitabilityWhole-cell patch-clamp recordingsRamp currentsHuman therapeutic rangeWhole-cell patch-clamp studiesPatch-clamp recordingsPatch-clamp studiesErythromelalgia mutationV400MNeuron hyperexcitabilityNeuropathic painM cell lineNav1.7 mutationPainful disordersSympathetic neuronsTherapeutic rangeBlood samplesAnimal studiesNormalizing effectPharmacological studiesErythromelalgiaPainSodium channelsCarbamazepineRole of hippocampal sodium channel Nav1.6 in kindling epileptogenesis
Blumenfeld H, Lampert A, Klein JP, Mission J, Chen MC, Rivera M, Dib‐Hajj S, Brennan AR, Hains BC, Waxman SG. Role of hippocampal sodium channel Nav1.6 in kindling epileptogenesis. Epilepsia 2009, 50: 44-55. PMID: 18637833, PMCID: PMC3741044, DOI: 10.1111/j.1528-1167.2008.01710.x.Peer-Reviewed Original ResearchConceptsHippocampal CA3 neuronsActivity-dependent facilitationCA3 neuronsCommon nervous system disordersSodium channel protein expressionSodium currentCentral nervous system plasticityChannel messenger RNAExpression of Nav1.6Sham-kindled controlsSodium channel Nav1.6Development of kindlingNervous system plasticityNervous system disordersWild-type miceRate of kindlingChannel protein expressionMessenger RNAPatch-clamp recordingsActivity-dependent plasticityPersistent sodium currentIon channel expressionNormal hippocampal functionAction potential generationAbnormal plasticity
2007
A Nav1.7 channel mutation associated with hereditary erythromelalgia contributes to neuronal hyperexcitability and displays reduced lidocaine sensitivity
Sheets PL, Jackson JO, Waxman SG, Dib‐Hajj S, Cummins TR. A Nav1.7 channel mutation associated with hereditary erythromelalgia contributes to neuronal hyperexcitability and displays reduced lidocaine sensitivity. The Journal Of Physiology 2007, 581: 1019-1031. PMID: 17430993, PMCID: PMC2170829, DOI: 10.1113/jphysiol.2006.127027.Peer-Reviewed Original ResearchMeSH KeywordsAction PotentialsAnesthetics, LocalBinding SitesCell LineComputer SimulationDose-Response Relationship, DrugErythromelalgiaGanglia, SpinalHumansIon Channel GatingKineticsLidocaineModels, NeurologicalMutationNAV1.7 Voltage-Gated Sodium ChannelNerve Tissue ProteinsNeurons, AfferentSodium Channel BlockersSodium ChannelsTransfectionVoltage-Gated Sodium Channel beta-2 SubunitConceptsErythromelalgia mutationLidocaine inhibitionLocal anesthetic binding siteLocal anestheticsK mutationWild-type Nav1.7Use-dependent inhibitionSlow inactivationSteady-state slow inactivationAnesthetic binding sitesLidocaine sensitivityNeuronal hyperexcitabilityLidocaine treatmentSensory neuronsNaV1.7 currentsErythromelalgiaLidocaineNav1.7Electrophysiological differencesInhibitory effectChannel mutationsSodium channelsHyperexcitabilityK channelsAnesthetics
2006
Differential modulation of sodium channel Nav1.6 by two members of the fibroblast growth factor homologous factor 2 subfamily
Rush AM, Wittmack EK, Tyrrell L, Black JA, Dib‐Hajj S, Waxman SG. Differential modulation of sodium channel Nav1.6 by two members of the fibroblast growth factor homologous factor 2 subfamily. European Journal Of Neuroscience 2006, 23: 2551-2562. PMID: 16817858, DOI: 10.1111/j.1460-9568.2006.04789.x.Peer-Reviewed Original ResearchMeSH KeywordsCerebellumElectrophoresis, Polyacrylamide GelFibroblast Growth FactorsGanglia, SpinalHippocampusHumansImmunoblottingImmunohistochemistryImmunoprecipitationNAV1.6 Voltage-Gated Sodium ChannelNerve Tissue ProteinsNeuronsPatch-Clamp TechniquesProtein IsoformsRanvier's NodesSciatic NerveSodium ChannelsTransfectionConceptsFibroblast growth factor homologous factor 2Dorsal root ganglion neuronsSodium channelsDifferential modulationTrains of stimulationND7/23 cell lineRapid firing ratesFactor 2Slowing of recoveryNodes of RanvierDRG neuronsGanglion neuronsSciatic nerveSpecific neuronal compartmentsAdult rat tissuesMotor nodesElectrophysiological propertiesCerebellar neuronsDifferent functional effectsNeuronal compartmentsFiring rateInactivated channelsElectrophysiological methodsRat tissuesNeuronsSporadic onset of erythermalgia: A gain‐of‐function mutation in Nav1.7
Han C, Rush AM, Dib‐Hajj S, Li S, Xu Z, Wang Y, Tyrrell L, Wang X, Yang Y, Waxman SG. Sporadic onset of erythermalgia: A gain‐of‐function mutation in Nav1.7. Annals Of Neurology 2006, 59: 553-558. PMID: 16392115, DOI: 10.1002/ana.20776.Peer-Reviewed Original ResearchMeSH KeywordsAdolescentAmino Acid SequenceCell LineChinaDNA Mutational AnalysisDose-Response Relationship, RadiationElectric StimulationErythromelalgiaExonsFamily HealthHumansLeucineMaleMembrane PotentialsModels, MolecularMutationNAV1.7 Voltage-Gated Sodium ChannelPatch-Clamp TechniquesPhenylalanineSodium ChannelsTransfectionConceptsSporadic casesPeripheral sensory neuronsWhole-cell patch-clamp analysisAsymptomatic family membersPatch-clamp analysisAutosomal dominant disorderMild thermal stimuliSporadic onsetSensory neuronsErythermalgiaAsymptomatic fatherSmall depolarizationSodium channelsFounder mutationDominant disorderClamp analysisChannel activationThermal stimuliPatientsFunction mutationsFamily membersMultigeneration familySingle amino acid substitutionAmino acid substitutionsChinese family
2005
Contactin regulates the current density and axonal expression of tetrodotoxin‐resistant but not tetrodotoxin‐sensitive sodium channels in DRG neurons
Rush AM, Craner MJ, Kageyama T, Dib‐Hajj S, Waxman SG, Ranscht B. Contactin regulates the current density and axonal expression of tetrodotoxin‐resistant but not tetrodotoxin‐sensitive sodium channels in DRG neurons. European Journal Of Neuroscience 2005, 22: 39-49. PMID: 16029194, DOI: 10.1111/j.1460-9568.2005.04186.x.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAxonsCell Adhesion Molecules, NeuronalCell MembraneCells, CulturedContactinsDown-RegulationGanglia, SpinalMembrane PotentialsMiceMice, Inbred C57BLMice, KnockoutNAV1.8 Voltage-Gated Sodium ChannelNAV1.9 Voltage-Gated Sodium ChannelNerve Fibers, UnmyelinatedNeurons, AfferentNeuropeptidesNociceptorsPatch-Clamp TechniquesPlant LectinsSodium Channel BlockersSodium ChannelsTetrodotoxinConceptsTTX-S channelsDRG neuronsSodium channelsSmall-diameter dorsal root ganglion neuronsSmall-diameter DRG neuronsWhole-cell patch-clamp recordingsTetrodotoxin-sensitive sodium channelsDorsal root ganglion neuronsChannel isoformsNociceptive DRG neuronsTTX-sensitive sodium channelsSodium channel Nav1.2Patch-clamp recordingsSodium channel isoformsPositive neuronsGanglion neuronsSciatic nerveCell surface expressionIsolectin B4Axonal expressionUnmyelinated axonsMammalian neuronal cellsLitter matesNav1.9Neuronal cellsErythromelalgia: A hereditary pain syndrome enters the molecular era
Waxman SG, Dib‐Hajj S. Erythromelalgia: A hereditary pain syndrome enters the molecular era. Annals Of Neurology 2005, 57: 785-788. PMID: 15929046, DOI: 10.1002/ana.20511.Peer-Reviewed Reviews, Practice Guidelines, Standards, and Consensus StatementsMeSH KeywordsAmino Acid SequenceErythromelalgiaHumansMolecular Sequence DataNAV1.7 Voltage-Gated Sodium ChannelSodium ChannelsConceptsPain syndromeGanglion neuronsCentral nervous system neuronsDorsal root ganglion neuronsChronic neuropathic painSodium channelsSympathetic ganglion neuronsIon channel mutationsChannel functionSodium channel functionAutosomal dominant disorderNeuropathic painPain disordersChronic painAltered excitabilityModerate exerciseSystem neuronsPrimary erythermalgiaRational therapyErythromelalgiaPainFirst human disorderModel diseaseWarm stimuliSyndromeElectrophysiological properties of two axonal sodium channels, Nav1.2 and Nav1.6, expressed in mouse spinal sensory neurones
Rush AM, Dib‐Hajj S, Waxman SG. Electrophysiological properties of two axonal sodium channels, Nav1.2 and Nav1.6, expressed in mouse spinal sensory neurones. The Journal Of Physiology 2005, 564: 803-815. PMID: 15760941, PMCID: PMC1464456, DOI: 10.1113/jphysiol.2005.083089.Peer-Reviewed Original Research
2003
Patterned electrical activity modulates sodium channel expression in sensory neurons
Klein JP, Tendi EA, Dib‐Hajj S, Fields RD, Waxman SG. Patterned electrical activity modulates sodium channel expression in sensory neurons. Journal Of Neuroscience Research 2003, 74: 192-198. PMID: 14515348, DOI: 10.1002/jnr.10768.Peer-Reviewed Original ResearchMeSH KeywordsAction PotentialsAnimalsCells, CulturedDown-RegulationElectric StimulationFetusGanglia, SpinalImmunohistochemistryMiceNAV1.8 Voltage-Gated Sodium ChannelNAV1.9 Voltage-Gated Sodium ChannelNerve Growth FactorNerve Tissue ProteinsNeurons, AfferentNeuropeptidesPeripheral NervesPeripheral Nervous System DiseasesRNA, MessengerSodium ChannelsConceptsExpression of Nav1.3Sodium channel expressionNerve growth factorSensory neuronsChannel expressionDorsal root ganglion neuronsEctopic neuronal dischargesPatterned electrical activitySodium channel Nav1.3Development of hyperexcitabilityPeripheral nerve injuryMouse sensory neuronsNeuronal activity levelsSubtype-specific mannerQuantitative polymerase chain reactionNav1.9 mRNANeuropathic painNerve injuryGanglion neuronsNeurotrophic factorPolymerase chain reactionNeuronal dischargeNeuronal activityElectrical stimulationNav1.8
2001
Glycosylation Alters Steady-State Inactivation of Sodium Channel Nav1.9/NaN in Dorsal Root Ganglion Neurons and Is Developmentally Regulated
Tyrrell L, Renganathan M, Dib-Hajj S, Waxman S. Glycosylation Alters Steady-State Inactivation of Sodium Channel Nav1.9/NaN in Dorsal Root Ganglion Neurons and Is Developmentally Regulated. Journal Of Neuroscience 2001, 21: 9629-9637. PMID: 11739573, PMCID: PMC6763018, DOI: 10.1523/jneurosci.21-24-09629.2001.Peer-Reviewed Original ResearchMeSH KeywordsAgingAnimalsAnimals, NewbornAntibody SpecificityAxotomyCell MembraneCells, CulturedFemaleGanglia, SpinalGlycosylationImmunoblottingMembrane PotentialsN-Acetylneuraminic AcidNAV1.9 Voltage-Gated Sodium ChannelNeuraminidaseNeuronsNeuropeptidesPatch-Clamp TechniquesRatsRats, Sprague-DawleySciatic NerveSodiumSodium ChannelsSubcellular FractionsTetrodotoxinTrigeminal GanglionConceptsImmunoreactive proteinMembrane fractionAdult DRG neuronsTranscription-PCR analysisHigh molecular weight immunoreactive proteinTheoretical molecular weightWhole-cell patch-clamp analysisLong transcriptsGlycosylation statePatch-clamp analysisAdult tissuesLarge proteinsLimited glycosylationEnzymatic deglycosylationExtensive glycosylationState of glycosylationProteinAdult dorsal root gangliaGlycosylationNative neuronsDevelopmental changesInactivationMembrane preparationsDRG neuronsDorsal root gangliaDiverse Functions and Dynamic Expression of Neuronal Sodium Channels
Waxman SG, Cummins TR, Black JA, Dib‐Hajj S. Diverse Functions and Dynamic Expression of Neuronal Sodium Channels. Novartis Foundation Symposia 2001, 241: 34-60. PMID: 11771649, DOI: 10.1002/0470846682.ch4.Peer-Reviewed Reviews, Practice Guidelines, Standards, and Consensus StatementsConceptsChannel gene expressionNervous systemChannel expressionNormal nervous systemTypes of neuronsNeuronal sodium channelsChannel genesChronic painGene expressionMultiple sclerosisPeripheral axonsChannel subtypesMaladaptive changesPathological neuronsNeuronal functionPurkinje cellsTherapeutic opportunitiesExperimental modelAmino acid sequenceSodium channelsNa channelsNeuronsDifferent amino acid sequencesRecent evidenceSelective modulatorsDirect Interaction with Contactin Targets Voltage-gated Sodium Channel Nav1.9/NaN to the Cell Membrane*
Liu C, Dib-Hajj S, Black J, Greenwood J, Lian Z, Waxman S. Direct Interaction with Contactin Targets Voltage-gated Sodium Channel Nav1.9/NaN to the Cell Membrane*. Journal Of Biological Chemistry 2001, 276: 46553-46561. PMID: 11581273, DOI: 10.1074/jbc.m108699200.Peer-Reviewed Original ResearchConceptsDorsal root gangliaRoot gangliaSodium channelsSmall sensory neuronsVoltage-gated sodium channelsTrigeminal ganglionNerve endingsC-fibersSensory neuronsNeuron somataChinese hamster ovary cell lineDifferent physiological propertiesGangliaHamster ovary cell lineNeuronal membranesChinese hamster ovary cellsOvary cell lineProtein complexesSurface expressionHamster ovary cellsCell linesAxonsSurface localizationCell membraneOvary cells