2024
Disease-causing Slack potassium channel mutations produce opposite effects on excitability of excitatory and inhibitory neurons
Wu J, Quraishi I, Zhang Y, Bromwich M, Kaczmarek L. Disease-causing Slack potassium channel mutations produce opposite effects on excitability of excitatory and inhibitory neurons. Cell Reports 2024, 43: 113904. PMID: 38457342, PMCID: PMC11013952, DOI: 10.1016/j.celrep.2024.113904.Peer-Reviewed Original ResearchInhibitory neuronsRegulation of neuronal excitabilityPotassium channel mutationsVoltage-dependent sodiumInhibitory cortical neuronsGain-of-function mutationsAxon initial segmentKCNT1 geneNeuronal excitabilityChannel subunitsChannel mutationsNetwork hyperexcitabilityMouse modelNeuron typesCortical neuronsTreat epilepsyNeuronsExcitable neuronsNeurological disordersSevere intellectual disabilityMutationsInitial segmentKCNT1ExpressionHyperexcitability
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
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 systemMutants
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
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