2023
The 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 targetsThe 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 advancesTherapyCliniciansResponse 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 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 homeostasisThe 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
THE 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 targetsThe 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 Research
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 guideLoss of NaV1.2-Dependent Backpropagating Action Potentials in Dendrites Contributes to Autism and Intellectual Disability
Kaczmarek LK. Loss of NaV1.2-Dependent Backpropagating Action Potentials in Dendrites Contributes to Autism and Intellectual Disability. Neuron 2019, 103: 551-553. PMID: 31437449, DOI: 10.1016/j.neuron.2019.07.032.Peer-Reviewed Original ResearchAn 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
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
Kv3 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 ResearchZika Virus Disrupts Phospho-TBK1 Localization and Mitosis in Human Neuroepithelial Stem Cells and Radial Glia
Onorati M, Li Z, Liu F, Sousa AMM, Nakagawa N, Li M, Dell’Anno M, Gulden FO, Pochareddy S, Tebbenkamp AT, Han W, Pletikos M, Gao T, Zhu Y, Bichsel C, Varela L, Szigeti-Buck K, Lisgo S, Zhang Y, Testen A, Gao XB, Mlakar J, Popovic M, Flamand M, Strittmatter SM, Kaczmarek LK, Anton ES, Horvath TL, Lindenbach BD, Sestan N. Zika Virus Disrupts Phospho-TBK1 Localization and Mitosis in Human Neuroepithelial Stem Cells and Radial Glia. Cell Reports 2016, 16: 2576-2592. PMID: 27568284, PMCID: PMC5135012, DOI: 10.1016/j.celrep.2016.08.038.Peer-Reviewed Original ResearchMeSH KeywordsAxl Receptor Tyrosine KinaseBrainCell DeathCentrosomeFetusGene Expression ProfilingHumansImmunity, InnateMicrocephalyMitochondriaMitosisNeocortexNeural Stem CellsNeuroepithelial CellsNeurogliaNeuronsNeuroprotective AgentsNucleosidesPhosphorylationProtein Kinase InhibitorsProtein Serine-Threonine KinasesProto-Oncogene ProteinsReceptor Protein-Tyrosine KinasesSpinal CordTranscription, GeneticVirus ReplicationZika VirusZika Virus InfectionConceptsRadial glial cellsNES cellsNeuroepithelial stem cellsZIKV infectionFetal brain slicesStem cellsEarly human neurodevelopmentHuman neuroepithelial stem cellsHuman neural stem cellsCell deathSingle-cell RNA-seqNeural stem cellsNeurodevelopment defectsZIKV replicationGlial cellsBrain slicesPotential treatmentRadial gliaZika virusPhospho-TBK1Neurodevelopmental defectsRNA-seqSupernumerary centrosomesNucleoside analoguesHuman neurodevelopment