2025
Enhanced trafficking of an inherited erythromelalgia NaV1.7 mutant channel at a physiological temperature
Mis M, Tyagi S, Akin E, Ghovanloo M, Zhao P, Dib-Hajj F, Randall A, Waxman S, Dib-Hajj S. Enhanced trafficking of an inherited erythromelalgia NaV1.7 mutant channel at a physiological temperature. Neurobiology Of Pain 2025, 18: 100188. PMID: 40606587, PMCID: PMC12221430, DOI: 10.1016/j.ynpai.2025.100188.Peer-Reviewed Original ResearchMutant channelsIB4- neuronsInherited ErythromelalgiaEnhanced traffickingActivity of Nav1.7Expressed sodium channelsHuman pain disordersCurrent-clamp recordingsDRG sensory neuronsVoltage-clamp recordingsAttacks of burning painGain-of-function mutationsIncreased membrane insertionHyperpolarizing shiftNeuronal hyperexcitabilityPain disordersCurrent-clampNav1.7 channelsWT channelsSensory neuronsSodium channelsIncreased firingTemporary reliefNeuronsSkin temperatureMutant prion protein enhances NMDA receptor activity, activates PKC, and triggers rapid excitotoxicity in mice
Lin J, Callender J, Mayfield J, McClatchy D, Ojeda-Juárez D, Pourhamzeh M, Soldau K, Kurt T, Danque G, Khuu H, Ronson J, Pizzo D, Du Y, Gruber M, Sevillano A, Wang J, Orrú C, Chen J, Funk G, Aguilar-Calvo P, Aulston B, Roy S, Rho J, Bui J, Newton A, Lipton S, Caughey B, Patrick G, Doré K, Yates J, Sigurdson C. Mutant prion protein enhances NMDA receptor activity, activates PKC, and triggers rapid excitotoxicity in mice. Journal Of Clinical Investigation 2025, 135: e186432. PMID: 40185484, PMCID: PMC12077891, DOI: 10.1172/jci186432.Peer-Reviewed Original ResearchConceptsN-methyl-D-aspartate receptorsProtein kinase CAmino terminusPrion proteinN-methyl-D-aspartateMutant prion proteinNMDA receptor activationN-linked glycosylation sitesExcitatory-inhibitory imbalanceHippocampal pyramidal neuronsDownstream signaling eventsActivate protein kinase CNMDAR channelsNeuronal hyperexcitabilityFunctional motifsGlutamate receptorsCalcium influxPhosphoproteomic analysisPyramidal neuronsGlycosylation sitesSignaling eventsReceptor activationPrion-infected miceDendritic beadingSynapse loss
2024
TRPM8 Mutations Associated With Persistent Pain After Surgical Injury of Corneal Trigeminal Axons
Ghovanloo M, Effraim P, Tyagi S, Aldrich A, Cheng X, Yuan J, Schulman B, Jacobs D, Dib-Hajj S, Waxman S. TRPM8 Mutations Associated With Persistent Pain After Surgical Injury of Corneal Trigeminal Axons. Neurology Genetics 2024, 10: e200206. PMID: 39555137, PMCID: PMC11567650, DOI: 10.1212/nxg.0000000000200206.Peer-Reviewed Original ResearchLaser-assisted in situ keratomileusisPostoperative ocular painTrigeminal ganglion neuronsOcular painMultielectrode array recordingsPersistent painGanglion neuronsLaser-assisted in situ keratomileusis surgeryAxonal injuryRat trigeminal ganglion neuronsTransient receptor potential cation channelCorneal refractive surgeryMultielectrode arraysAnalysis of patientsPatch-clamp analysisGenomic analysis of patientsWild-typePatch-clamp resultsExposure to mentholRefractive surgeryHyperpolarizing directionNeuronal hyperexcitabilityPain-freeTrigeminal axonsWT channelsInterplay 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. 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 generationNeuro-oncologic Emergencies
Maciel C, Busl K. Neuro-oncologic Emergencies. CONTINUUM Lifelong Learning In Neurology 2024, 30: 845-877. PMID: 38830073, DOI: 10.1212/con.0000000000001435.Peer-Reviewed Original ResearchConceptsNeuro-oncologic emergenciesNeurological complicationsCentral nervous system malignanciesPrimary central nervous system malignancySystemic disease progressionTumor-specific characteristicsAcute neurologic complicationsNervous system malignanciesTreatment-resistant seizuresCSF flow dynamicsIntracranial burdenTumor-mediatedBrain metastasesImmunological therapiesNeuronal hyperexcitabilitySystem malignanciesTumor-relatedNeurotoxicity syndromeIntracranial hypertensionRisk stratificationFavorable outcomeTreatment-relatedSystem cancersDisease progressionComplicationsMolecular Pharmacology of Selective NaV1.6 and Dual NaV1.6/NaV1.2 Channel Inhibitors that Suppress Excitatory Neuronal Activity Ex Vivo
Goodchild S, Shuart N, Williams A, Ye W, Parrish R, Soriano M, Thouta S, Mezeyova J, Waldbrook M, Dean R, Focken T, Ghovanloo M, Ruben P, Scott F, Cohen C, Empfield J, Johnson J. Molecular Pharmacology of Selective NaV1.6 and Dual NaV1.6/NaV1.2 Channel Inhibitors that Suppress Excitatory Neuronal Activity Ex Vivo. ACS Chemical Neuroscience 2024, 15: 1169-1184. PMID: 38359277, PMCID: PMC10958515, DOI: 10.1021/acschemneuro.3c00757.Peer-Reviewed Original ResearchExcitatory pyramidal neuronsPyramidal neuronsNeuronal action potential firingSeizure modelsActivity of excitatory neuronsInhibition of firingAction potential firingVoltage-gated sodium channelsSuppress epileptiform activityTherapeutic safety marginActivity ex vivoNeuronal hyperexcitabilityInhibitory interneuronsChannel inhibitorsEpileptiform activityInhibitory neuronsPotential firingExcitatory neuronsAntiseizure medicationsExcitatory circuitsBrain slicesReduced excitabilityPharmacological dissectionAntiseizure medication carbamazepineSodium channels
2023
Comprehensive multi-omic profiling of somatic mutations in malformations of cortical development
Chung C, Yang X, Bae T, Vong K, Mittal S, Donkels C, Westley Phillips H, Li Z, Marsh A, Breuss M, Ball L, Garcia C, George R, Gu J, Xu M, Barrows C, James K, Stanley V, Nidhiry A, Khoury S, Howe G, Riley E, Xu X, Copeland B, Wang Y, Kim S, Kang H, Schulze-Bonhage A, Haas C, Urbach H, Prinz M, Limbrick D, Gurnett C, Smyth M, Sattar S, Nespeca M, Gonda D, Imai K, Takahashi Y, Chen H, Tsai J, Conti V, Guerrini R, Devinsky O, Silva W, Machado H, Mathern G, Abyzov A, Baldassari S, Baulac S, Gleeson J. Comprehensive multi-omic profiling of somatic mutations in malformations of cortical development. Nature Genetics 2023, 55: 209-220. PMID: 36635388, PMCID: PMC9961399, DOI: 10.1038/s41588-022-01276-9.Peer-Reviewed Original ResearchConceptsSingle-nucleus RNA sequencingSpatiotemporal expression patternsSomatic mutationsTarget amplicon sequencingLow allelic fractionsMulti-omics profilingGene setsRNA sequencingFunctional validationCellular organizationExpression patternsGenotype-phenotype correlation analysisGenetic landscapeCortical developmentMutationsGenetic causeUtero electroporationSomatic mosaic mutationsGenesCritical roleMosaic mutationsSequencingNeuronal hyperexcitabilityBrain resectionProfiling
2022
Stem cell-derived sensory neurons modelling inherited erythromelalgia: normalization of excitability
Alsaloum M, Labau JIR, Liu S, Effraim P, Waxman SG. Stem cell-derived sensory neurons modelling inherited erythromelalgia: normalization of excitability. Brain 2022, 146: 359-371. PMID: 35088838, PMCID: PMC10060693, DOI: 10.1093/brain/awac031.Peer-Reviewed Original ResearchConceptsSensory neuronsPluripotent stem cell-derived sensory neuronsDynamic clamp electrophysiologyMediators of painUnmet healthcare needsEffective therapeutic approachErythromelalgia mutationAmeliorate painNeuronal hyperexcitabilityPain disordersClinical studiesNeuronal excitabilityPreclinical studiesTherapeutic approachesEffective treatmentNaV1.7 currentsBaseline levelsClamp electrophysiologyHealthcare needsNav1.7 channelsPainErythromelalgiaHyperexcitabilityFunction mutationsNav1.7
2021
A novel gain-of-function sodium channel β2 subunit mutation in idiopathic small fiber neuropathy
Alsaloum M, Labau JIR, Sosniak D, Zhao P, Almomani R, Gerrits M, Hoeijmakers JGJ, Lauria G, Faber CG, Waxman SG, Dib-Hajj S. A novel gain-of-function sodium channel β2 subunit mutation in idiopathic small fiber neuropathy. Journal Of Neurophysiology 2021, 126: 827-839. PMID: 34320850, PMCID: PMC8461825, DOI: 10.1152/jn.00184.2021.Peer-Reviewed Original ResearchConceptsSmall fiber neuropathyVoltage-gated sodium channel α-subunitsDorsal root ganglion neuronsSodium channel β subunitsSodium channel α subunitDiscernible causeChannel α-subunitsGanglion neuronsChannel β subunitΒ2 subunitIdiopathic small fiber neuropathySodium currentTetrodotoxin-resistant sodium currentTetrodotoxin-sensitive sodium currentPainful diabetic neuropathySubset of patientsUnmyelinated C-fibersCurrent-clamp analysisAction potential firingHuman pain disordersFirst evidenceNeuropathic painDiabetic neuropathyNeuronal hyperexcitabilityPain disordersConditional RAC1 knockout in motor neurons restores H-reflex rate-dependent depression after spinal cord injury
Benson CA, Olson KL, Patwa S, Reimer ML, Bangalore L, Hill M, Waxman SG, Tan AM. Conditional RAC1 knockout in motor neurons restores H-reflex rate-dependent depression after spinal cord injury. Scientific Reports 2021, 11: 7838. PMID: 33837249, PMCID: PMC8035187, DOI: 10.1038/s41598-021-87476-5.Peer-Reviewed Original ResearchConceptsSpinal cord injuryDendritic spine dysgenesisMotor neuronsSpine dysgenesisSCI animalsHyperexcitability disordersCord injurySpinal alpha motor neuronsVentral horn motor neuronsAbnormal dendritic spine morphologyRac1 knockoutH-reflex pathwayRate-dependent depressionAlpha motor neuronsDevelopment of spasticityAdeno-associated viralMushroom dendritic spinesSpine head sizeOverall spine lengthDendritic spine morphologyRac1 protein expressionNeuronal hyperexcitabilityMajor complicationsClinical symptomsReflex excitability
2020
Preclinical insights into therapeutic targeting of KCC2 for disorders of neuronal hyperexcitability
Duy PQ, He M, He Z, Kahle KT. Preclinical insights into therapeutic targeting of KCC2 for disorders of neuronal hyperexcitability. Expert Opinion On Therapeutic Targets 2020, 24: 629-637. PMID: 32336175, PMCID: PMC8104019, DOI: 10.1080/14728222.2020.1762174.Peer-Reviewed Original ResearchConceptsNeuronal hyperexcitabilityKCC2 functionSynaptic inhibitionKCC2 activityPreclinical insightsRole of KCC2Treatment of epilepsyCommon neurological disorderNovel therapeutic strategiesPotential adverse effectsDrug targetsKCC2 dysfunctionSeizure reductionUnprovoked seizuresIntractable epilepsySeizure activityEpilepsy therapyCotransporter KCC2Clinical urgencyPreclinical proofTherapeutic benefitTherapeutic strategiesNew drug targetsTherapeutic targetingKCC2Differential effect of lacosamide on Nav1.7 variants from responsive and non-responsive patients with small fibre neuropathy
Labau J, Estacion M, Tanaka BS, de Greef B, Hoeijmakers J, Geerts M, Gerrits MM, Smeets H, Faber CG, Merkies I, Lauria G, Dib-Hajj SD, Waxman SG. Differential effect of lacosamide on Nav1.7 variants from responsive and non-responsive patients with small fibre neuropathy. Brain 2020, 143: 771-782. PMID: 32011655, PMCID: PMC7089662, DOI: 10.1093/brain/awaa016.Peer-Reviewed Original ResearchConceptsSmall fiber neuropathyEffects of lacosamideNon-responsive patientsSubset of patientsCommon pain disordersRecent clinical studiesUse-dependent inhibitionUse-dependent mannerVoltage-clamp recordingsPotent sodium channel inhibitorSlow inactivationSodium channel inhibitorsNeuronal hyperexcitabilityResponsive patientsPain disordersNav1.7 mutationClinical studiesAchievable concentrationsPatientsLacosamideNeuropathyChannel inhibitorsSodium channelsPainFunction mutations
2019
Potassium channel dysfunction in human neuronal models of Angelman syndrome
Sun A, Yuan Q, Fukuda M, Yu W, Yan H, Lim G, Nai M, D'Agostino G, Tran H, Itahana Y, Wang D, Lokman H, Itahana K, Lim S, Tang J, Chang Y, Zhang M, Cook S, Rackham O, Lim C, Tan E, Ng H, Lim K, Jiang Y, Je H. Potassium channel dysfunction in human neuronal models of Angelman syndrome. Science 2019, 366: 1486-1492. PMID: 31857479, PMCID: PMC7735558, DOI: 10.1126/science.aav5386.Peer-Reviewed Original ResearchConceptsAngelman syndromePotassium channel dysfunctionAS mouse modelUbiquitin protein ligase E3A (UBE3A) geneHuman neuronal modelNeuronal hyperexcitabilityNetwork hyperactivityAS patientsSeizure susceptibilitySynaptic dysfunctionModel miceIntrinsic excitabilityNeuronal excitabilityMouse modelBig potassium channelsHuman neuronsChannel dysfunctionEpilepsy susceptibilityBK channelopathyMouse neuronsPotassium channelsIndividual neuronsBrain organoidsNeuronsDysfunctionIdentification of KCC2 Mutations in Human Epilepsy Suggests Strategies for Therapeutic Transporter Modulation
Duy PQ, David WB, Kahle KT. Identification of KCC2 Mutations in Human Epilepsy Suggests Strategies for Therapeutic Transporter Modulation. Frontiers In Cellular Neuroscience 2019, 13: 515. PMID: 31803025, PMCID: PMC6873151, DOI: 10.3389/fncel.2019.00515.Peer-Reviewed Original ResearchHuman epilepsySignificant drug-related adverse effectsDrug-related adverse effectsMedication-refractory epilepsyDevelopment of epilepsyCommon neurological disorderPotential therapeutic strategyKCC2 dysfunctionNeuronal hyperexcitabilityGABA inhibitionGABAergic inhibitionSeizure disorderUnprovoked seizuresImpaired balanceKCC2 activityNeuronal excitabilityNeuronal excitationTherapeutic strategiesTransporter modulationEpileptic seizuresEpilepsyNeurological disordersChloride homeostasisSatisfactory treatmentAdverse effects
2018
Anti-nociceptive effects of bupivacaine-encapsulated PLGA nanoparticles applied to the compressed dorsal root ganglion in mice
Wang T, Hurwitz O, Shimada SG, Tian D, Dai F, Zhou J, Ma C, LaMotte RH. Anti-nociceptive effects of bupivacaine-encapsulated PLGA nanoparticles applied to the compressed dorsal root ganglion in mice. Neuroscience Letters 2018, 668: 154-158. PMID: 29355697, PMCID: PMC5829013, DOI: 10.1016/j.neulet.2018.01.031.Peer-Reviewed Original ResearchConceptsDorsal root gangliaBehavioral hypersensitivityNeuronal hyperexcitabilityRoot gangliaCompressed dorsal root ganglionNormal nociceptive responsesAnti-nociceptive effectsChronic neuropathic painPostoperative pain managementCentral nervous systemIntact DRGsL4 DRGChronic compressionIpsilateral pawNeuropathic painRadicular painHind pawsPain managementIpsilateral hindNociceptive informationNociceptive responsesPain behaviorIntervertebral foramenNociceptive stimuliLocal anesthetics
2014
Enhanced excitability of MRGPRA3- and MRGPRD-positive nociceptors in a model of inflammatory itch and pain
Qu L, Fan N, Ma C, Wang T, Han L, Fu K, Wang Y, Shimada SG, Dong X, LaMotte RH. Enhanced excitability of MRGPRA3- and MRGPRD-positive nociceptors in a model of inflammatory itch and pain. Brain 2014, 137: 1039-1050. PMID: 24549959, PMCID: PMC3959553, DOI: 10.1093/brain/awu007.Peer-Reviewed Original ResearchConceptsContact hypersensitivityPruriceptive neuronsEnhanced excitabilityNervous systemNociceptive dorsal root ganglion (DRG) neuronsSodium currentVehicle-treated control animalsDorsal root ganglion neuronsSquaric acid dibutyl esterItch-like behaviorsPain-related behaviorsResistant sodium currentsAllergic contact dermatitisAction potential activityWhole-cell recordingsInflammatory itchPersistent itchPruritic disordersSpontaneous itchSpontaneous scratchingAcute itchNeuronal hyperexcitabilityNociceptive neuronsPruritic diseasesCommon symptoms
2011
Rac1-regulated dendritic spine remodeling contributes to neuropathic pain after peripheral nerve injury
Tan AM, Chang YW, Zhao P, Hains BC, Waxman SG. Rac1-regulated dendritic spine remodeling contributes to neuropathic pain after peripheral nerve injury. Experimental Neurology 2011, 232: 222-233. PMID: 21963650, DOI: 10.1016/j.expneurol.2011.08.028.Peer-Reviewed Original ResearchConceptsDorsal horn neuronsPeripheral nerve injuryChronic constriction injuryWide dynamic range dorsal horn neuronsRange dorsal horn neuronsNerve injuryNeuropathic painDendritic spinesTactile allodyniaThermal hyperalgesiaSpine morphologyInjury-induced hyperexcitabilityNoxious peripheral stimuliSpinal cord injuryMushroom-shaped spinesDendritic spine developmentDendritic spine morphologyConstriction injuryHyperexcitable responsesCCI animalsNeuronal hyperexcitabilityIpsilateral hindNociceptive thresholdSpine densityCord injury
2009
Unilateral Focal Burn Injury Is Followed by Long-Lasting Bilateral Allodynia and Neuronal Hyperexcitability in Spinal Cord Dorsal Horn
Chang YW, Tan A, Saab C, Waxman S. Unilateral Focal Burn Injury Is Followed by Long-Lasting Bilateral Allodynia and Neuronal Hyperexcitability in Spinal Cord Dorsal Horn. Journal Of Pain 2009, 11: 119-130. PMID: 19744891, DOI: 10.1016/j.jpain.2009.06.009.Peer-Reviewed Original ResearchMeSH KeywordsAction PotentialsAnalysis of VarianceAnimalsBrain InjuriesCalcitonin Gene-Related PeptideCD11b AntigenDisease Models, AnimalFunctional LateralityHyperesthesiaMaleMicrogliap38 Mitogen-Activated Protein KinasesPainPain MeasurementPain ThresholdPhysical StimulationPosterior Horn CellsRatsSpinal CordSubstance PConceptsSpinal cord dorsal hornBurn injuryBurn injury modelBilateral allodyniaDorsal hornNeuronal hyperexcitabilityInjury modelSpinal cordDorsal horn neuronal hyperexcitabilitySecond-order sensory neuronsCentral neuropathic mechanismsIpsilateral mechanical allodyniaDorsal horn neuronsActivation of microgliaPathogenesis of painPotential therapeutic targetNovel animal modelContralateral allodyniaMechanical allodyniaNeuropathic mechanismsSpinal microgliaBilateral painMicroglial activationNerve injuryWeeks postinjury
2008
Neuropathic Pain Memory Is Maintained by Rac1-Regulated Dendritic Spine Remodeling after Spinal Cord Injury
Tan AM, Stamboulian S, Chang YW, Zhao P, Hains AB, Waxman SG, Hains BC. Neuropathic Pain Memory Is Maintained by Rac1-Regulated Dendritic Spine Remodeling after Spinal Cord Injury. Journal Of Neuroscience 2008, 28: 13173-13183. PMID: 19052208, PMCID: PMC6671613, DOI: 10.1523/jneurosci.3142-08.2008.Peer-Reviewed Original ResearchMeSH KeywordsAction PotentialsAnimalsComputer SimulationDendritic SpinesDisease Models, AnimalEnzyme ActivationEnzyme InhibitorsExcitatory Postsynaptic PotentialsHyperalgesiaLearningMaleMemoryNeuralgiaNeuronal PlasticityPain MeasurementPain ThresholdPosterior Horn Cellsrac1 GTP-Binding ProteinRatsRats, Sprague-DawleySpinal Cord InjuriesSynaptic TransmissionConceptsSpinal cord injuryNeuropathic painCord injuryWide dynamic range neuronsContusion spinal cord injuryDendritic spine pathologyInjury-induced hyperexcitabilityNoxious peripheral stimuliRats 1 monthChronic neuropathic painDorsal horn neuronsDendritic spine remodelingIncreased spine densityRange neuronsSpine morphometryDH neuronsTactile allodyniaNeuronal hyperexcitabilitySCI animalsThermal hyperalgesiaSham surgerySpine densityLamina IVControl neuronsSynaptic basis
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
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