2024
Molecular Profiling of Mouse Models of Loss or Gain of Function of the KCNT1 (Slack) Potassium Channel and Antisense Oligonucleotide Treatment
Sun F, Wang H, Wu J, Quraishi I, Zhang Y, Pedram M, Gao B, Jonas E, Nguyen V, Wu S, Mabrouk O, Jafar-nejad P, Kaczmarek L. Molecular Profiling of Mouse Models of Loss or Gain of Function of the KCNT1 (Slack) Potassium Channel and Antisense Oligonucleotide Treatment. Biomolecules 2024, 14: 1397. DOI: 10.3390/biom14111397.Peer-Reviewed Original ResearchWild-type miceKO miceSpectrum of epilepsy syndromesAntisense oligonucleotidesGain-of-function variantsAntisense oligonucleotide treatmentEpileptic phenotypePotassium channelsKCNT1Molecular profilingOligonucleotide treatmentAnimal modelsEpilepsy syndromesC-terminal mutationsIncreased expressionCerebral cortexMiceExpression of multiple proteinsComprehensive proteomic analysisDisease modelsCortical mitochondriaMolecular differencesDensity of mitochondrial cristaeMitochondrial membraneTreatment
2023
Calcium- and sodium-activated potassium channels (K<sub>Ca</sub>, K<sub>Na</sub>) in GtoPdb v.2023.1
Aldrich R, Chandy K, Grissmer S, Gutman G, Kaczmarek L, Wei A, Wulff H. Calcium- and sodium-activated potassium channels (KCa, KNa) in GtoPdb v.2023.1. IUPHAR/BPS Guide To Pharmacology CITE 2023, 2023 DOI: 10.2218/gtopdb/f69/2023.1.Peer-Reviewed Original ResearchModulation of potassium conductances optimizes fidelity of auditory information
Kaczmarek L. Modulation of potassium conductances optimizes fidelity of auditory information. Proceedings Of The National Academy Of Sciences Of The United States Of America 2023, 120: e2216440120. PMID: 36930599, PMCID: PMC10041146, DOI: 10.1073/pnas.2216440120.Peer-Reviewed Original ResearchConceptsPotassium currentAuditory brainstem neuronsAuditory stimuliHigh-frequency firingGroups of neuronsLow-frequency stimuliBrainstem neuronsHigh-frequency stimuliIntrinsic excitabilityEnsembles of neuronsPostsynaptic neuronsAuditory neuronsNeurotransmitter releaseModulatory mechanismsAuditory stimulationFiring ratePotassium conductanceNeuronsPotassium channelsSingle neuronsAmplitude of currentsLoud soundsEnvironmental sound levelsChannel activityPositive membrane potentials
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 miceCalcium- and sodium-activated potassium channels (K<sub>Ca</sub>, K<sub>Na</sub>) in GtoPdb v.2021.3
Aldrich R, Chandy K, Grissmer S, Gutman G, Kaczmarek L, Wei A, Wulff H. Calcium- and sodium-activated potassium channels (KCa, KNa) in GtoPdb v.2021.3. IUPHAR/BPS Guide To Pharmacology CITE 2021, 2021 DOI: 10.2218/gtopdb/f69/2021.3.Peer-Reviewed Original ResearchThe 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 ResearchA 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 inactivationCaspasesModulation of Neuronal Potassium Channels During Auditory Processing
Wu J, Kaczmarek LK. Modulation of Neuronal Potassium Channels During Auditory Processing. Frontiers In Neuroscience 2021, 15: 596478. PMID: 33613177, PMCID: PMC7887315, DOI: 10.3389/fnins.2021.596478.Peer-Reviewed Reviews, Practice Guidelines, Standards, and Consensus StatementsPotassium channelsAuditory brainstem neuronsAuditory brainstem nucleiNeuronal potassium channelsAuditory informationBrainstem neuronsBrainstem nucleiCertain neuronsPotassium currentFiring patternsNeuronsGene mutationsAuditory processingAuditory stimuliHigh rateLong-term modulationComplex auditory informationIntrinsic electrical propertiesSuch modulationHuman gene mutationsIntensity of soundAuditory environmentModulationPresynaptic 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
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 systemMutantsCalcium- and sodium-activated potassium channels (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database
Aldrich R, Chandy K, Grissmer S, Gutman G, Kaczmarek L, Wei A, Wulff H. Calcium- and sodium-activated potassium channels (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database. IUPHAR/BPS Guide To Pharmacology CITE 2019, 2019 DOI: 10.2218/gtopdb/f69/2019.4.Peer-Reviewed Reviews, Practice Guidelines, Standards, and Consensus StatementsAn 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 cellsRole of KCNQ potassium channels in stress-induced deficit of working memory
Arnsten AFT, Jin LE, Gamo NJ, Ramos B, Paspalas CD, Morozov YM, Kata A, Bamford NS, Yeckel MF, Kaczmarek LK, El-Hassar L. Role of KCNQ potassium channels in stress-induced deficit of working memory. Neurobiology Of Stress 2019, 11: 100187. PMID: 31832507, PMCID: PMC6889760, DOI: 10.1016/j.ynstr.2019.100187.Peer-Reviewed Original ResearchStress-induced deficitsKCNQ potassium channelsKCNQ blockersPrefrontal cortexNeuronal firingLayers II/IIIRat medial prefrontal cortexStress exposurePotassium channelsRat medial PFCMedial PFCChronic stress exposurePatch-clamp recordingsPyramidal cell firingMedial prefrontal cortexSystemic administrationPyramidal cellsAged ratsLow dosePFC dysfunctionHigh dosesKCNQ channelsLow dosesCell firingCognitive function
2017
Tuning Neuronal Potassium Channels to the Auditory Environment
Kaczmarek L. Tuning Neuronal Potassium Channels to the Auditory Environment. Springer Handbook Of Auditory Research 2017, 64: 133-159. DOI: 10.1007/978-3-319-21530-3_6.Peer-Reviewed Reviews, Practice Guidelines, Standards, and Consensus StatementsBrainstem nucleiPotassium channelsAuditory brainstem nucleiVoltage-dependent potassium channelsNeuronal potassium channelsAuditory discrimination taskAuditory neuronsAuditory environmentChannel isoformsNeuronsHigh rateAuditory informationKv3.1Molecular mechanismsDifferent auditory environmentsRapid alterationsDiscrimination task
2016
International Union of Basic and Clinical Pharmacology. C. Nomenclature and Properties of Calcium-Activated and Sodium-Activated Potassium Channels
Kaczmarek LK, Aldrich RW, Chandy KG, Grissmer S, Wei AD, Wulff H. International Union of Basic and Clinical Pharmacology. C. Nomenclature and Properties of Calcium-Activated and Sodium-Activated Potassium Channels. Pharmacological Reviews 2016, 69: 1-11. PMID: 28267675, PMCID: PMC11060434, DOI: 10.1124/pr.116.012864.Peer-Reviewed Original ResearchStimulation 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
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