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 mutations
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
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 Research
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
2004
Association 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 cortexActivation of Human TRPC6 Channels by Receptor Stimulation*
Estacion M, Li S, Sinkins W, Gosling M, Bahra P, Poll C, Westwick J, Schilling W. Activation of Human TRPC6 Channels by Receptor Stimulation*. Journal Of Biological Chemistry 2004, 279: 22047-22056. PMID: 15023993, DOI: 10.1074/jbc.m402320200.Peer-Reviewed Original ResearchMeSH KeywordsCalcium ChannelsCarbacholCell LineCell MembraneCholinergic AgonistsDNA, ComplementaryDose-Response Relationship, DrugElectrophysiologyEnzyme InhibitorsHumansIonomycinIonophoresKineticsLac OperonMembrane PotentialsProtein BindingTetradecanoylphorbol AcetateThapsigarginTime FactorsTransfectionTRPC Cation ChannelsTRPC6 Cation ChannelConceptsReceptor stimulationTRPC6 currentsTRPC6 channelsSteep dose-response relationshipEffect of carbacholConcentrations of carbacholSteep concentration-response relationshipReceptor-mediated eventsActivation of TRPC6Channel activityDose-response relationshipWhole-cell membrane currentsSignificant acute effectConcentration-response relationshipCell membrane currentsAcute effectsCarbacholGeneration of DAGHuman embryonic kidney cellsPrior stimulationPatch pipetteTRPC6 activityEmbryonic kidney cellsMembrane currentsMembrane depolarization
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
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 regulation
1999
Maitotoxin activates a nonselective cation channel and a P2Z/P2X7-like cytolytic pore in human skin fibroblasts
Schilling W, Sinkins W, Estacion M. Maitotoxin activates a nonselective cation channel and a P2Z/P2X7-like cytolytic pore in human skin fibroblasts. American Journal Of Physiology 1999, 277: c755-c765. PMID: 10516106, DOI: 10.1152/ajpcell.1999.277.4.c755.Peer-Reviewed Original ResearchConceptsEffects of maitotoxinConcentration-dependent increaseNonselective cation channelsCation channelsHuman skin fibroblastsPlasmalemmal permeabilitySkin fibroblastsUptake of ethidiumIntracellular fura-2Cytolytic poreYO-PRO-1Permeable cation channelFura-2Receptor stimulationTypes of cellsCytosolic freeLactate dehydrogenaseMembrane currentsPotent cytolytic agentCytolytic agentsMaitotoxinCell typesPresent studyCell levelSingle-cell levelStimulation 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
1997
Mutations Causing Achondroplasia and Thanatophoric Dysplasia Alter bFGF-Induced Calcium Signals in Human Diploid Fibroblasts
Nguyen H, Estacion M, Gargus J. Mutations Causing Achondroplasia and Thanatophoric Dysplasia Alter bFGF-Induced Calcium Signals in Human Diploid Fibroblasts. Human Molecular Genetics 1997, 6: 681-688. PMID: 9158142, DOI: 10.1093/hmg/6.5.681.Peer-Reviewed Original ResearchMeSH KeywordsAchondroplasiaBradykininCalciumCell LineDiploidyFibroblast Growth Factor 2FibroblastsHomozygoteHumansMutationProtein-Tyrosine KinasesReceptor Protein-Tyrosine KinasesReceptor, Fibroblast Growth Factor, Type 1Receptor, Fibroblast Growth Factor, Type 2Receptor, Fibroblast Growth Factor, Type 3Receptors, Fibroblast Growth FactorRNA SplicingSignal TransductionThanatophoric DysplasiaConceptsThanatophoric dysplasiaCalcium signalsBasic fibroblast growth factorCell linesCalcium-imaging analysesFibroblast growth factorFibroblast growth factor receptor (FGFR) gene familyHuman diploid fibroblastsPathophysiological mechanismsIntracellular calciumBlinded studyFGFR3 mutationsUnresponsive linesReceptor functionHereditary disorderTransient increaseGrowth factorDiploid fibroblastsControl cellsBone developmentFibroblast cell lineCalcium wavesReceptor gene familyHeterogeneous signalsAchondroplasia