2018
NaV1.7 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
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 neuronsSubtype-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
2010
A 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
2006
Palytoxin-induced cell death cascade in bovine aortic endothelial cells
Schilling W, Snyder D, Sinkins W, Estacion M. Palytoxin-induced cell death cascade in bovine aortic endothelial cells. American Journal Of Physiology - Cell Physiology 2006, 291: c657-c667. PMID: 16672692, DOI: 10.1152/ajpcell.00063.2006.Peer-Reviewed Original ResearchMeSH KeywordsAcrylamidesAnimalsAortaCalciumCattleCell DeathCells, CulturedCnidarian VenomsComputer SystemsDose-Response Relationship, DrugDrug Administration ScheduleEndothelial CellsEthidiumFluorescent DyesGreen Fluorescent ProteinsIntracellular MembranesMicroscopy, VideoOsmolar ConcentrationOuabainPertussis ToxinPropidiumConceptsAortic endothelial cellsBovine aortic endothelial cellsEndothelial cellsConcentration-dependent increaseCell deathAddition of ouabainMonovalent cation channelCell death cascadeCell lysisMarine toxin palytoxinCation channelsOuabainOncotic cell deathEB uptakeATPase pumpDeath cascadeTime-lapse video microscopyPropidium iodideDeathYO-PRO-1ExtracellularEthidium bromideDownstream eventsRapid uptake
2005
Identification and localization of TRPC channels in the rat kidney
Goel M, Sinkins W, Zuo C, Estacion M, Schilling W. Identification and localization of TRPC channels in the rat kidney. American Journal Of Physiology. Renal Physiology 2005, 290: f1241-f1252. PMID: 16303855, DOI: 10.1152/ajprenal.00376.2005.Peer-Reviewed Original ResearchConceptsTubular cellsDuct cellsTransient receptor potential channelsG protein-coupled membrane receptorsPresence of TRPC1Aquaporin-2Western blot analysisMesangial cell culturesKidney sectionsProximal tubulesOuter medullaRat kidneyTRPC channelsRenal nephronKidney lysateTRPC3Immunopositive labelingTRPC1PLC-dependent signalingRat kidney lysateInner medullaAffinity-purified antibodiesPrinciple cellsPolarized culturesCell lines
2004
Maitotoxin Induces Biphasic Interleukin-1β Secretion and Membrane Blebbing in Murine Macrophages
Verhoef P, Kertesy S, Estacion M, Schilling W, Dubyak G. Maitotoxin Induces Biphasic Interleukin-1β Secretion and Membrane Blebbing in Murine Macrophages. Molecular Pharmacology 2004, 66: 909-920. PMID: 15385641, DOI: 10.1124/mol.66.4.909.Peer-Reviewed Original ResearchConceptsMTX treatmentMIL-1betaIL-1betaCytolytic releaseProIL-1betaProinflammatory cytokine interleukin-1betaProinflammatory cytokine secretionCytokine interleukin-1betaMature IL-1betaMurine macrophagesInterleukin-1β secretionCytokine releaseInflammatory leukocytesCytokine secretionP2X7 receptorInterleukin-1betaInflammatory macrophagesExtracellular Ca2Extracellular glycineIntracellular Ca2Vivo responseMacrophagesCation channelsSecretionLytic phaseAssociation of Immunophilins with Mammalian TRPC Channels*
Sinkins W, Goel M, Estacion M, Schilling W. Association of Immunophilins with Mammalian TRPC Channels*. Journal Of Biological Chemistry 2004, 279: 34521-34529. PMID: 15199065, DOI: 10.1074/jbc.m401156200.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBaculoviridaeBrainCalcium ChannelsCell LineDose-Response Relationship, DrugElectrophysiologyGlutamineHumansImmunoblottingImmunophilinsInsectaMutationPeptidesPrecipitin TestsProlineProtein BindingProtein Structure, TertiaryRatsTacrolimus Binding Protein 1ATacrolimus Binding ProteinsTime FactorsTRPC Cation ChannelsConceptsTRPC channel proteinsChannel proteinsMammalian TRPC channelsTRPC channelsHEK cellsBinding of FKBP12Rat brain lysatesImmunosuppressant drug FK506Receptor-mediated activationSf9 cellsAccessory proteinsRat cerebral cortexImmunophilinsDrug FK506Brain lysatesFKBP52FKBP12Membrane lysatesGln mutationINADProteinFKBP59SignalplexTRPC1Cerebral cortexMaitotoxin-induced cell death cascade in bovine aortic endothelial cells: divalent cation specificity and selectivity
Wisnoskey B, Estacion M, Schilling W. Maitotoxin-induced cell death cascade in bovine aortic endothelial cells: divalent cation specificity and selectivity. American Journal Of Physiology - Cell Physiology 2004, 287: c345-c356. PMID: 15044153, DOI: 10.1152/ajpcell.00473.2003.Peer-Reviewed Original ResearchConceptsCell death cascadeSingle-cell levelBovine aortic endothelial cellsDeath cascadeMembrane blebsAortic endothelial cellsCell population levelGreen fluorescent proteinSubsequent cell lysisPlasmalemmal permeabilityCell demiseEndothelial cellsFluorescent proteinLarge proteinsCation specificityNonselective cation channelsProteinCation channelsLytic phaseCytosolic freeCell lysisPropidium iodidePopulation levelEthidium bromideCascade
2003
P2X7 Receptor-Dependent Blebbing and the Activation of Rho-Effector Kinases, Caspases, and IL-1β Release
Verhoef P, Estacion M, Schilling W, Dubyak G. P2X7 Receptor-Dependent Blebbing and the Activation of Rho-Effector Kinases, Caspases, and IL-1β Release. The Journal Of Immunology 2003, 170: 5728-5738. PMID: 12759456, DOI: 10.4049/jimmunol.170.11.5728.Peer-Reviewed Original ResearchMeSH Keywords1-(5-Isoquinolinesulfonyl)-2-MethylpiperazineAdenosine TriphosphateAmidesAnimalsCaspase InhibitorsCaspasesCell LineEnzyme ActivationExtracellular SpaceHumansInterleukin-1Intracellular Signaling Peptides and ProteinsMacrophagesMiceProtein Serine-Threonine KinasesPseudopodiaPyridinesReceptors, Purinergic P2Receptors, Purinergic P2X7RhoA GTP-Binding ProteinRho-Associated KinasesSignal TransductionConceptsPlasma membrane organizationRho effector kinasesHuman embryonic kidney 293 cellsMurine macrophagesEmbryonic kidney 293 cellsPlasma membrane morphologyInhibitor KN-62Activation of RhoAKidney 293 cellsMembrane organizationTime-lapse moviesIL-1 beta releaseBlebbingKN-62Cation channel activationPore formationBiochemical analysisActivation signalsATPATP additionATP treatmentChannel activationAgonist BzATPATP concentrationCells
2002
Blockade of maitotoxin-induced endothelial cell lysis by glycine and l-alanine
Estacion M, Weinberg J, Sinkins W, Schilling W. Blockade of maitotoxin-induced endothelial cell lysis by glycine and l-alanine. American Journal Of Physiology - Cell Physiology 2002, 284: c1006-c1020. PMID: 12477666, DOI: 10.1152/ajpcell.00258.2002.Peer-Reviewed Original ResearchBlockade of maitotoxin-induced oncotic cell death reveals zeiosis
Estacion M, Schilling W. Blockade of maitotoxin-induced oncotic cell death reveals zeiosis. BMC Physiology 2002, 2: 2. PMID: 11825342, PMCID: PMC65053, DOI: 10.1186/1472-6793-2-2.Peer-Reviewed Original Research
2001
Regulation of Drosophila TRPL Channels by Immunophilin FKBP59*
Goel M, Garcia R, Estacion M, Schilling W. Regulation of Drosophila TRPL Channels by Immunophilin FKBP59*. Journal Of Biological Chemistry 2001, 276: 38762-38773. PMID: 11514552, DOI: 10.1074/jbc.m104125200.Peer-Reviewed Original ResearchMeSH KeywordsAmino Acid MotifsAmino Acid SequenceAnimalsBinding SitesCalciumCalmodulin-Binding ProteinsCationsCell LineChelating AgentsDNA, ComplementaryDrosophilaDrosophila ProteinsEgtazic AcidElectrophysiologyGene LibraryGlutathione TransferaseHumansImmunohistochemistryInsectaMembrane ProteinsMicroscopy, FluorescenceMolecular Sequence DataMutationPhotoreceptor Cells, InvertebratePolymerase Chain ReactionPrecipitin TestsProtein BindingProtein Structure, TertiaryRecombinant ProteinsSequence Homology, Amino AcidSignal TransductionTacrolimus Binding ProteinsTime FactorsTransient Receptor Potential ChannelsTwo-Hybrid System TechniquesConceptsS2 cellsTRPL channelsDrosophila head cDNA libraryDrosophila photoreceptor cellsHuman FK506-binding proteinMultimeric signaling complexesTwo-hybrid screenDrosophila S2 cellsDrosophila TRPL channelsSf9 cell lysatesFK506-binding proteinChannel activitySite-directed mutagenesisCytoplasmic membrane surfaceFura-2 assayTransient receptor potentialDrosophila homologPermeable cation channelSignaling ComplexNovel proteinCDNA librarySf9 cellsINADCytoplasmic mouthChannel regulationMaitotoxin-induced membrane blebbing and cell death in bovine aortic endothelial cells
Estacion M, Schilling W. Maitotoxin-induced membrane blebbing and cell death in bovine aortic endothelial cells. BMC Physiology 2001, 1: 2. PMID: 11231888, PMCID: PMC32181, DOI: 10.1186/1472-6793-1-2.Peer-Reviewed Original ResearchRegulation of Drosophila transient receptor potential‐like (TrpL) channels by phospholipase C‐dependent mechanisms
Estacion M, Sinkins W, Schilling W. Regulation of Drosophila transient receptor potential‐like (TrpL) channels by phospholipase C‐dependent mechanisms. The Journal Of Physiology 2001, 530: 1-19. PMID: 11136854, PMCID: PMC2278390, DOI: 10.1111/j.1469-7793.2001.0001m.x.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBaculoviridaeCalciumCalmodulin-Binding ProteinsCell LineCHO CellsCricetinaeDrosophilaDrosophila ProteinsFluorescent DyesFura-2Indicators and ReagentsMembrane PotentialsMembrane ProteinsOocytesPatch-Clamp TechniquesPhosphatidylinositol 4,5-DiphosphateSpodopteraTransient Receptor Potential ChannelsType C PhospholipasesXenopusConceptsPhospholipase CPhospholipase DDrosophila TRPL channelsTRPL channel activitySf9 insect cellsBacterial PI-PLCsPLC-dependent mechanismChannel activityFura-2 assayReceptor stimulationHydrolysis of PIP2Generation of diacylglycerolPoly-unsaturated fatty acidsTRPL channelsReceptor-mediated activationAddition of phosphatidylinositolInsect cellsExogenous applicationPI-PLCTransient receptor potential-like channelPC-PLCPIP2Spontaneous channel activityTRPLDiacylglycerol
1999
Stimulation of Drosophila TrpL by capacitative Ca2+ entry.
Estacion M, Sinkins W, Schilling W. Stimulation of Drosophila TrpL by capacitative Ca2+ entry. Biochemical Journal 1999, 341 ( Pt 1): 41-9. PMID: 10377243, PMCID: PMC1220328, DOI: 10.1042/0264-6021:3410041.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBariumBiological TransportCalciumCalcium-Transporting ATPasesCalmodulinCalmodulin-Binding ProteinsCations, DivalentDrosophilaDrosophila ProteinsEndoplasmic ReticulumHumansIon Channel GatingIon ChannelsLanthanumMembrane ProteinsPatch-Clamp TechniquesRecombinant Fusion ProteinsSpodopteraStrontiumThapsigarginTransient Receptor Potential ChannelsConceptsCapacitative Ca2Internal Ca2Receptor-activated channelsCell-attached patch recordingsTRP-like proteinsNon-selective cation channelsCytosolic free Ca2CBS-2Fura-2Cation entryPatch recordingsHuman TRPC1Single-channel activityDrosophila TRPLTRPL activityFree Ca2Dependent mechanismCation influxGel overlay experimentsCation channelsPhotoreceptor cellsChannel activityPhospholipase CTRPC1TRPL channel activity
1998
Functional expression of TrpC1: a human homologue of the Drosophila Trp channel
SINKINS W, ESTACION M, SCHILLING W. Functional expression of TrpC1: a human homologue of the Drosophila Trp channel. Biochemical Journal 1998, 331: 331-339. PMID: 9512497, PMCID: PMC1219356, DOI: 10.1042/bj3310331.Peer-Reviewed Original ResearchConceptsStore-operated channelsPost-infection timesBasal cytosolic free Ca2Mammalian cellsExpression of TRPC1Whole-cell membrane currentsSf9 cellsNon-selective cation channelsCytosolic free Ca2Drosophila TRP channelsSf9 insect cellsInternal Ca2Baculovirus expression systemPlasmalemmal Ca2Basal Ba2TRPC1Free Ca2TRP channelsCation channelsGluconate solutionMembrane currentsInsect cellsAdditional subunitsHuman homologueCytoplasmic factors