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 ResearchConceptsDiabetic 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 ResearchConceptsSensory neuronsVoltage-sensing domainNav channelsTransmembrane proteinAccessory proteinsVoltage-gated sodium channelsCritical regulatorPore domainChannel gatingExtracellular loopToxin-mediated effectsNeuronal excitabilityPeptide toxinsProteinSodium channelsPharmacological activitiesNav1.7 functionKnottin peptidesNeuronsImportant insightsToxinSubunitsRegulatorDomainExcelsaConserved but not critical: Trafficking and function of NaV1.7 are independent of highly conserved polybasic motifs
Tyagi S, Sarveswaran N, Higerd-Rusli G, Liu S, Dib-Hajj F, Waxman S, Dib-Hajj S. Conserved but not critical: Trafficking and function of NaV1.7 are independent of highly conserved polybasic motifs. Frontiers In Molecular Neuroscience 2023, 16: 1161028. PMID: 37008789, PMCID: PMC10060856, DOI: 10.3389/fnmol.2023.1161028.Peer-Reviewed Original ResearchSensory axonsPeripheral voltage-gated sodium channelsMajor unmet clinical needFunction of Nav1.7Non-addictive treatmentsUnmet clinical needVoltage-clamp recordingsVoltage-gated sodium channelsPain therapyChronic painPrimary afferentsNoxious stimuliTherapeutic modalitiesAction potentialsAxonal transportClinical needVesicular packagingSodium channelsHuman painPainAxonal traffickingAxonal surfaceAxonal membraneAxonsAttractive targetHigh-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
Non-psychotropic phytocannabinoid interactions with voltage-gated sodium channels: An update on cannabidiol and cannabigerol
Ghovanloo M, Dib-Hajj S, Goodchild S, Ruben P, Waxman S. Non-psychotropic phytocannabinoid interactions with voltage-gated sodium channels: An update on cannabidiol and cannabigerol. Frontiers In Physiology 2022, 13: 1066455. PMID: 36439273, PMCID: PMC9691960, DOI: 10.3389/fphys.2022.1066455.Peer-Reviewed Original Research
2019
NaV1.6 regulates excitability of mechanosensitive sensory neurons
Israel MR, Tanaka BS, Castro J, Thongyoo P, Robinson SD, Zhao P, Deuis JR, Craik DJ, Durek T, Brierley SM, Waxman SG, Dib‐Hajj S, Vetter I. NaV1.6 regulates excitability of mechanosensitive sensory neurons. The Journal Of Physiology 2019, 597: 3751-3768. PMID: 31087362, DOI: 10.1113/jp278148.Peer-Reviewed Original ResearchConceptsPeripheral sensory neuronsPeripheral nervous systemDorsal root ganglion neuronsSensory neuronsVoltage-gated sodium channelsGanglion neuronsSodium channelsLarge-diameter dorsal root ganglion neuronsTonic action potential firingWhole-cell patch-clamp recordingsMultiple voltage-gated sodium channelsIntra-plantar injectionMechanosensitive sensory neuronsVivo behavioral assessmentsAction potential firingChannel activationPatch-clamp recordingsPotential therapeutic targetMechanical stimuliΒ-scorpion toxinSodium channel isoformsPain pathwaysThermal allodyniaPain generationSensory afferents
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 channels
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 potentialsCells
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 shiftActivationRednessMutations
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 StatementsConceptsDifferent 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 channelsCarbamazepine
2008
Voltage‐Gated Sodium Channels: Multiple Roles in the Pathophysiology of Pain
Dib‐Hajj S, Hains B, Black J, Waxman S. Voltage‐Gated Sodium Channels: Multiple Roles in the Pathophysiology of Pain. 2008, 67-104. DOI: 10.1002/9780470429907.ch3.Chapters
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 StatementsConceptsPain 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