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 ResearchMeSH KeywordsAnimalsCHO CellsCricetinaeCricetulusEpilepsyMutationPhosphorylationProtein Kinase CShaw Potassium ChannelsSialyltransferasesConceptsFunctional 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 ResearchMeSH KeywordsActinsAnimalsCHO CellsCricetulusEndocytosisMiceMutationPresynaptic TerminalsShaw Potassium ChannelsSynaptic TransmissionSynaptic VesiclesConceptsSlow 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
2019
Modulators of Kv3 Potassium Channels Rescue the Auditory Function of Fragile X Mice
El-Hassar L, Song L, Tan WJT, Large CH, Alvaro G, Santos-Sacchi J, Kaczmarek LK. Modulators of Kv3 Potassium Channels Rescue the Auditory Function of Fragile X Mice. Journal Of Neuroscience 2019, 39: 4797-4813. PMID: 30936239, PMCID: PMC6561694, DOI: 10.1523/jneurosci.0839-18.2019.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAuditory PathwaysAuditory PerceptionBrain StemCochlear NucleusElectrophysiological PhenomenaEvoked Potentials, Auditory, Brain StemFemaleFragile X Mental Retardation ProteinFragile X SyndromeHydantoinsIn Vitro TechniquesMaleMiceMice, KnockoutPatch-Clamp TechniquesPyridinesShaw Potassium ChannelsConceptsAuditory brainstem responseWild-type animalsRepetitive firingABR wave ICurrent-clamp recordingsAuditory brainstem nucleiVoltage-clamp recordingsHigh-frequency firingSingle action potentialFragile X syndromeTrapezoid bodyBrainstem nucleiBrainstem responseMedial nucleusAuditory brainstemAuditory nerveWave IWave IVAction potentialsSensory stimuliKv3.1 channelsCentral processingMental retardation proteinHigh sound levelsMice
2018
C-terminal proline deletions in KCNC3 cause delayed channel inactivation and an adult-onset progressive SCA13 with spasticity
Khare S, Galeano K, Zhang Y, Nick JA, Nick HS, Subramony SH, Sampson J, Kaczmarek LK, Waters MF. C-terminal proline deletions in KCNC3 cause delayed channel inactivation and an adult-onset progressive SCA13 with spasticity. The Cerebellum 2018, 17: 692-697. PMID: 29949095, PMCID: PMC8299775, DOI: 10.1007/s12311-018-0950-5.Peer-Reviewed Original ResearchConceptsIon channel functionMammalian cell cultureMutant proteinsIntracellular cSpinocerebellar ataxia 13Autosomal dominant neurological diseaseChannel functionAllelic heterogeneityProline deletionSCA13 patientsTerminal portionProgressive clinical symptomsNormal membranesCell culturesProteinElectrophysiological characterizationChannel inactivationInactivationClinical symptomsElectrophysiological profileNeurological diseasesClinical importanceSCA13Slow inactivationDeletion
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 kinaseA KCNC3 mutation causes a neurodevelopmental, non-progressive SCA13 subtype associated with dominant negative effects and aberrant EGFR trafficking
Khare S, Nick JA, Zhang Y, Galeano K, Butler B, Khoshbouei H, Rayaprolu S, Hathorn T, Ranum LPW, Smithson L, Golde TE, Paucar M, Morse R, Raff M, Simon J, Nordenskjöld M, Wirdefeldt K, Rincon-Limas DE, Lewis J, Kaczmarek LK, Fernandez-Funez P, Nick HS, Waters MF. A KCNC3 mutation causes a neurodevelopmental, non-progressive SCA13 subtype associated with dominant negative effects and aberrant EGFR trafficking. PLOS ONE 2017, 12: e0173565. PMID: 28467418, PMCID: PMC5414954, DOI: 10.1371/journal.pone.0173565.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCHO CellsCricetinaeCricetulusDrosophila melanogasterErbB ReceptorsFemaleHumansMalePedigreeProtein TransportShaw Potassium ChannelsSpinocerebellar DegenerationsConceptsDominant negative effectEpidermal growth factor receptorGrowth factor receptorDrosophila epidermal growth factor receptorCongenital onsetPlasma membrane targetingMammalian cells resultsWild-type proteinHuman epidermal growth factor receptorFactor receptorMotor neuron pathologyDominant inheritanceSpinocerebellar ataxiaMembrane targetingEGFR traffickingAberrant retentionEye phenotypeMammalian cellsMammalian systemsVoltage-gated potassium channel KCNC3Autonomic dysfunctionEndosomal vesiclesNeuron pathologyCompensatory neural mechanismsPsychiatric manifestations
2016
Physiological 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
2015
Kv3.3 potassium channels and spinocerebellar ataxia
Zhang Y, Kaczmarek LK. Kv3.3 potassium channels and spinocerebellar ataxia. The Journal Of Physiology 2015, 594: 4677-4684. PMID: 26442672, PMCID: PMC4983625, DOI: 10.1113/jp271343.Peer-Reviewed Original ResearchConceptsPurkinje cellsPotassium channelsAuditory brainstem nucleiCentral nervous systemUnique neurodegenerative diseaseCerebellar Purkinje cellsVoltage-dependent potassium channelsSpinocerebellar ataxia type 13Neuronal survivalBrainstem nucleiExtracerebellar symptomsCerebellar degenerationNervous systemNeurodegenerative diseasesComplex spikesNormal functionKv3.3Disease-causing mutationsType 13Kv3.3 potassium channelSpinocerebellar ataxiaHigh rateCerebellumDifferent mutationsPhysiological functions
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 ResearchMeSH KeywordsAnimalsBrain StemCaenorhabditis elegansEvolution, MolecularMembrane PotentialsMiceMice, Inbred C57BLNeuronsPhosphorylationShaw Potassium ChannelsConceptsEffect 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 analysis
2011
Potassium 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 stimulationSpecific and rapid effects of acoustic stimulation on the tonotopic distribution of Kv3.1b potassium channels in the adult rat
Strumbos J, Polley D, Kaczmarek L. Specific and rapid effects of acoustic stimulation on the tonotopic distribution of Kv3.1b potassium channels in the adult rat. Neuroscience 2010, 167: 567-572. PMID: 20219640, PMCID: PMC2854512, DOI: 10.1016/j.neuroscience.2010.02.046.Peer-Reviewed Original ResearchMeSH KeywordsAcoustic StimulationAdaptation, PhysiologicalAnimalsAntibody SpecificityAuditory PathwaysAuditory ThresholdImmunohistochemistryIon Channel GatingNerve Tissue ProteinsNeuronal PlasticityRatsRats, Sprague-DawleyReaction TimeRhombencephalonShaw Potassium ChannelsSound LocalizationSynaptic TransmissionTime FactorsUp-RegulationConceptsTotal cellular levelsCytoplasmic C-terminusCellular levelVoltage-gated potassium channel subunitsPotassium channel subunitsTonotopic distributionAdult ratsC-terminusChannel proteinsChannel subunitsSound localization circuitIon channelsProteinExperience-dependent plasticityCultured neuronsPotassium channelsHigh-frequency stimuliAcute slicesMedial nucleusSynaptic activityAuditory neuronsKv3.1 proteinMin of exposureAction potentialsAcoustic stimulation
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
2006
Modulation of Kv3.1b Potassium Channel Phosphorylation in Auditory Neurons by Conventional and Novel Protein Kinase C Isozymes*
Song P, Kaczmarek LK. Modulation of Kv3.1b Potassium Channel Phosphorylation in Auditory Neurons by Conventional and Novel Protein Kinase C Isozymes*. Journal Of Biological Chemistry 2006, 281: 15582-15591. PMID: 16595659, DOI: 10.1074/jbc.m512866200.Peer-Reviewed Original ResearchConceptsAuditory neuronsMNTB neuronsTrapezoid bodyBrief high-frequency electrical stimulationProtein kinase CMetabotropic glutamate receptor activationHigh-frequency electrical stimulationBasal phosphorylationGlutamate receptor activationHigh-frequency stimulationFrequency electrical stimulationHigh-frequency firingMature nervous systemKv3.1 potassium channelNeuronal abilityBrainstem slicesMedial nucleusFrequency stimulationAuditory brainstemFrequency firingConventional protein kinase CPharmacological activationNervous systemElectrical stimulationPKC isozymes
2005
Aminoglycosides block the Kv3.1 potassium channel and reduce the ability of inferior colliculus neurons to fire at high frequencies
Liu S, Kaczmarek LK. Aminoglycosides block the Kv3.1 potassium channel and reduce the ability of inferior colliculus neurons to fire at high frequencies. Developmental Neurobiology 2005, 62: 439-452. PMID: 15547932, DOI: 10.1002/neu.20112.Peer-Reviewed Original ResearchConceptsInferior colliculus neuronsKv3.1 potassium channelColliculus neuronsKv3.1 currentsHearing lossAuditory neuronsPotassium channelsInhibition of Kv3.1Progressive hearing lossRate of repolarizationAuditory nucleiPotassium currentFiring propertiesPipette solutionAction potentialsNeuronsHigh frequencyEffect of streptomycinExtracellular TEAKv3.1 geneKv3.1 channelsAminoglycoside antibioticsStreptomycinKv3.1Presence of streptomycin
2004
Loss of Kv3.1 Tonotopicity and Alterations in cAMP Response Element-Binding Protein Signaling in Central Auditory Neurons of Hearing Impaired Mice
von Hehn CA, Bhattacharjee A, Kaczmarek LK. Loss of Kv3.1 Tonotopicity and Alterations in cAMP Response Element-Binding Protein Signaling in Central Auditory Neurons of Hearing Impaired Mice. Journal Of Neuroscience 2004, 24: 1936-1940. PMID: 14985434, PMCID: PMC6730406, DOI: 10.1523/jneurosci.4554-03.2004.Peer-Reviewed Original ResearchMeSH KeywordsAcoustic StimulationAge FactorsAnimalsAuditory PathwaysBrain StemCerebellumCyclic AMP Response Element-Binding ProteinDisease ProgressionMaleMiceMice, Inbred C57BLMice, Inbred CBAMice, Inbred DBANeuronsNeuropeptidesPhosphorylationPotassium ChannelsPotassium Channels, Voltage-GatedPresbycusisReflex, StartleShaw Potassium ChannelsConceptsCAMP response element-binding proteinResponse element-binding proteinTonotopic axisBL/6 miceElement-binding proteinCochlear hair cell lossPCREB-positive cellsAuditory brainstem neuronsCentral auditory neuronsHair cell lossCBA/JTranscription factor cAMP response element-binding proteinBrainstem neuronsKv3.1 potassium channel geneTrapezoid bodyImpaired miceMedial nucleusAuditory brainstemImmunopositive cellsAuditory neuronsMedial endPotassium channel genesGood hearingCell lossCREB expression