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
Suppression of Kv3.3 channels by antisense oligonucleotides reverses biochemical effects and motor impairment in spinocerebellar ataxia type 13 mice
Zhang Y, Quraishi IH, McClure H, Williams LA, Cheng Y, Kale S, Dempsey GT, Agrawal S, Gerber DJ, McManus OB, Kaczmarek LK. Suppression of Kv3.3 channels by antisense oligonucleotides reverses biochemical effects and motor impairment in spinocerebellar ataxia type 13 mice. The FASEB Journal 2021, 35: e22053. PMID: 34820911, PMCID: PMC8630780, DOI: 10.1096/fj.202101356r.Peer-Reviewed Original ResearchConceptsHAX-1Wild-type animalsMultivesicular bodiesKv3.3 channelsLate endosomes/multivesicular bodiesTank Binding Kinase 1Type animalsCell survival proteinsDisease-causing mutationsVoltage-dependent potassium channelsSpinocerebellar ataxia type 13Survival proteinsKinase 1Mature intact animalsTBK1 activationAge-matched wild-type animalsLevels of CD63Progressive cerebellar degenerationWild-type miceMutationsProtein levelsMutant micePotassium channelsDependent potassium channelsType miceA KCNC1 mutation in epilepsy of infancy with focal migrating seizures produces functional channels that fail to be regulated by PKC phosphorylation
Zhang Y, Ali SR, Nabbout R, Barcia G, Kaczmarek LK. A KCNC1 mutation in epilepsy of infancy with focal migrating seizures produces functional channels that fail to be regulated by PKC phosphorylation. Journal Of Neurophysiology 2021, 126: 532-539. PMID: 34232791, PMCID: PMC8409950, DOI: 10.1152/jn.00257.2021.Peer-Reviewed Original ResearchConceptsFunctional channelsProtein kinase C.Serious human diseasesPotassium channelsWild-type channelsEpilepsy of infancyChannel modulationTerminal domainIon channel mutationsPKC phosphorylationC-terminusNormal neuronal functionChannel proteinsKv3.1 potassium channelRegulatory sitesKinase C.Human diseasesChannel functionPhosphorylationIon channelsMutationsNovo variantsChannel mutationsBiophysical propertiesNeuronal functionCerebellar Kv3.3 potassium channels activate TANK-binding kinase 1 to regulate trafficking of the cell survival protein Hax-1
Zhang Y, Varela L, Szigeti-Buck K, Williams A, Stoiljkovic M, Šestan-Peša M, Henao-Mejia J, D’Acunzo P, Levy E, Flavell RA, Horvath TL, Kaczmarek LK. Cerebellar Kv3.3 potassium channels activate TANK-binding kinase 1 to regulate trafficking of the cell survival protein Hax-1. Nature Communications 2021, 12: 1731. PMID: 33741962, PMCID: PMC7979925, DOI: 10.1038/s41467-021-22003-8.Peer-Reviewed Original ResearchConceptsTank Binding Kinase 1HAX-1Kv3.3 potassium channelMultivesicular bodiesKinase 1TANK-binding kinase 1Activation of caspasesAnti-apoptotic proteinsPotassium channelsMembrane proteinsBiochemical pathwaysCerebellar neuronsChannels bindCell deathTBK1 activityIon channelsMutant channelsCellular constituentsTraffickingKv3.3 channelsProteinNeuronal survivalMutationsChannel inactivationCaspasesPresynaptic Kv3 channels are required for fast and slow endocytosis of synaptic vesicles
Wu XS, Subramanian S, Zhang Y, Shi B, Xia J, Li T, Guo X, El-Hassar L, Szigeti-Buck K, Henao-Mejia J, Flavell RA, Horvath TL, Jonas EA, Kaczmarek LK, Wu LG. Presynaptic Kv3 channels are required for fast and slow endocytosis of synaptic vesicles. Neuron 2021, 109: 938-946.e5. PMID: 33508244, PMCID: PMC7979485, DOI: 10.1016/j.neuron.2021.01.006.Peer-Reviewed Original ResearchConceptsSlow endocytosisVesicle mobilizationF-actin cytoskeletonChannel mutationsPotassium channelsKv3.3 proteinsInhibits endocytosisRapid endocytosisNovel functionF-actinEndocytosisCrucial functionSynaptic vesiclesFamily channelsSynaptic transmissionDiscovery decadesMembrane potentialNeurotransmitter releaseDiverse neurological disordersIon conductanceMutationsReleasable poolMouse nerve terminalsPotassium channel mutationsPathological effects
2020
Impaired motor skill learning and altered seizure susceptibility in mice with loss or gain of function of the Kcnt1 gene encoding Slack (KNa1.1) Na+-activated K+ channels
Quraishi IH, Mercier MR, McClure H, Couture RL, Schwartz ML, Lukowski R, Ruth P, Kaczmarek LK. Impaired motor skill learning and altered seizure susceptibility in mice with loss or gain of function of the Kcnt1 gene encoding Slack (KNa1.1) Na+-activated K+ channels. Scientific Reports 2020, 10: 3213. PMID: 32081855, PMCID: PMC7035262, DOI: 10.1038/s41598-020-60028-z.Peer-Reviewed Original ResearchConceptsMaximum electroshock-induced seizuresEpilepsy of infancyPentylenetetrazole-induced seizuresVideo-EEG monitoringElectroshock-induced seizuresForms of epilepsyWild-type miceSlack channelsImpaired motor skillsProcedural motor learningMotor skillsWild-type animalsSevere intellectual disabilityOpen-field behaviorCortical seizuresKCNT1 geneSpontaneous seizuresFocal seizuresSeizure susceptibilitySeizure activityType miceMouse modelAnimal modelsInterictal spikesSeizures
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
An 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
Stimulation 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 disabilityActivatorKv3.3 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
Clinical whole-genome sequencing in severe early-onset epilepsy reveals new genes and improves molecular diagnosis
Martin HC, Kim GE, Pagnamenta AT, Murakami Y, Carvill GL, Meyer E, Copley RR, Rimmer A, Barcia G, Fleming MR, Kronengold J, Brown MR, Hudspith KA, Broxholme J, Kanapin A, Cazier JB, Kinoshita T, Nabbout R, Consortium T, Bentley D, McVean G, Heavin S, Zaiwalla Z, McShane T, Mefford HC, Shears D, Stewart H, Kurian MA, Scheffer IE, Blair E, Donnelly P, Kaczmarek LK, Taylor JC. Clinical whole-genome sequencing in severe early-onset epilepsy reveals new genes and improves molecular diagnosis. Human Molecular Genetics 2014, 23: 3200-3211. PMID: 24463883, PMCID: PMC4030775, DOI: 10.1093/hmg/ddu030.Peer-Reviewed Original ResearchMeSH KeywordsChildChild, PreschoolChromosomes, Human, Pair 9EpilepsyGenetic Predisposition to DiseaseGenome-Wide Association StudyHigh-Throughput Nucleotide SequencingHumansKCNQ2 Potassium ChannelMaleMembrane ProteinsMutationNAV1.2 Voltage-Gated Sodium ChannelNerve Tissue ProteinsPathology, MolecularPotassium ChannelsPotassium Channels, Sodium-ActivatedProto-Oncogene Proteins c-cblUniparental DisomyYoung AdultConceptsSevere early-onset epilepsyEarly-onset epilepsyOhtahara syndromeMolecular diagnosisWhole-genome sequencingClinical whole-genome sequencingPathogenic de novo mutationsHomozygous missense variantPotassium channel currentsSeizure typesO patientsDiagnostic yieldOS casesPatientsPower of WGSMolecular genetic diagnosisEpilepsyClinical phenotypeClinical diagnosisClinical toolHeterogeneous disorderDevelopmental delayDe novo mutationsDiagnosisMissense variants
2012
De 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
2008
Protein Kinase C Modulates Inactivation of Kv3.3 Channels*
Desai R, Kronengold J, Mei J, Forman SA, Kaczmarek LK. Protein Kinase C Modulates Inactivation of Kv3.3 Channels*. Journal Of Biological Chemistry 2008, 283: 22283-22294. PMID: 18539595, PMCID: PMC2494927, DOI: 10.1074/jbc.m801663200.Peer-Reviewed Original Research
2007
Bcl-xL Inhibitor ABT-737 Reveals a Dual Role for Bcl-xL in Synaptic Transmission
Hickman JA, Hardwick JM, Kaczmarek LK, Jonas EA. Bcl-xL Inhibitor ABT-737 Reveals a Dual Role for Bcl-xL in Synaptic Transmission. Journal Of Neurophysiology 2007, 99: 1515-1522. PMID: 18160428, PMCID: PMC2836590, DOI: 10.1152/jn.00598.2007.Peer-Reviewed Original ResearchConceptsMitochondrial outer membraneEndogenous Bcl-xLMitochondrial channel activityBcl-xLInhibitor ABT-737ABT-737Outer membraneBcl-xL.Pro-apoptotic cleavage productRecombinant Bcl-xLChannel activityBcl-xL proteinSynaptic functionDual roleGenetic toolsDomain pocketSynaptic transmissionSynaptic activityGiant presynaptic terminalEquivalent modificationEndogenous proteolysisRepetitive synaptic activityBH3Cleavage productsProtein
2005
Requirement of Voltage-Gated Calcium Channel ß4 Subunit for T Lymphocyte Functions
Badou A, Basavappa S, Desai R, Peng YQ, Matza D, Mehal WZ, Kaczmarek LK, Boulpaep EL, Flavell RA. Requirement of Voltage-Gated Calcium Channel ß4 Subunit for T Lymphocyte Functions. Science 2005, 307: 117-121. PMID: 15637280, DOI: 10.1126/science.1100582.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCalciumCalcium Channels, L-TypeCalcium SignalingCD4-Positive T-LymphocytesCytokinesDNA-Binding ProteinsIon Channel GatingLymphocyte ActivationMembrane PotentialsMiceMice, Inbred C3HMice, Inbred C57BLMutationNFATC Transcription FactorsNuclear ProteinsPatch-Clamp TechniquesPhosphorylationProtein SubunitsReceptors, Antigen, T-CellT-LymphocytesTranscription FactorsConceptsT lymphocytesCalcium channelsVoltage-gated calcium channelsT lymphocyte functionT cell receptor stimulationCell receptor stimulationCytokine productionLymphocyte functionCalcium influxReceptor stimulationCalcium responseCalcium entryTranscription factor NFATCav1 channelsLymphocytesAlpha1 subunitCav channelsNormal functionNonexcitable cellsDisplay impairmentsExcitable cellsChannel openingMolecular identityDiverse physiological processesPhysiological processes
2003
The Sodium-Activated Potassium Channel Is Encoded by a Member of the Slo Gene Family
Yuan A, Santi CM, Wei A, Wang Z, Pollak K, Nonet M, Kaczmarek L, Crowder CM, Salkoff L. The Sodium-Activated Potassium Channel Is Encoded by a Member of the Slo Gene Family. Neuron 2003, 37: 765-773. PMID: 12628167, DOI: 10.1016/s0896-6273(03)00096-5.Peer-Reviewed Original ResearchMeSH KeywordsAmino Acid SequenceAnimalsCaenorhabditis elegansCells, CulturedFemaleLarge-Conductance Calcium-Activated Potassium ChannelsMembrane PotentialsMolecular Sequence DataMultigene FamilyMutationNerve Tissue ProteinsOocytesPotassium ChannelsPotassium Channels, Calcium-ActivatedPotassium Channels, Sodium-ActivatedSequence Homology, Amino AcidSodiumXenopus
2001
Targeted Attenuation of Electrical Activity in Drosophila Using a Genetically Modified K+ Channel
White B, Osterwalder T, Yoon K, Joiner W, Whim M, Kaczmarek L, Keshishian H. Targeted Attenuation of Electrical Activity in Drosophila Using a Genetically Modified K+ Channel. Neuron 2001, 31: 699-711. PMID: 11567611, DOI: 10.1016/s0896-6273(01)00415-9.Peer-Reviewed Original ResearchMeSH KeywordsAdaptation, PhysiologicalAnimalsBehavior, AnimalCells, CulturedDrosophila melanogasterDrosophila ProteinsFemaleGene DosageGene Expression Regulation, DevelopmentalGene TargetingGenes, LethalLarvaMembrane PotentialsMusclesMutationNervous SystemNeural InhibitionNeuronsNeurons, AfferentPhenotypePhotoreceptor Cells, InvertebratePotassium ChannelsShaker Superfamily of Potassium ChannelsSynaptic TransmissionTransgenes