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
An 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 disabilityActivator
2015
The sodium-activated potassium channel Slack is required for optimal cognitive flexibility in mice
Bausch AE, Dieter R, Nann Y, Hausmann M, Meyerdierks N, Kaczmarek LK, Ruth P, Lukowski R. The sodium-activated potassium channel Slack is required for optimal cognitive flexibility in mice. Learning & Memory 2015, 22: 323-335. PMID: 26077685, PMCID: PMC4478330, DOI: 10.1101/lm.037820.114.Peer-Reviewed Original ResearchConceptsFragile X Mental Retardation ProteinCognitive flexibilityFragile X syndromeNormal working memoryAspects of memoryIntellectual disabilityMental retardation proteinSpatial learning capabilitiesSlack channelsWorking memoryBehavioral tasksReference memorySodium-activated potassium channel SlackHigher brain functionsUnfamiliar situationsBrain functionSevere intellectual disabilityMemoryIntellectual developmentSodium-activated potassium channelsNull mouse modelGeneral locomotor activityX syndromeProper functionLearning capabilities
2014
Human Slack Potassium Channel Mutations Increase Positive Cooperativity between Individual Channels
Kim GE, Kronengold J, Barcia G, Quraishi IH, Martin HC, Blair E, Taylor JC, Dulac O, Colleaux L, Nabbout R, Kaczmarek LK. Human Slack Potassium Channel Mutations Increase Positive Cooperativity between Individual Channels. Cell Reports 2014, 9: 1661-1672. PMID: 25482562, PMCID: PMC4294418, DOI: 10.1016/j.celrep.2014.11.015.Peer-Reviewed Original ResearchUse 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 receptorsClinical 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 variantsDisrupted 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
2010
Fragile X mental retardation protein controls gating of the sodium-activated potassium channel Slack
Brown MR, Kronengold J, Gazula VR, Chen Y, Strumbos JG, Sigworth FJ, Navaratnam D, Kaczmarek LK. Fragile X mental retardation protein controls gating of the sodium-activated potassium channel Slack. Nature Neuroscience 2010, 13: 819-821. PMID: 20512134, PMCID: PMC2893252, DOI: 10.1038/nn.2563.Peer-Reviewed Original ResearchThe Slack Sodium-Activated Potassium Channel Provides a Major Outward Current in Olfactory Neurons of Kv1.3−/− Super-Smeller Mice
Lu S, Das P, Fadool DA, Kaczmarek LK. The Slack Sodium-Activated Potassium Channel Provides a Major Outward Current in Olfactory Neurons of Kv1.3−/− Super-Smeller Mice. Journal Of Neurophysiology 2010, 103: 3311-3319. PMID: 20393063, PMCID: PMC2888249, DOI: 10.1152/jn.00607.2009.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAnimals, NewbornBiophysicsCardiovascular AgentsCells, CulturedElectric StimulationGene Expression RegulationIn Vitro TechniquesKv1.3 Potassium ChannelMembrane PotentialsMiceMice, Inbred C57BLMice, KnockoutNerve Tissue ProteinsNeuronsOlfactory BulbPatch-Clamp TechniquesPotassium ChannelsPotassium Channels, Sodium-ActivatedPyrimidinesRNA InterferenceSodium Channel BlockersTetrodotoxinTransfectionConceptsMitral cellsOlfactory bulbOutward currentsOlfactory neuronsWildtype animalsPotassium channelsMajor outward currentVoltage-clamp recordingsVoltage-dependent potassium channelsNet outward currentIntracellular sodiumOB slicesPotassium channel genesCompensatory increaseFiring patternsWestern blottingRNA interference approachPrimary culturesEnhanced expressionDetection of odorsSame treatmentChannel genesMiceNeuronsOlfactory phenotypesSpecific 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
2009
The N-Terminal Domain of Slack Determines the Formation and Trafficking of Slick/Slack Heteromeric Sodium-Activated Potassium Channels
Chen H, Kronengold J, Yan Y, Gazula VR, Brown MR, Ma L, Ferreira G, Yang Y, Bhattacharjee A, Sigworth FJ, Salkoff L, Kaczmarek LK. The N-Terminal Domain of Slack Determines the Formation and Trafficking of Slick/Slack Heteromeric Sodium-Activated Potassium Channels. Journal Of Neuroscience 2009, 29: 5654-5665. PMID: 19403831, PMCID: PMC3688047, DOI: 10.1523/jneurosci.5978-08.2009.Peer-Reviewed Original ResearchConceptsTerminal domainN-terminal domainAlternative splice variantsPotassium channelsSubcellular localizationPlasma membraneMolecular explanationHeteromer formationSplice variantsHeteromeric channelsDistinct rolesSingle-channel levelSubunitsUnitary conductanceCentral neuronsSlack channelsImmunocytochemical studyFiring patternsDomainLocalizationNeuronsGenesTraffickingChannel levelHomomers
2008
Amino‐termini isoforms of the Slack K+ channel, regulated by alternative promoters, differentially modulate rhythmic firing and adaptation
Brown MR, Kronengold J, Gazula V, Spilianakis CG, Flavell RA, Von Hehn CA, Bhattacharjee A, Kaczmarek LK. Amino‐termini isoforms of the Slack K+ channel, regulated by alternative promoters, differentially modulate rhythmic firing and adaptation. The Journal Of Physiology 2008, 586: 5161-5179. PMID: 18787033, PMCID: PMC2652154, DOI: 10.1113/jphysiol.2008.160861.Peer-Reviewed Original ResearchAction PotentialsAdaptation, PhysiologicalAmino Acid SequenceAnimalsBrainCloning, MolecularGene Expression RegulationMiceMice, Inbred C57BLMolecular Sequence DataNerve Tissue ProteinsNeuronsPotassium ChannelsPotassium Channels, Sodium-ActivatedPromoter Regions, GeneticProtein IsoformsRatsRNA, Messenger
2007
Slack and Slick KNa Channels Regulate the Accuracy of Timing of Auditory Neurons
Yang B, Desai R, Kaczmarek LK. Slack and Slick KNa Channels Regulate the Accuracy of Timing of Auditory Neurons. Journal Of Neuroscience 2007, 27: 2617-2627. PMID: 17344399, PMCID: PMC6672517, DOI: 10.1523/jneurosci.5308-06.2007.Peer-Reviewed Original ResearchMeSH KeywordsAction PotentialsAnimalsAnimals, NewbornAuditory PathwaysBithionolBrain StemComputer SimulationElectric ConductivityElectric StimulationElectrophysiologyIn Vitro TechniquesMiceModels, NeurologicalNerve Tissue ProteinsNeuronsNeurons, AfferentPotassium ChannelsPotassium Channels, Sodium-ActivatedReaction TimeSodium
2006
Opposite Regulation of Slick and Slack K+ Channels by Neuromodulators
Santi CM, Ferreira G, Yang B, Gazula VR, Butler A, Wei A, Kaczmarek LK, Salkoff L. Opposite Regulation of Slick and Slack K+ Channels by Neuromodulators. Journal Of Neuroscience 2006, 26: 5059-5068. PMID: 16687497, PMCID: PMC6674240, DOI: 10.1523/jneurosci.3372-05.2006.Peer-Reviewed Original ResearchConceptsSlo2 channelsHippocampal brain sectionsCultured hippocampal neuronsProtein kinase CWhole-cell currentsPKC activator PMANeuronal excitabilityHippocampal neuronsBrain sectionsBasal levelsImmunocytochemical techniquesGalphaq proteinElectrical activitySlo2.1Activator PMAReceptorsChannel gene familyWidespread expressionChannel activityExcitabilityNeuromodulatorsIntracellular concentrationPotential of cellsBrainXenopus oocytesModulation 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
2004
Kv1.3 Channel Gene-Targeted Deletion Produces “Super-Smeller Mice” with Altered Glomeruli, Interacting Scaffolding Proteins, and Biophysics
Fadool DA, Tucker K, Perkins R, Fasciani G, Thompson RN, Parsons AD, Overton JM, Koni PA, Flavell RA, Kaczmarek LK. Kv1.3 Channel Gene-Targeted Deletion Produces “Super-Smeller Mice” with Altered Glomeruli, Interacting Scaffolding Proteins, and Biophysics. Neuron 2004, 41: 389-404. PMID: 14766178, PMCID: PMC2737549, DOI: 10.1016/s0896-6273(03)00844-4.Peer-Reviewed Original ResearchMeSH Keywords14-3-3 ProteinsAdaptor Proteins, Vesicular TransportAnimalsBehavior, AnimalBlotting, WesternBody WeightBrain-Derived Neurotrophic FactorCalcium ChannelsCells, CulturedDensitometryDifferential ThresholdDiscrimination, PsychologicalDose-Response Relationship, DrugDrinkingElectric StimulationEmbryo, MammalianEnergy IntakeExploratory BehaviorGene DeletionGRB10 Adaptor ProteinHabituation, PsychophysiologicHumansInsulinKidneyKineticsKv1.3 Potassium ChannelMembrane PotentialsMiceMice, KnockoutMotor ActivityNerve Tissue ProteinsNeuronsNeurotoxinsNuclear Matrix-Associated ProteinsOdorantsOlfactory BulbPatch-Clamp TechniquesPotassium ChannelsPotassium Channels, Voltage-GatedProteinsRas ProteinsReceptor, trkBReverse Transcriptase Polymerase Chain ReactionRNA, MessengerScorpion VenomsSensory ThresholdsSrc-Family KinasesTime FactorsTyrosine 3-MonooxygenaseConceptsKv1.3-/- miceProtein-protein interactionsGene-targeted deletionKv1.3-null miceSignal transductionScaffolding proteinSignaling cascadesChannel genesC-type inactivationDeletionMembrane potentialNull miceOlfactory codingDetection of odorsPotassium channelsKv1.3 channelsProteinSense of smellSlow inactivation kineticsWild-type miceTransductionGenesOlfactory bulb mitral cellsMiceRole
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
2002
Localization of the Slack potassium channel in the rat central nervous system
Bhattacharjee A, Gan L, Kaczmarek LK. Localization of the Slack potassium channel in the rat central nervous system. The Journal Of Comparative Neurology 2002, 454: 241-254. PMID: 12442315, DOI: 10.1002/cne.10439.Peer-Reviewed Original ResearchConceptsRat central nervous systemSlack potassium channelsChannel subunitsRat brain slicesCentral nervous systemRat brain membranesOnly cortical regionDeep cerebellar nucleiGiant presynaptic terminalSlo subunitWestern blot analysisSubstantia nigraTrigeminal systemImmunohistochemical studyMedial nucleusOculomotor nucleusReticular formationBrain slicesFrontal cortexOlfactory bulbPresynaptic terminalsRed nucleusNervous systemCerebellar nucleiBrain membranes