2023
Kv7-specific activators hyperpolarize resting membrane potential and modulate human iPSC-derived sensory neuron excitability
Estacion M, Liu S, Cheng X, Dib-Hajj S, Waxman S. Kv7-specific activators hyperpolarize resting membrane potential and modulate human iPSC-derived sensory neuron excitability. Frontiers In Pharmacology 2023, 14: 1138556. PMID: 36923357, PMCID: PMC10008904, DOI: 10.3389/fphar.2023.1138556.Peer-Reviewed Original ResearchA novel high throughput combined voltage-clamp/current-clamp analysis of single primary neurons
Ghovanloo M, Tyagi S, Zhao P, Kiziltug E, Estacion M, Dib-Hajj S, Waxman S. A novel high throughput combined voltage-clamp/current-clamp analysis of single primary neurons. Biophysical Journal 2023, 122: 101a. DOI: 10.1016/j.bpj.2022.11.734.Peer-Reviewed Original ResearchHigh-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
Fibroblast growth factor homologous factor 2 attenuates excitability of DRG neurons
Effraim PR, Estacion M, Zhao P, Sosniak D, Waxman SG, Dib-Hajj SD. Fibroblast growth factor homologous factor 2 attenuates excitability of DRG neurons. Journal Of Neurophysiology 2022, 128: 1258-1266. PMID: 36222860, PMCID: PMC9909838, DOI: 10.1152/jn.00361.2022.Peer-Reviewed Original ResearchConceptsDRG neuron excitabilityDRG neuronal excitabilityNeuronal excitabilityFibroblast growth factor homologous factorsNerve injuryDRG neuronsInflammatory mediatorsNeuron excitabilityDorsal root ganglion neuronsFunction of Nav1.7Peripheral nerve axotomyMultiple neurological disordersVoltage-gated sodium channelsDRG excitabilityFibroblast growth factor homologous factor 2Inflammatory painNerve axotomyGanglion neuronsIsoform-dependent mannerNeurological disordersBasal conditionsExcitabilityGating propertiesNeuron firingInjury
2020
Differential 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 mutationsA 49-residue sequence motif in the C terminus of Nav1.9 regulates trafficking of the channel to the plasma membrane
Sizova D, Huang J, Akin E, Estacion M, Gomis-Perez C, Waxman S, Dib-Hajj S. A 49-residue sequence motif in the C terminus of Nav1.9 regulates trafficking of the channel to the plasma membrane. Journal Of Biological Chemistry 2020, 295: 1077-1090. DOI: 10.1016/s0021-9258(17)49917-0.Peer-Reviewed Original ResearchPlasma membraneC-terminusHEK293 cellsHigh-resolution live microscopyC-terminal motifHeterologous expression systemC-terminal chimerasHigh-throughput assaysSequence motifsCytoplasmic faceHeterologous systemsVoltage-gated sodium channel Nav1.9Live microscopyRecombinant expressionExpression systemLong motifsMechanistic basisFunctional expressionFunctional studiesTerminusLow functional expressionMotifChannel chimeraExpression levelsChimeras
2018
Gain of Function NaV1.7 Mutations in Idiopathic Small Fiber Neuropathy
Faber C, Hoeijmakers J, Ahn H, Cheng X, Han C, Choi J, Estacion M, Lauria G, Vanhoutte E, Gerrits M, Dib-Hajj S, Drenth J, Waxman S, Merkies I. Gain of Function NaV1.7 Mutations in Idiopathic Small Fiber Neuropathy. 2018, 175-194. DOI: 10.7551/mitpress/10310.003.0022.Peer-Reviewed Original ResearchStructural Modelling and Mutant Cycle Analysis Predict Pharmacoresponsiveness of a NaV1.7 Mutant Channel
Yang Y, Dib-Hajj S, Zhang J, Zhang Y, Tyrrell L, Estacion M, Waxman S. Structural Modelling and Mutant Cycle Analysis Predict Pharmacoresponsiveness of a NaV1.7 Mutant Channel. 2018, 251-270. DOI: 10.7551/mitpress/10310.003.0029.Peer-Reviewed Original ResearchPharmacotherapy for Pain in a Family with Inherited Erythromelalgia Guided by Genomic Analysis and Functional Profiling
Geha P, Yang Y, Estacion M, Schulman B, Tokuno H, Apkarian A, Dib-Hajj S, Waxman S. Pharmacotherapy for Pain in a Family with Inherited Erythromelalgia Guided by Genomic Analysis and Functional Profiling. 2018, 275-288. DOI: 10.7551/mitpress/10310.003.0031.Peer-Reviewed Original ResearchNaV1.7 as a Pharmacogenomic Target for Pain: Moving Toward Precision Medicine
Yang Y, Mis MA, Estacion M, Dib-Hajj SD, Waxman SG. NaV1.7 as a Pharmacogenomic Target for Pain: Moving Toward Precision Medicine. Trends In Pharmacological Sciences 2018, 39: 258-275. PMID: 29370938, DOI: 10.1016/j.tips.2017.11.010.Peer-Reviewed Original ResearchConceptsChronic painPeripheral voltage-gated sodium channelsTreatment of painHuman translational studiesUnmet medical needInduced pluripotent stem cellsGlobal unmet medical needVoltage-gated sodium channelsVoltage-gated sodium channel NaPain pharmacotherapySodium channel NaPrecision pharmacotherapyPatient-specific induced pluripotent stem cellsSensory neuronsSide effectsTranslational studiesPainMedical needExisting treatmentsSodium channelsMost existing treatmentsChannel NaPrecision medicinePharmacotherapyPharmacogenomic targets
2017
Safety and efficacy of a Nav1.7 selective sodium channel blocker in patients with trigeminal neuralgia: a double-blind, placebo-controlled, randomised withdrawal phase 2a trial
Zakrzewska JM, Palmer J, Morisset V, Giblin GM, Obermann M, Ettlin DA, Cruccu G, Bendtsen L, Estacion M, Derjean D, Waxman SG, Layton G, Gunn K, Tate S, investigators S. Safety and efficacy of a Nav1.7 selective sodium channel blocker in patients with trigeminal neuralgia: a double-blind, placebo-controlled, randomised withdrawal phase 2a trial. The Lancet Neurology 2017, 16: 291-300. PMID: 28216232, DOI: 10.1016/s1474-4422(17)30005-4.Peer-Reviewed Original ResearchConceptsDouble-blind phaseFrequent adverse eventsOpen-label phaseSerious adverse eventsPhase 2a trialAdverse eventsTrigeminal neuralgiaSodium channel blockersTreatment failurePrimary endpointInteractive web response systemSelective sodium channel blockerPhase 2a studyCommon adverse eventsDouble-blind treatmentOpen-label treatmentSecondary care centresWeb response systemPhase 1 studyFuture clinical trialsSimilar adverse eventsNumber of patientsSodium channel blockers carbamazepineComputer-generated scheduleEligible patients
2016
Nav1.7-A1632G Mutation from a Family with Inherited Erythromelalgia: Enhanced Firing of Dorsal Root Ganglia Neurons Evoked by Thermal Stimuli
Yang Y, Huang J, Mis MA, Estacion M, Macala L, Shah P, Schulman BR, Horton DB, Dib-Hajj SD, Waxman SG. Nav1.7-A1632G Mutation from a Family with Inherited Erythromelalgia: Enhanced Firing of Dorsal Root Ganglia Neurons Evoked by Thermal Stimuli. Journal Of Neuroscience 2016, 36: 7511-7522. PMID: 27413160, PMCID: PMC6705539, DOI: 10.1523/jneurosci.0462-16.2016.Peer-Reviewed Original ResearchConceptsRat DRG neuronsDorsal root ganglion neuronsDRG neuronsCurrent-clamp recordingsSodium channel Nav1.7Pain syndromeNav1.7 mutationGanglion neuronsThermal stimuliIEM patientsChannel Nav1.7Whole-cell current-clamp recordingsNav1.7 channelsFunction Nav1.7 mutationsSevere pain syndromeVoltage-gated sodium channel Nav1.7Voltage-clamp recordingsMutant Nav1.7 channelsMean firing frequencyMultielectrode array recordingsMutant channelsG mutationMultigeneration familySpontaneous firingSympathetic neuronsPharmacotherapy 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 awakeningsPlaceboSubtype-Selective Small Molecule Inhibitors Reveal a Fundamental Role for Nav1.7 in Nociceptor Electrogenesis, Axonal Conduction and Presynaptic Release
Alexandrou AJ, Brown AR, Chapman ML, Estacion M, Turner J, Mis MA, Wilbrey A, Payne EC, Gutteridge A, Cox PJ, Doyle R, Printzenhoff D, Lin Z, Marron BE, West C, Swain NA, Storer RI, Stupple PA, Castle NA, Hounshell JA, Rivara M, Randall A, Dib-Hajj SD, Krafte D, Waxman SG, Patel MK, Butt RP, Stevens EB. Subtype-Selective Small Molecule Inhibitors Reveal a Fundamental Role for Nav1.7 in Nociceptor Electrogenesis, Axonal Conduction and Presynaptic Release. PLOS ONE 2016, 11: e0152405. PMID: 27050761, PMCID: PMC4822888, DOI: 10.1371/journal.pone.0152405.Peer-Reviewed Original ResearchConceptsPeripheral neuropeptide releaseSodium channel 1.7Dorsal hornPresynaptic releaseNociceptive signalingPain sensationAxonal conductionNeuropeptide releaseSpinal cordSynaptic transmissionPF-05089771Small molecule inhibitorsHuman nociceptorsAction potentialsNav1.7Nav1.7 inhibitorsUpstroke phaseHuman genetic studiesKey molecular determinantsNociceptorsSelective inhibitorMolecule inhibitorsRelative functional contributionInhibitorsFunctional contribution
2011
Intra- and Interfamily Phenotypic Diversity in Pain Syndromes Associated with a Gain-of-Function Variant of NaV1.7
Estación M, Han C, Choi JS, Hoeijmakers J, Lauria G, Drenth J, Gerrits MM, Dib-Hajj SD, Faber CG, Merkies I, Waxman SG. Intra- and Interfamily Phenotypic Diversity in Pain Syndromes Associated with a Gain-of-Function Variant of NaV1.7. Molecular Pain 2011, 7: 1744-8069-7-92. PMID: 22136189, PMCID: PMC3248882, DOI: 10.1186/1744-8069-7-92.Peer-Reviewed Original ResearchConceptsParoxysmal extreme pain disorderSmall fiber neuropathyDorsal root gangliaInherited ErythromelalgiaPain syndromeFunction variantsTrigeminal ganglionIdiopathic small fiber neuropathySevere facial painQuantitative sensory testingSympathetic ganglion neuronsDifferent clinical presentationsSodium channel Nav1.7Distal painNeuropathic painFacial painAutonomic symptomsDRG neuronsPain disordersClinical presentationClinical pictureSyndrome AssociatedGanglion neuronsRoot gangliaSkin biopsies
2010
Can 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 ResearchA sodium channel mutation linked to epilepsy increases ramp and persistent current of Nav1.3 and induces hyperexcitability in hippocampal neurons
Estacion M, Gasser A, Dib-Hajj SD, Waxman SG. A sodium channel mutation linked to epilepsy increases ramp and persistent current of Nav1.3 and induces hyperexcitability in hippocampal neurons. Experimental Neurology 2010, 224: 362-368. PMID: 20420834, DOI: 10.1016/j.expneurol.2010.04.012.Peer-Reviewed Original ResearchConceptsHippocampal neuronsCardiac muscle sodium channelsCryptogenic partial epilepsyHippocampal neuron excitabilitySodium channelsSomatic pain disordersDifferent sodium channel isoformsHuman chromosome 2Sodium channel isoformsPain disordersPartial epilepsyNeuron excitabilityPathophysiological basisExcitability disordersSpontaneous firingSodium channel mutationsGene SCN1ASodium channelopathiesCharge-neutralizing mutationsRamp currentsMuscle sodium channelsChromosome 2Channel isoformsChannel mutationsFunctional analysis
2009
Maitotoxin converts the plasmalemmal Ca2+ pump into a Ca2+-permeable nonselective cation channel
Sinkins W, Estacion M, Prasad V, Goel M, Shull G, Kunze D, Schilling W. Maitotoxin converts the plasmalemmal Ca2+ pump into a Ca2+-permeable nonselective cation channel. American Journal Of Physiology - Cell Physiology 2009, 297: c1533-c1543. PMID: 19794142, PMCID: PMC2793065, DOI: 10.1152/ajpcell.00252.2009.Peer-Reviewed Original ResearchMeSH KeywordsAdenosine TriphosphateAnimalsAnimals, Genetically ModifiedCalciumCation Transport ProteinsCationsCell MembraneCells, CulturedDown-RegulationElectric ConductivityFibroblastsHumansIon ChannelsKidneyMarine ToxinsMiceOxocinsPermeabilityPlasma Membrane Calcium-Transporting ATPasesRNA, Small InterferingSpodopteraUp-RegulationConceptsPermeable nonselective cation channelNonselective cation channelsCation channelsSpodoptera frugiperda (Sf9) insect cellsHEK cellsMouse embryonic fibroblastsHuman embryonic kidney 293 cellsEmbryonic kidney 293 cellsKidney 293 cellsInsect cellsEmbryonic fibroblastsWhole-cell membrane currentsMolecular identityCell membrane currentsCell typesPMCACytosolic freeMarine toxinsEnhanced expressionWhole-cell currentsPlasmalemmal Ca2PalytoxinATPaseCellsMaitotoxin
2008
NaV1.7 Gain-of-Function Mutations as a Continuum: A1632E Displays Physiological Changes Associated with Erythromelalgia and Paroxysmal Extreme Pain Disorder Mutations and Produces Symptoms of Both Disorders
Estacion M, Dib-Hajj SD, Benke PJ, Morsche R, Eastman EM, Macala LJ, Drenth JP, Waxman SG. NaV1.7 Gain-of-Function Mutations as a Continuum: A1632E Displays Physiological Changes Associated with Erythromelalgia and Paroxysmal Extreme Pain Disorder Mutations and Produces Symptoms of Both Disorders. Journal Of Neuroscience 2008, 28: 11079-11088. PMID: 18945915, PMCID: PMC6671384, DOI: 10.1523/jneurosci.3443-08.2008.Peer-Reviewed Original ResearchMeSH KeywordsAlanineAnimalsAnimals, NewbornCells, CulturedChildDose-Response Relationship, RadiationElectric StimulationErythromelalgiaGanglia, SpinalGlutamic AcidHumansMaleMembrane PotentialsModels, MolecularMutationNAV1.7 Voltage-Gated Sodium ChannelNeuronsPatch-Clamp TechniquesRatsRats, Sprague-DawleySodium ChannelsSomatoform DisordersTime FactorsTransfectionConceptsParoxysmal extreme pain disorderDorsal root gangliaTrigeminal ganglion neuronsClinical phenotypeGanglion neuronsMixed clinical phenotypePersistent inward currentsFunction mutationsPatch-clamp analysisPEPD mutationsPain disordersFast inactivationRoot gangliaInward currentsDistinct disordersCurrent clampErythromelalgiaDisordersPainChannel functionVoltage dependencePhysiological changesNeuronsIEMPhenotypeParoxysmal Extreme Pain Disorder M1627K Mutation in Human Nav1.7 Renders DRG Neurons Hyperexcitable
Dib-Hajj SD, Estacion M, Jarecki BW, Tyrrell L, Fischer TZ, Lawden M, Cummins TR, Waxman SG. Paroxysmal Extreme Pain Disorder M1627K Mutation in Human Nav1.7 Renders DRG Neurons Hyperexcitable. Molecular Pain 2008, 4: 1744-8069-4-37. PMID: 18803825, PMCID: PMC2556659, DOI: 10.1186/1744-8069-4-37.Peer-Reviewed Original ResearchConceptsParoxysmal extreme pain disorderDRG neuronsAction potentialsVoltage-gated sodium channel Nav1.7Severe pain episodesCurrent-clamp recordingsSingle action potentialSodium channel Nav1.7K mutationPain episodesPainful neuropathyPain disordersMutant channelsChannel Nav1.7Mandibular areaSporadic casesBowl movementRamp stimuliNeuronsClosed-state inactivationEnglish patientsPainPatientsK channelsFunction mutations