2022
The role of altered translation in intellectual disability and epilepsy
Malone TJ, Kaczmarek LK. The role of altered translation in intellectual disability and epilepsy. Progress In Neurobiology 2022, 213: 102267. PMID: 35364140, PMCID: PMC10583652, DOI: 10.1016/j.pneurobio.2022.102267.Peer-Reviewed Original ResearchConceptsIntellectual disabilityNeuronal stimulationLocal synaptic activityActivity-dependent changesActivity-dependent translationOverall excitabilitySynaptic activityEpileptic seizuresSynaptic componentsCellular compositionEpilepsyDisabilityIon channelsCell typesDisordersHigher proportionStimulationSeizuresStimuliWorld populationPopulationExcitabilityOriginal stimulusDiseaseMutations
2021
The NaVy paradox: reducing sodium currents increases excitability
Kaczmarek LK. The NaVy paradox: reducing sodium currents increases excitability. Trends In Neurosciences 2021, 44: 767-768. PMID: 34373125, PMCID: PMC8813127, DOI: 10.1016/j.tins.2021.07.008.Peer-Reviewed Original Research
2019
Phactr1 regulates Slack (KCNT1) channels via protein phosphatase 1 (PP1)
Ali SR, Malone TJ, Zhang Y, Prechova M, Kaczmarek LK. Phactr1 regulates Slack (KCNT1) channels via protein phosphatase 1 (PP1). The FASEB Journal 2019, 34: 1591-1601. PMID: 31914597, PMCID: PMC6956700, DOI: 10.1096/fj.201902366r.Peer-Reviewed Original ResearchConceptsProtein phosphatase 1Phosphatase 1Binding of PP1C-terminusCytoplasmic signaling proteinsCytoplasmic C-terminusActin-binding proteinsSlack channelsPKC phosphorylation sitesPhosphoprotein substratesDisease-causing mutationsPhosphorylation sitesSignaling proteinsSlack currentsHuman mutationsSodium-activated potassium channelsPHACTR1Slack genePotassium channelsProteinActinMutationsPatch-clamp recordingsCentral nervous systemMutantsAn Epilepsy-Associated KCNT1 Mutation Enhances Excitability of Human iPSC-Derived Neurons by Increasing Slack KNa Currents
Quraishi IH, Stern S, Mangan KP, Zhang Y, Ali SR, Mercier MR, Marchetto MC, McLachlan MJ, Jones EM, Gage FH, Kaczmarek LK. An Epilepsy-Associated KCNT1 Mutation Enhances Excitability of Human iPSC-Derived Neurons by Increasing Slack KNa Currents. Journal Of Neuroscience 2019, 39: 7438-7449. PMID: 31350261, PMCID: PMC6759030, DOI: 10.1523/jneurosci.1628-18.2019.Peer-Reviewed Original ResearchConceptsSevere epileptic encephalopathyAction potentialsEpileptic encephalopathyFiring rateCurrent-clamp recordingsSodium-activated potassium channelsMaximal firing rateIntensity of firingMean firing rateKCNT1 mutationsCortical neuronsCell-autonomous mechanismsEffective treatmentHuman neuronsPotassium currentActive neuronsNeuronsPotassium channelsCompensatory changesDisease-causing mutationsHyperexcitabilityHuman iPSCEncephalopathyExcitabilityStem cells
2017
Pharmacological modulation of Kv3.1 mitigates auditory midbrain temporal processing deficits following auditory nerve damage
Chambers AR, Pilati N, Balaram P, Large CH, Kaczmarek LK, Polley DB. Pharmacological modulation of Kv3.1 mitigates auditory midbrain temporal processing deficits following auditory nerve damage. Scientific Reports 2017, 7: 17496. PMID: 29235497, PMCID: PMC5727503, DOI: 10.1038/s41598-017-17406-x.Peer-Reviewed Original ResearchMeSH KeywordsAction PotentialsAnimalsAuditory PathwaysAuditory PerceptionCochlear NerveCompulsive BehaviorDisease Models, AnimalImidazolesMembrane Transport ModulatorsMesencephalonMiceModels, BiologicalNeuronsOuabainPyrimidinesRecovery of FunctionShaw Potassium ChannelsTissue Culture TechniquesVestibulocochlear Nerve DiseasesConceptsTemporal processing deficitsAuditory nerve damageCochlear nerve synapsesTemporal sound featuresCentral auditory pathwayAuditory brainstem neuronsPromising therapeutic approachPatch-clamp recordingsOtotoxic drug exposurePrecise temporal codingTemporal firing patternsHigh-threshold channelsVoltage-gated potassium channelsProcessing deficitsNerve damageBrainstem neuronsAfferent inputCentral neuronsDrug exposureAfferent synapsesContralateral earSystemic injectionCompensatory plasticityTherapeutic approachesAuditory cortexKv3 Channels: Enablers of Rapid Firing, Neurotransmitter Release, and Neuronal Endurance
Kaczmarek LK, Zhang Y. Kv3 Channels: Enablers of Rapid Firing, Neurotransmitter Release, and Neuronal Endurance. Physiological Reviews 2017, 97: 1431-1468. PMID: 28904001, PMCID: PMC6151494, DOI: 10.1152/physrev.00002.2017.Peer-Reviewed Original ResearchConceptsKv3 channelsAuditory brain stem neuronsNeurotransmitter releaseBrain stem neuronsOngoing neuronal activityFire action potentialsHigh-frequency firingChannel genesStem neuronsGABAergic interneuronsMultiple protein isoformsCertain neuronsProtein-protein interactionsNeuronal activityNeuronal functionAlzheimer's diseaseNeurological disordersAction potentialsPurkinje cellsUnique expression patternKv3 familyNeuronsAbnormal regulationProtein isoformsProtein kinaseAn ALS-Associated Mutant SOD1 Rapidly Suppresses KCNT1 (Slack) Na+-Activated K+ Channels in Aplysia Neurons
Zhang Y, Ni W, Horwich AL, Kaczmarek LK. An ALS-Associated Mutant SOD1 Rapidly Suppresses KCNT1 (Slack) Na+-Activated K+ Channels in Aplysia Neurons. Journal Of Neuroscience 2017, 37: 2258-2265. PMID: 28119399, PMCID: PMC5338764, DOI: 10.1523/jneurosci.3102-16.2017.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAplysiaBiophysicsCells, CulturedElectric StimulationEnzyme InhibitorsGanglia, InvertebrateHumansLuminescent ProteinsMembrane PotentialsMicroinjectionsMorpholinosMutationNerve Tissue ProteinsNeuronsPatch-Clamp TechniquesPotassium ChannelsPotassium Channels, Sodium-ActivatedRNA, Small InterferingSodiumSuperoxide Dismutase-1ConceptsAmyotrophic lateral sclerosisSuperoxide dismutase 1Mutant superoxide dismutase 1Potassium currentC-Jun N-terminal kinaseNeuronal excitabilityLateral sclerosisFatal adult-onset neurodegenerative diseaseN-terminal kinaseMutant human Cu/ZnNeuronal developmentDismutase 1Adult-onset neurodegenerative diseaseCurrent-clamp recordingsMotor neuron toxicityOutward potassium currentHuman Cu/ZnWild-type superoxide dismutase 1Neuron toxicityActivity of NaBag cell neuronsClamp recordingsNeuronal functionCell neuronsAction potentials
2016
Zika Virus Disrupts Phospho-TBK1 Localization and Mitosis in Human Neuroepithelial Stem Cells and Radial Glia
Onorati M, Li Z, Liu F, Sousa AMM, Nakagawa N, Li M, Dell’Anno M, Gulden FO, Pochareddy S, Tebbenkamp AT, Han W, Pletikos M, Gao T, Zhu Y, Bichsel C, Varela L, Szigeti-Buck K, Lisgo S, Zhang Y, Testen A, Gao XB, Mlakar J, Popovic M, Flamand M, Strittmatter SM, Kaczmarek LK, Anton ES, Horvath TL, Lindenbach BD, Sestan N. Zika Virus Disrupts Phospho-TBK1 Localization and Mitosis in Human Neuroepithelial Stem Cells and Radial Glia. Cell Reports 2016, 16: 2576-2592. PMID: 27568284, PMCID: PMC5135012, DOI: 10.1016/j.celrep.2016.08.038.Peer-Reviewed Original ResearchMeSH KeywordsAxl Receptor Tyrosine KinaseBrainCell DeathCentrosomeFetusGene Expression ProfilingHumansImmunity, InnateMicrocephalyMitochondriaMitosisNeocortexNeural Stem CellsNeuroepithelial CellsNeurogliaNeuronsNeuroprotective AgentsNucleosidesPhosphorylationProtein Kinase InhibitorsProtein Serine-Threonine KinasesProto-Oncogene ProteinsReceptor Protein-Tyrosine KinasesSpinal CordTranscription, GeneticVirus ReplicationZika VirusZika Virus InfectionConceptsRadial glial cellsNES cellsNeuroepithelial stem cellsZIKV infectionFetal brain slicesStem cellsEarly human neurodevelopmentHuman neuroepithelial stem cellsHuman neural stem cellsCell deathSingle-cell RNA-seqNeural stem cellsNeurodevelopment defectsZIKV replicationGlial cellsBrain slicesPotential treatmentRadial gliaZika virusPhospho-TBK1Neurodevelopmental defectsRNA-seqSupernumerary centrosomesNucleoside analoguesHuman neurodevelopmentStimulation of Slack K+ Channels Alters Mass at the Plasma Membrane by Triggering Dissociation of a Phosphatase-Regulatory Complex
Fleming MR, Brown MR, Kronengold J, Zhang Y, Jenkins DP, Barcia G, Nabbout R, Bausch AE, Ruth P, Lukowski R, Navaratnam DS, Kaczmarek LK. Stimulation of Slack K+ Channels Alters Mass at the Plasma Membrane by Triggering Dissociation of a Phosphatase-Regulatory Complex. Cell Reports 2016, 16: 2281-2288. PMID: 27545877, PMCID: PMC5123741, DOI: 10.1016/j.celrep.2016.07.024.Peer-Reviewed Original ResearchMeSH KeywordsAdaptor Proteins, Signal TransducingAnimalsBiosensing TechniquesBithionolBridged Bicyclo Compounds, HeterocyclicCell MembraneCerebral CortexFragile X Mental Retardation ProteinGene Expression RegulationHEK293 CellsHumansIon TransportMiceMice, KnockoutMicrofilament ProteinsMutationNerve Tissue ProteinsNeuronsPatch-Clamp TechniquesPhosphorylationPotassium ChannelsPotassium Channels, Sodium-ActivatedPrimary Cell CultureProtein BindingRNA, Small InterferingSignal TransductionThiazolidinesXenopus laevisConceptsProtein phosphatase 1Plasma membraneProtein kinase C.C-terminal residuesPhactr-1Potassium channelsPhosphatase 1Terminal domainSlack channelsHuman mutationsKinase C.Sodium-activated potassium channelsPharmacological activatorsOptical biosensor assayChannel stimulationSlack currentsBiosensor assaysMembraneMutantsPhosphorylationIntellectual disabilityProteinMutationsSevere intellectual disabilityActivatorPhysiological modulators of Kv3.1 channels adjust firing patterns of auditory brain stem neurons
Brown MR, El-Hassar L, Zhang Y, Alvaro G, Large CH, Kaczmarek LK. Physiological modulators of Kv3.1 channels adjust firing patterns of auditory brain stem neurons. Journal Of Neurophysiology 2016, 116: 106-121. PMID: 27052580, PMCID: PMC4961756, DOI: 10.1152/jn.00174.2016.Peer-Reviewed Original ResearchConceptsKv3.1 channelsAuditory brain stem neuronsAuditory brain stemBrain stem neuronsBrain slice recordingsKv3.1 potassium channelVoltage of activationMNTB neuronsStem neuronsTrapezoid bodyBrain stemMedial nucleusKv3.1 currentsNeuronal excitabilitySlice recordingsTherapeutic benefitImidazolidinedione derivativesAction potentialsPhysiological modulatorPotassium channelsResting potentialsNeuronsSingle-channel recordingsChinese hamster ovary cellsPharmaceutical modulationKv3.3 Channels Bind Hax-1 and Arp2/3 to Assemble a Stable Local Actin Network that Regulates Channel Gating
Zhang Y, Zhang XF, Fleming MR, Amiri A, El-Hassar L, Surguchev AA, Hyland C, Jenkins DP, Desai R, Brown MR, Gazula VR, Waters MF, Large CH, Horvath TL, Navaratnam D, Vaccarino FM, Forscher P, Kaczmarek LK. Kv3.3 Channels Bind Hax-1 and Arp2/3 to Assemble a Stable Local Actin Network that Regulates Channel Gating. Cell 2016, 165: 434-448. PMID: 26997484, PMCID: PMC4826296, DOI: 10.1016/j.cell.2016.02.009.Peer-Reviewed Original ResearchMeSH KeywordsActin CytoskeletonActin-Related Protein 2Actin-Related Protein 2-3 ComplexActin-Related Protein 3Adaptor Proteins, Signal TransducingAmino Acid SequenceCell MembraneMolecular Sequence DataMutationNeuronsPluripotent Stem CellsRac GTP-Binding ProteinsShaw Potassium ChannelsSignal TransductionSpinocerebellar AtaxiasConceptsCytoplasmic C-terminusProline-rich domainPlasma membraneHAX-1Actin nucleationC-terminusCortical actin filament networkLocal actin networkStem cell-derived neuronsActin filament networkCell-derived neuronsAnti-apoptotic proteinsActin cytoskeletonKv3.3 potassium channelActin assemblyActin structuresActin networkArp2/3Channel gatingFilament networkGrowth conesCerebellar neurodegenerationKv3.3TerminusPotassium channels
2014
More Than a Pore: Ion Channel Signaling Complexes
Lee A, Fakler B, Kaczmarek LK, Isom LL. More Than a Pore: Ion Channel Signaling Complexes. Journal Of Neuroscience 2014, 34: 15159-15169. PMID: 25392484, PMCID: PMC4228125, DOI: 10.1523/jneurosci.3275-14.2014.Peer-Reviewed Original ResearchConceptsIon channelsHeterologous expression systemIon channel complexSignaling ComplexFunctional dissectionHuman genomeMolecular basisExpression systemSecond messengerHuman diseasesChannel complexCellular excitabilityProteinNew insightsSuch interactionsInteractomeGenomeUnexpected propertiesComplexesMessengerPathwayInteractionDysregulationLocalizationVivoUse of label-free optical biosensors to detect modulation of potassium channels by G-protein coupled receptors.
Fleming MR, Shamah SM, Kaczmarek LK. Use of label-free optical biosensors to detect modulation of potassium channels by G-protein coupled receptors. Journal Of Visualized Experiments 2014, e51307. PMID: 24562095, PMCID: PMC4122194, DOI: 10.3791/51307.Peer-Reviewed Original ResearchConceptsG protein-coupled receptorsOptical biosensorPlasma membraneLabel-free optical biosensorProtein-protein interactionsIon channelsChannel-protein interactionsExcitable cell typesReceptor tyrosine kinasesProtein-coupled receptorsLigand-induced changesCell surface receptorsPotassium channelsRegulatory proteinsTyrosine kinaseG proteinsProtein behaviorSodium-activated potassium channelsExogenous labelsPhysiological relevanceCell adhesionLiving cellsCell typesHeteromeric channelsSurface receptorsDisrupted in Schizophrenia 1 Modulates Medial Prefrontal Cortex Pyramidal Neuron Activity Through cAMP Regulation of Transient Receptor Potential C and Small-Conductance K+ Channels
El-Hassar L, Simen AA, Duque A, Patel KD, Kaczmarek LK, Arnsten AF, Yeckel MF. Disrupted in Schizophrenia 1 Modulates Medial Prefrontal Cortex Pyramidal Neuron Activity Through cAMP Regulation of Transient Receptor Potential C and Small-Conductance K+ Channels. Biological Psychiatry 2014, 76: 476-485. PMID: 24560582, PMCID: PMC4104266, DOI: 10.1016/j.biopsych.2013.12.019.Peer-Reviewed Original ResearchConceptsCyclic adenosine monophosphateIntracellular Ca2Prefrontal cortical pyramidal neuronsReceptor-mediated intracellular Ca2Regulation of cAMPPrefrontal cortical slicesCortical pyramidal neuronsDISC1 functionMajor depressive disorderPyramidal neuron activityPatch-clamp recordingsTRPC channel activityDISC1 disruptionPrefrontal cortex activityPyramidal neuronsCortical slicesDepressive disorderAdult ratsIntracellular calcium wavesSustained depolarizationViral knockdownNeuron activityBipolar disorderMental disordersCAMP generation
2012
An evolutionarily conserved mode of modulation of Shaw‐like K+ channels
Cotella D, Hernandez‐Enriquez B, Duan Z, Wu X, Gazula V, Brown MR, Kaczmarek LK, Sesti F. An evolutionarily conserved mode of modulation of Shaw‐like K+ channels. The FASEB Journal 2012, 27: 1381-1393. PMID: 23233530, PMCID: PMC3606535, DOI: 10.1096/fj.12-222778.Peer-Reviewed Original ResearchConceptsEffect of phosphorylationC. elegansACP-2Acid phosphataseMammalian homologMammalian homologueCaenorhabditis elegansMouse nervous systemRegulatory partnersBiochemical experimentsMolecular mechanismsElegansBehavioral defectsMode of modulationPhosphorylationPharmacological disruptionShaw familyMammalian brainSubset of neuronsVentricular zonePhosphataseModel systemNervous systemMice resultsElectrophysiological analysisRegulation of Neuronal Excitability by Interaction of Fragile X Mental Retardation Protein with Slack Potassium Channels
Zhang Y, Brown MR, Hyland C, Chen Y, Kronengold J, Fleming MR, Kohn AB, Moroz LL, Kaczmarek LK. Regulation of Neuronal Excitability by Interaction of Fragile X Mental Retardation Protein with Slack Potassium Channels. Journal Of Neuroscience 2012, 32: 15318-15327. PMID: 23115170, PMCID: PMC3518385, DOI: 10.1523/jneurosci.2162-12.2012.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAnisomycinAplysiaCHO CellsCloning, MolecularCricetinaeCricetulusElectrophysiological PhenomenaFragile X Mental Retardation ProteinImmunohistochemistryImmunoprecipitationNeuronsPatch-Clamp TechniquesPotassium ChannelsProtein Synthesis InhibitorsRNA InterferenceRNA, Small InterferingSodiumSynapsesConceptsNeuronal excitabilitySlack potassium channelsTetrodotoxin-sensitive componentCurrent-clamp recordingsSlack channelsMental retardation proteinBag cell neuronsSustained componentIntracellular injectionNeuronal firingInhibitory periodSynaptic stimulationPotassium currentCell neuronsAction potentialsOutward currentsPotassium channelsProlonged changesNeuronsAplysia bag cell neuronsProtein synthesis inhibitor anisomycinExcitabilityFragile X Mental Retardation ProteinCommon formIntellectual disabilityDe novo gain-of-function KCNT1 channel mutations cause malignant migrating partial seizures of infancy
Barcia G, Fleming MR, Deligniere A, Gazula VR, Brown MR, Langouet M, Chen H, Kronengold J, Abhyankar A, Cilio R, Nitschke P, Kaminska A, Boddaert N, Casanova JL, Desguerre I, Munnich A, Dulac O, Kaczmarek LK, Colleaux L, Nabbout R. De novo gain-of-function KCNT1 channel mutations cause malignant migrating partial seizures of infancy. Nature Genetics 2012, 44: 1255-1259. PMID: 23086397, PMCID: PMC3687547, DOI: 10.1038/ng.2441.Peer-Reviewed Original Research
2011
Bcl-xL regulates mitochondrial energetics by stabilizing the inner membrane potential
Chen YB, Aon MA, Hsu YT, Soane L, Teng X, McCaffery JM, Cheng WC, Qi B, Li H, Alavian KN, Dayhoff-Brannigan M, Zou S, Pineda FJ, O'Rourke B, Ko YH, Pedersen PL, Kaczmarek LK, Jonas EA, Hardwick JM. Bcl-xL regulates mitochondrial energetics by stabilizing the inner membrane potential. Journal Of Cell Biology 2011, 195: 263-276. PMID: 21987637, PMCID: PMC3198165, DOI: 10.1083/jcb.201108059.Peer-Reviewed Original ResearchConceptsMitochondrial membrane potentialMitochondrial membraneMitochondrial ATP synthase β-subunitATP synthase β subunitBcl-2 family proteinsOuter membrane permeabilizationInner mitochondrial membrane potentialMembrane potentialMitochondrial energetic capacityOuter mitochondrial membraneSynthase β subunitInner mitochondrial membraneInner membrane potentialATP synthaseFamily proteinsBiochemical approachesGenetic evidenceEndogenous BclMembrane permeabilizationCellular resourcesΒ-subunitBcl-xLMitochondrial energeticsEnergetic capacityMitochondrial cristaePotassium channel modulation and auditory processing
Brown MR, Kaczmarek LK. Potassium channel modulation and auditory processing. Hearing Research 2011, 279: 32-42. PMID: 21414395, PMCID: PMC3137660, DOI: 10.1016/j.heares.2011.03.004.Peer-Reviewed Original ResearchConceptsAuditory brainstem nucleiBrainstem nucleiPotassium channelsPotassium channel modulationSynaptic stimulationFiring patternsOverall sensitivityChannel modulationNeuronsAuditory environmentAuditory processingAuditory systemHigh rateAuditory informationIntrinsic electrical propertiesKey proteinsReview article
2010
Fragile X Mental Retardation Protein Is Required for Rapid Experience-Dependent Regulation of the Potassium Channel Kv3.1b
Strumbos JG, Brown MR, Kronengold J, Polley DB, Kaczmarek LK. Fragile X Mental Retardation Protein Is Required for Rapid Experience-Dependent Regulation of the Potassium Channel Kv3.1b. Journal Of Neuroscience 2010, 30: 10263-10271. PMID: 20685971, PMCID: PMC3485078, DOI: 10.1523/jneurosci.1125-10.2010.Peer-Reviewed Original ResearchConceptsMental retardation proteinAnterior ventral cochlear nucleusFragile X Mental Retardation ProteinRNA-binding proteinProtein translationFMRPWild-type animalsSpecific mRNAsSound localization circuitVentral cochlear nucleusBrainstem synaptosomesExperience-dependent regulationProtein levelsAmplitude-modulated stimuliProteinTrapezoid bodyCochlear nucleusMale miceMedial nucleusNeuronal activityPotassium currentWT controlsSynaptic plasticityTonotopic axisAcoustic stimulation