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 membraneTreatmentDisease-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 segmentKCNT1ExpressionHyperexcitabilitySlack (KCNT1) potassium channels regulate levels of proteins of the inner mitochondrial membrane
Wang H, Wu J, Sun F, Wu S, Jafar-nejad P, Quraishi I, Pedram M, Kaczmarek L. Slack (KCNT1) potassium channels regulate levels of proteins of the inner mitochondrial membrane. Biophysical Journal 2024, 123: 250a. DOI: 10.1016/j.bpj.2023.11.1582.Peer-Reviewed Original Research
2023
Interaction Between HCN and Slack Channels Regulates mPFC Pyramidal Cell Excitability in Working Memory Circuits
Wu J, El-Hassar L, Datta D, Thomas M, Zhang Y, Jenkins D, DeLuca N, Chatterjee M, Gribkoff V, Arnsten A, Kaczmarek L. Interaction Between HCN and Slack Channels Regulates mPFC Pyramidal Cell Excitability in Working Memory Circuits. Molecular Neurobiology 2023, 61: 2430-2445. PMID: 37889366, DOI: 10.1007/s12035-023-03719-8.Peer-Reviewed Original ResearchPFC pyramidal neuronsPyramidal cellsHCN channelsPrefrontal cortexPyramidal neuronsNeuronal firingSlack channelsPyramidal cell excitabilityRat prefrontal cortexPFC pyramidal cellsCell linesNon-selective cation channelsRecurrent excitatory connectionsCortical extractsNeuronal depolarizationNeuronal excitabilityPharmacological blockersSpecific blockerDendritic spinesKNa channelsCell excitabilityPostsynaptic spinesPersistent firingExcitatory connectionsNeural circuitsThe Concise Guide to PHARMACOLOGY 2023/24: Ion channels
Alexander S, Mathie A, Peters J, Veale E, Striessnig J, Kelly E, Armstrong J, Faccenda E, Harding S, Davies J, Aldrich R, Attali B, Baggetta A, Becirovic E, Biel M, Bill R, Caceres A, Catterall W, Conner A, Davies P, De Clerq K, Delling M, Di Virgilio F, Falzoni S, Fenske S, Fortuny-Gomez A, Fountain S, George C, Goldstein S, Grimm C, Grissmer S, Ha K, Hammelmann V, Hanukoglu I, Hu M, Ijzerman A, Jabba S, Jarvis M, Jensen A, Jordt S, Kaczmarek L, Kellenberger S, Kennedy C, King B, Kitchen P, Liu Q, Lynch J, Meades J, Mehlfeld V, Nicke A, Offermanns S, Perez-Reyes E, Plant L, Rash L, Ren D, Salman M, Sieghart W, Sivilotti L, Smart T, Snutch T, Tian J, Trimmer J, Van den Eynde C, Vriens J, Wei A, Winn B, Wulff H, Xu H, Yang F, Fang W, Yue L, Zhang X, Zhu M. The Concise Guide to PHARMACOLOGY 2023/24: Ion channels. British Journal Of Pharmacology 2023, 180: s145-s222. PMID: 38123150, PMCID: PMC11339754, DOI: 10.1111/bph.16178.Peer-Reviewed Original ResearchConceptsBest available pharmacological toolsOpen access knowledgebase sourceOfficial IUPHAR classificationAvailable pharmacological toolsDrug targetsG protein-coupled receptorsIon channelsProtein-coupled receptorsNomenclature guidanceClinical pharmacologyMajor pharmacological targetCatalytic receptorsSelective pharmacologyNuclear hormone receptorsPharmacological targetsPharmacological toolsHormone receptorsPrevious GuidesReceptorsLandscape formatHuman drug targetsPharmacologyConcise guideBiennial publicationRelated targetsCalcium- 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 ResearchThe 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 advancesTherapyCliniciansModulation 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 potentialsResponse to: Elevated L1 expression in ataxia telangiectasia likely explained by an RNA-seq batch effect
Takahashi T, Stoiljkovic M, Song E, Gao X, Yasumoto Y, Kudo E, Carvalho F, Kong Y, Park A, Shanabrough M, Szigeti-Buck K, Liu Z, Kristant A, Zhang Y, Sulkowski P, Glazer P, Kaczmarek L, Horvath T, Iwasaki A. Response to: Elevated L1 expression in ataxia telangiectasia likely explained by an RNA-seq batch effect. Neuron 2023, 111: 612-613. PMID: 36863323, DOI: 10.1016/j.neuron.2023.02.006.Peer-Reviewed Original ResearchModulation of potassium channels preserves temporal fidelity in auditory network models
Kaczmarek L. Modulation of potassium channels preserves temporal fidelity in auditory network models. Biophysical Journal 2023, 122: 245a. DOI: 10.1016/j.bpj.2022.11.1428.Peer-Reviewed Original Research
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 courseEditorial: Alterations in the Sound Localization Pathway Related to Impaired Cocktail-Party Performance
McCullagh EA, Kaczmarek LK, Tollin DJ, Klug A. Editorial: Alterations in the Sound Localization Pathway Related to Impaired Cocktail-Party Performance. Frontiers In Neuroscience 2022, 16: 902197. PMID: 35546884, PMCID: PMC9082812, DOI: 10.3389/fnins.2022.902197.Peer-Reviewed Original ResearchThe 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 miceTHE CONCISE GUIDE TO PHARMACOLOGY 2021/22: Ion channels
Alexander SP, Mathie A, Peters JA, Veale EL, Striessnig J, Kelly E, Armstrong JF, Faccenda E, Harding SD, Pawson AJ, Southan C, Davies JA, Aldrich RW, Attali B, Baggetta AM, Becirovic E, Biel M, Bill RM, Catterall WA, Conner AC, Davies P, Delling M, Virgilio FD, Falzoni S, Fenske S, George C, Goldstein SAN, Grissmer S, Ha K, Hammelmann V, Hanukoglu I, Jarvis M, Jensen AA, Kaczmarek LK, Kellenberger S, Kennedy C, King B, Kitchen P, Lynch JW, Perez-Reyes E, Plant LD, Rash L, Ren D, Salman MM, Sivilotti LG, Smart TG, Snutch TP, Tian J, Trimmer JS, Van den Eynde C, Vriens J, Wei AD, Winn BT, Wulff H, Xu H, Yue L, Zhang X, Zhu M. THE CONCISE GUIDE TO PHARMACOLOGY 2021/22: Ion channels. British Journal Of Pharmacology 2021, 178: s157-s245. PMID: 34529831, DOI: 10.1111/bph.15539.Peer-Reviewed Original ResearchConceptsBest available pharmacological toolsOpen access knowledgebase sourceOfficial IUPHAR classificationAvailable pharmacological toolsDrug targetsG protein-coupled receptorsHuman drug targetsIon channelsProtein-coupled receptorsNomenclature guidanceClinical pharmacologyMajor pharmacological targetCatalytic receptorsSelective pharmacologyNuclear hormone receptorsPharmacological targetsPharmacological toolsHormone receptorsPrevious GuidesReceptorsLandscape formatConcise guidePharmacologyBiennial publicationRelated targetsCalcium- 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 ResearchThe voltage-gated K+ channel Kv1.3 modulates platelet motility and α2β1 integrin-dependent adhesion to collagen
Wright JR, Jones S, Parvathy S, Kaczmarek LK, Forsythe I, Farndale RW, Gibbins JM, Mahaut-Smith MP. The voltage-gated K+ channel Kv1.3 modulates platelet motility and α2β1 integrin-dependent adhesion to collagen. Platelets 2021, 33: 1942818. PMID: 34348571, PMCID: PMC8935947, DOI: 10.1080/09537104.2021.1942818.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 function