2023
The Difficult Path to the Discovery of Novel Treatments in Psychiatric Disorders
Gribkoff V, Kaczmarek L. The Difficult Path to the Discovery of Novel Treatments in Psychiatric Disorders. Advances In Neurobiology 2023, 30: 255-285. PMID: 36928854, PMCID: PMC10599454, DOI: 10.1007/978-3-031-21054-9_11.Peer-Reviewed Original ResearchConceptsNervous system diseasesSystem diseasesPsychiatric disordersPsychiatric patientsNew drugsDetermination of efficacyDiseases/disordersNovel therapiesNovel treatmentsPsychiatric diseasesDiscovery effortsNew therapeuticsDisordersDiseaseDrugsPatientsFace validityPredictive validityTreatmentDiscoveryPresent particular challengesHuman healthRecent advancesTherapyClinicians
2022
LINE-1 activation in the cerebellum drives ataxia
Takahashi T, Stoiljkovic M, Song E, Gao XB, Yasumoto Y, Kudo E, Carvalho F, Kong Y, Park A, Shanabrough M, Szigeti-Buck K, Liu ZW, Kristant A, Zhang Y, Sulkowski P, Glazer PM, Kaczmarek LK, Horvath TL, Iwasaki A. LINE-1 activation in the cerebellum drives ataxia. Neuron 2022, 110: 3278-3287.e8. PMID: 36070749, PMCID: PMC9588660, DOI: 10.1016/j.neuron.2022.08.011.Peer-Reviewed Original ResearchConceptsLINE-1 activationL1 activationAtaxia telangiectasia patientsNuclear element-1Transposable elementsEpigenetic silencersHuman genomeL1 promoterMolecular regulatorsDNA damagePurkinje cell dysfunctionElement 1First direct evidenceTelangiectasia patientsDirect targetingCerebellar expressionNeurodegenerative diseasesDisease etiologyCalcium homeostasisAuditory brainstem development of naked mole-rats (Heterocephalus glaber)
McCullagh EA, Peacock J, Lucas A, Poleg S, Greene NT, Gaut A, Lagestee S, Zhang Y, Kaczmarek LK, Park TJ, Tollin DJ, Klug A. Auditory brainstem development of naked mole-rats (Heterocephalus glaber). Proceedings Of The Royal Society B 2022, 289: 20220878. PMID: 35946148, PMCID: PMC9363996, DOI: 10.1098/rspb.2022.0878.Peer-Reviewed Original ResearchConceptsCentral auditory systemHearing onsetAuditory brainstem response recordingsSimilar developmental time courseProtein levelsAuditory brainstem developmentPostnatal day 9Central auditory processingAuditory systemPotassium channel KVoltage-gated potassium channel KBrainstem developmentAuditory brainstemDay 9RatsBrain developmentKey developmental time pointsRat showDevelopmental time courseResponse recordingsTime pointsAuditory processingBrainstemDevelopmental time pointsTime course
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 spikesSeizuresMechanisms underlying auditory processing deficits in Fragile X syndrome
McCullagh EA, Rotschafer SE, Auerbach BD, Klug A, Kaczmarek LK, Cramer KS, Kulesza RJ, Razak KA, Lovelace JW, Lu Y, Koch U, Wang Y. Mechanisms underlying auditory processing deficits in Fragile X syndrome. The FASEB Journal 2020, 34: 3501-3518. PMID: 32039504, PMCID: PMC7347277, DOI: 10.1096/fj.201902435r.Peer-Reviewed Original ResearchConceptsAuditory dysfunctionAutism spectrum disorderAuditory brainstem circuitsFragile X syndromeAuditory processing deficitsCommon monogenetic causeNetwork hyperexcitabilityBrainstem circuitsAuditory pathwayAuditory cortexNeuronal plasticityAnimal modelsAuditory hypersensitivitySynaptic developmentHyperacusisMonogenetic causeDysfunctionX syndromeAberrant synaptic developmentBody of dataUnderlying mechanismMultiple mechanismsHuman therapySyndromeProcessing deficits
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 systemMutantsTHE CONCISE GUIDE TO PHARMACOLOGY 2019/20: Ion channels
Alexander S, Mathie A, Peters J, Veale E, Striessnig J, Kelly E, Armstrong J, Faccenda E, Harding S, Pawson A, Sharman J, Southan C, Davies J, Collaborators C, Aldrich R, Becirovic E, Biel M, Catterall W, Conner A, Davies P, Delling M, Di Virgilio F, Falzoni S, George C, Goldstein S, Grissmer S, Ha K, Hammelmann V, Hanukoglu I, Jarvis M, Jensen A, Kaczmarek L, Kellenberger S, Kennedy C, King B, Lynch J, Perez-Reyes E, Plant L, Rash L, Ren D, Sivilotti L, Smart T, Snutch T, Tian J, Van den Eynde C, Vriens J, Wei A, Winn B, Wulff H, Xu H, Yue L, Zhang X, Zhu M. THE CONCISE GUIDE TO PHARMACOLOGY 2019/20: Ion channels. British Journal Of Pharmacology 2019, 176: s142-s228. PMID: 31710715, PMCID: PMC6844578, DOI: 10.1111/bph.14749.Peer-Reviewed Reviews, Practice Guidelines, Standards, and Consensus StatementsConceptsBest available pharmacological toolsOpen access knowledgebase sourceOfficial IUPHAR classificationAvailable pharmacological toolsDrug targetsClinical Pharmacology CommitteeG protein-coupled receptorsHuman drug targetsIon channelsProtein-coupled receptorsPharmacology CommitteeNomenclature guidanceMajor pharmacological targetCatalytic receptorsReceptor NomenclatureSelective pharmacologyNuclear hormone receptorsPharmacological targetsPharmacological toolsHormone receptorsPrevious GuidesReceptorsDrug classificationLandscape formatConcise guideModulators 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 ResearchConceptsDominant 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 manifestationsAn 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
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 modulation