2024
PAK1 inhibition with Romidepsin attenuates H‐reflex hyperexcitability after spinal cord injury
Kauer S, Benson C, Carrara J, Tarafder A, Ibrahim Y, Estacion M, Waxman S, Tan A. PAK1 inhibition with Romidepsin attenuates H‐reflex hyperexcitability after spinal cord injury. The Journal Of Physiology 2024 PMID: 39231098, DOI: 10.1113/jp284976.Peer-Reviewed Original ResearchDendritic spine dysgenesisSpinal cord injurySCI-induced spasticityRomidepsin treatmentSpine dysgenesisLoss of rate-dependent depressionCutaneous T-cell lymphomaTreatment of cutaneous T-cell lymphomaContusive spinal cord injuryT-cell lymphomaSpinal cord injury animalsCord injuryRate-dependent depressionExaggerated reflex responsesH-reflex changesSpinal cord injury mouse modelManaging spasticityReduce spasticityReporter micePreclinical utilityDrug responseRomidepsinControl cohortIntervention effectsSpinal hyperreflexiaTRPV1 corneal neuralgia mutation: Enhanced pH response, bradykinin sensitization, and capsaicin desensitization
Gualdani R, Barbeau S, Yuan J, Jacobs D, Gailly P, Dib-Hajj S, Waxman S. TRPV1 corneal neuralgia mutation: Enhanced pH response, bradykinin sensitization, and capsaicin desensitization. Proceedings Of The National Academy Of Sciences Of The United States Of America 2024, 121: e2406186121. PMID: 39226353, PMCID: PMC11406256, DOI: 10.1073/pnas.2406186121.Peer-Reviewed Original ResearchConceptsLaser-assisted in situ keratomileusisPhotorefractive keratectomyOcular Surface Disease Index scoreCapsaicin-induced desensitizationPhotorefractive keratectomy enhancementDisease Index scorePhysiological membrane potentialsCorneal neuralgiaTRPV1 variantsCorneal painRefractive surgeryRefractive errorCapsaicin desensitizationPersistent painBradykinin sensitivityNerve injuryM mutationPatch clampChannel activitySurgical techniqueLeftward shiftInflammatory mediatorsM-channelPainIndex scoreThe evolution of patch-clamp electrophysiology: robotic, multiplex, and dynamic.
Ghovanloo M, Dib-Hajj S, Waxman S. The evolution of patch-clamp electrophysiology: robotic, multiplex, and dynamic. Molecular Pharmacology 2024 PMID: 39164111, DOI: 10.1124/molpharm.124.000954.Peer-Reviewed Original ResearchPatch-clamp techniquePatch-clamp electrophysiologyPatch clampVoltage- and current-clamp modesIon channelsContribution of ion channelsCurrent-clamp modePatch-clamp methodOhm's lawDynamic-clampGating mechanisms of ion channelsMuscle cellsCardiac excitabilityGold standardExcitable cellsReceptorsGate conductionElectrophysiologyNeuronsElectrogenesisSimultaneous recordingCellsHigh-throughput automated platformMechanisms of ion channelsGating mechanismIon channels in osteoarthritis: emerging roles and potential targets
Zhou R, Fu W, Vasylyev D, Waxman S, Liu C. Ion channels in osteoarthritis: emerging roles and potential targets. Nature Reviews Rheumatology 2024, 20: 545-564. PMID: 39122910, DOI: 10.1038/s41584-024-01146-0.Peer-Reviewed Original ResearchIon channelsVoltage-dependent calcium channelsAcid-sensing ion channelsTransient receptor potential channelsVoltage-gated sodium channelsIon channel modulatorsFunction of ion channelsPotential clinical applicationsCalcium channelsPreclinical studiesClinical impactSymptomatic reliefPotassium channelsChloride channelsDisease-modifying treatmentsClinical trialsSodium channelsBone hyperplasiaChannel modulationIon channel biologySynovial inflammationClinical applicationPiezo channelsModel of OAPotential targetA FAIR, open-source virtual reality platform for dendritic spine analysis
Reimer M, Kauer S, Benson C, King J, Patwa S, Feng S, Estacion M, Bangalore L, Waxman S, Tan A. A FAIR, open-source virtual reality platform for dendritic spine analysis. Patterns 2024, 101041. DOI: 10.1016/j.patter.2024.101041.Peer-Reviewed Original ResearchVirtual realityVirtual reality platformSoftware ecosystemReality platformData standardSuperior accuracyDatasetWorkflowValidation processDendritic spine morphologySpine analysisDendritic spinesReconstruction techniqueSpine lengthMethod's superior accuracyDendritic spine lengthSpine morphologyMetricsMorphological metricsNeurodataFairnessDisordered but effective: short linear motifs as gene therapy targets for hyperexcitability disorders
Dib-Hajj S, Waxman S. Disordered but effective: short linear motifs as gene therapy targets for hyperexcitability disorders. Journal Of Clinical Investigation 2024, 134: e182198. PMID: 38949022, PMCID: PMC11213459, DOI: 10.1172/jci182198.Peer-Reviewed Original ResearchConceptsTetrodotoxin-sensitiveHyperexcitability disordersSensory neuronsExcitability of sensory neuronsGene therapy modalitiesPeripheral sensory neuronsVoltage-gated sodiumMinimal side effectsGene therapyInduce analgesiaTherapy modalitiesSide effectsTherapeutic strategiesNav channelsAttenuating excitationIn vivoHyperexcitabilityAnalgesiaNeuronsDisordersPainTherapyGenesBiodistributionRatsReal-time imaging of axonal membrane protein life cycles
Tyagi S, Higerd-Rusli G, Akin E, Baker C, Liu S, Dib-Hajj F, Waxman S, Dib-Hajj S. Real-time imaging of axonal membrane protein life cycles. Nature Protocols 2024, 1-32. PMID: 38831222, DOI: 10.1038/s41596-024-00997-x.Peer-Reviewed Reviews, Practice Guidelines, Standards, and Consensus StatementsMembrane proteinsRecycling of membrane proteinsProtein subcellular localizationMembrane protein homeostasisMembrane protein traffickingEngineered membrane proteinsMultiple membrane proteinsSelf-labeling tagsCell culturesProtein traffickingProtein tagsSubcellular localizationProtein homeostasisSpatiotemporal regulationCellular processesMultiple proteinsSubcellular distributionVesicular packagingThroughput mannerProteinNeuronal compartmentsDistal axonsProtein spatial organizationFluorescent labelingNeuronal culturesAuthor Correction: A multi-ancestry genetic study of pain intensity in 598,339 veterans
Toikumo S, Vickers-Smith R, Jinwala Z, Xu H, Saini D, Hartwell E, Pavicic M, Sullivan K, Xu K, Jacobson D, Gelernter J, Rentsch C, Stahl E, Cheatle M, Zhou H, Waxman S, Justice A, Kember R, Kranzler H. Author Correction: A multi-ancestry genetic study of pain intensity in 598,339 veterans. Nature Medicine 2024, 30: 2088-2088. PMID: 38714900, DOI: 10.1038/s41591-024-03024-4.Peer-Reviewed Original ResearchNav1.8 in small dorsal root ganglion neurons contributes to vincristine-induced mechanical allodynia
Nascimento de Lima A, Zhang H, Chen L, Effraim P, Gomis-Perez C, Cheng X, Huang J, Waxman S, Dib-Hajj S. Nav1.8 in small dorsal root ganglion neurons contributes to vincristine-induced mechanical allodynia. Brain 2024, 147: 3157-3170. PMID: 38447953, DOI: 10.1093/brain/awae071.Peer-Reviewed Original ResearchDorsal root ganglion neuronsDorsal root ganglionVincristine-induced mechanical allodyniaVincristine-induced peripheral neuropathyMechanical allodyniaVincristine treatmentNav1.8 channelsSmall dorsal root ganglion neuronsDevelopment of mechanical allodyniaTTX-R current densityVoltage-gated sodium channel Nav1.6Vincristine-treated animalsCurrent-clamp recordingsSodium channel Nav1.8Voltage-clamp recordingsReducing current thresholdSodium channel Nav1.6Investigate pathophysiological mechanismsTTX-RHyperpolarizing shiftRoot ganglionAllodyniaGanglion neuronsVincristine administrationPeripheral neuropathyA multi-ancestry genetic study of pain intensity in 598,339 veterans
Toikumo S, Vickers-Smith R, Jinwala Z, Xu H, Saini D, Hartwell E, Pavicic M, Sullivan K, Xu K, Jacobson D, Gelernter J, Rentsch C, Stahl E, Cheatle M, Zhou H, Waxman S, Justice A, Kember R, Kranzler H. A multi-ancestry genetic study of pain intensity in 598,339 veterans. Nature Medicine 2024, 30: 1075-1084. PMID: 38429522, DOI: 10.1038/s41591-024-02839-5.Peer-Reviewed Original ResearchPain intensityChronic painTreat chronic painCalcium channel blockersCross-ancestry meta-analysisGenome-wide association studiesExperience of painSamples of European ancestryPain phenotypesFunctional genomics dataGABAergic neuronsCalcium channelsAnalgesic effectB-blockersDrug groupMillion Veteran ProgramPainSubstance use disordersQuality of lifeDrug repurposing analysisOpioid crisisGenetic architectureCausal genesGenetic lociGenomic dataTRPM8 mutations associated with persistent ocular pain after refractive surgery: D665N and V915M
Ghovanloo M, Effraim P, Tyagi S, Cheng X, Yuan J, Schulman B, Jacobs D, Dib-Hajj S, Waxman S. TRPM8 mutations associated with persistent ocular pain after refractive surgery: D665N and V915M. Biophysical Journal 2024, 123: 391a. DOI: 10.1016/j.bpj.2023.11.2376.Peer-Reviewed Original ResearchA corneal neuralgia TRPV1 mutation increases response to acidic pH and alters agonist sensitization and desensitization
Gualdani R, Gailly P, Barbeau S, Jacobs D, Dib-Hajj S, Waxman S. A corneal neuralgia TRPV1 mutation increases response to acidic pH and alters agonist sensitization and desensitization. Biophysical Journal 2024, 123: 391a. DOI: 10.1016/j.bpj.2023.11.2378.Peer-Reviewed Original ResearchFunctionally-selective inhibition of threshold sodium currents and excitability in dorsal root ganglion neurons by cannabinol
Ghovanloo M, Effraim P, Tyagi S, Zhao P, Dib-Hajj S, Waxman S. Functionally-selective inhibition of threshold sodium currents and excitability in dorsal root ganglion neurons by cannabinol. Communications Biology 2024, 7: 120. PMID: 38263462, PMCID: PMC10805714, DOI: 10.1038/s42003-024-05781-x.Peer-Reviewed Original ResearchConceptsDorsal root ganglionDorsal root ganglion neuronal excitabilityDorsal root ganglion neuronsNeuronal excitabilityCurrent-clamp analysisSteady-state inactivationVoltage-dependent sodiumSlow inactivated stateAutomated patch clamp platformMultielectrode array recordingsNav currentsNeuropathic painSodium currentRoot ganglionGanglion neuronsSlow inactivationInactivated stateCurrent inhibitorsIon channelsNeuronsInhibitory effectCannabinolArray recordingsEndocannabinoidCannabinoidCompartment-specific regulation of NaV1.7 in sensory neurons after acute exposure to TNF-α
Tyagi S, Higerd-Rusli G, Ghovanloo M, Dib-Hajj F, Zhao P, Liu S, Kim D, Shim J, Park K, Waxman S, Choi J, Dib-Hajj S. Compartment-specific regulation of NaV1.7 in sensory neurons after acute exposure to TNF-α. Cell Reports 2024, 43: 113685. PMID: 38261513, PMCID: PMC10947185, DOI: 10.1016/j.celrep.2024.113685.Peer-Reviewed Original ResearchTNF-aSensory neuronsEffect of TNF-aSensory neuron excitabilityTumor necrosis factor-aRegulation of NaV1.7Voltage-gated sodiumPro-inflammatory cytokinesCompartment-specific effectsNeuronal plasma membraneSensitize nociceptorsNeuronal excitabilitySomatic membraneChannel N terminusElectrophysiological recordingsP38 MAPKIon channelsFactor AAcute exposureMolecular determinantsNeuronsAxonal endingsPhospho-acceptor sitesPlasma membraneCompartment-specific regulationNav1.7 as a chondrocyte regulator and therapeutic target for osteoarthritis
Fu W, Vasylyev D, Bi Y, Zhang M, Sun G, Khleborodova A, Huang G, Zhao L, Zhou R, Li Y, Liu S, Cai X, He W, Cui M, Zhao X, Hettinghouse A, Good J, Kim E, Strauss E, Leucht P, Schwarzkopf R, Guo E, Samuels J, Hu W, Attur M, Waxman S, Liu C. Nav1.7 as a chondrocyte regulator and therapeutic target for osteoarthritis. Nature 2024, 625: 557-565. PMID: 38172636, PMCID: PMC10794151, DOI: 10.1038/s41586-023-06888-7.Peer-Reviewed Original ResearchVoltage-gated sodium channelsOA progressionDorsal root ganglion neuronsStructural joint damagePain relief treatmentHuman OA chondrocytesCommon joint diseaseMultiple mouse modelsNav1.7 blockersPain behaviorGanglion neuronsPharmacological blockadeJoint damageJoint degenerationChannel blockersJoint diseaseOA chondrocytesMouse modelTherapeutic targetOsteoarthritisIntracellular Ca2Nav1.7Nav1.7 channelsGenetic ablationLimited evidence
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 hornIncreased astrocytic GLT-1 expression in tripartite synapses is associated with SCI-induced hyperreflexia
Benson C, King J, Kauer S, Waxman S, Tan A. Increased astrocytic GLT-1 expression in tripartite synapses is associated with SCI-induced hyperreflexia. Journal Of Neurophysiology 2023, 130: 1358-1366. PMID: 37877184, PMCID: PMC10972632, DOI: 10.1152/jn.00234.2023.Peer-Reviewed Original ResearchConceptsSpinal cord injuryRate-dependent depressionTripartite synapsesGLT-1Astrocytic GLT-1 expressionChronic neurological complicationsGLT-1 expressionAstrocyte involvementChronic spasticityUninjured shamsNeurological complicationsNeuropathic painHyperexcitability disordersH-reflexPSD-95 proteinReactive astrocytesVentral hornCord injuryMuscle toneAstrocytes' roleSpinal cordSpinal circuitsSynaptic transmissionHyperreflexiaSpasticityIh 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 ResearchConceptsFunction 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 firing9. THE GENETIC ARCHITECTURE OF PAIN INTENSITY IN THE MILLION VETERAN PROGRAM
Toikumo S, Vickers-Smith R, Jinwala Z, Xu H, Saini D, Hartwell E, Pavicic M, Sullivan K, Jacobson D, Cheatle M, Zhou H, Waxman S, Justice A, Kember R, Kranzler H. 9. THE GENETIC ARCHITECTURE OF PAIN INTENSITY IN THE MILLION VETERAN PROGRAM. European Neuropsychopharmacology 2023, 75: s60-s61. DOI: 10.1016/j.euroneuro.2023.08.120.Peer-Reviewed Original ResearchIndependent lociGenetic architectureMillion Veteran ProgramGenome-wide association testingIndependent genetic lociLinkage disequilibrium score regressionDrug-gene interaction databaseDisequilibrium score regressionNovel genetic variantsPotential drug targetsComplex traitsGWAS resultsCausal genesDruggable genomeDrug repurposing analysisGenetic lociDruggable genesInteraction databasesDrug targetsGenetic correlationsMolecular contributorsAssociation testingLociPsychiatric traitsScore regression