Leonard Kaczmarek, PhD
Professor of Pharmacology and of Cellular And Molecular PhysiologyCards
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Professor of Pharmacology and of Cellular And Molecular Physiology
Biography
Dr. Kaczmarek carried out his undergraduate and graduate work at the University of London. He continued his research career at the University of California Los Angeles (where he learned electrophysiology), the Free University of Brussels, Belgium (where he learned how to make neural network models) and the California Institute of Technology (where he made the fundamental discovery that phosphorylation state changes ionic currents) before joining the Yale faculty in 1981. The Kaczmarek group studies biochemical changes in neurons that result in prolonged changes in the behavior of an animal or detect specific patterns of sensory inputs. He is well-known for discovering the genes for several ion channel proteins that are directly responsible for the excitability of nerve cells. His work was the first to demonstrate directly that rapid changes in phosphorylation state of ion channels occur in vivo in response to changes in the animal’s environment. Currently his lab is focused on the way mutations in these proteins may be responsible for several forms of intellectual disability and autism. He has been very fortunate to have many exceptionally talented pre- and postdoctoral trainees in his laboratory. Thirty-two of the students and postdocs from the Kaczmarek laboratory have gone on to hold tenure-track faculty positions at major institutions including Brown University, Yale University, UCSF, UCSD, Vanderbilt and many more.
Appointments
Pharmacology
ProfessorPrimaryCellular & Molecular Physiology
ProfessorSecondary
Other Departments & Organizations
Education & Training
- PhD
- University of London (1971)
Research
Overview
Our laboratory has investigates the role of potassium channels, as well as other classes of ion channels, in the short-term and long-term regulation of neuronal excitability. Our group was the first to demonstrate directly, using purified enzymes, that excitability of neurons is regulated by cyclic AMP-dependent protein kinase, protein kinase C and tyrosine phosphatases. As part of this work we isolated the genes for over fourteen novel ion channels and were the first to identify the “two-pore” family of potassium channels. Among the channels that our group cloned and characterized are Kv3.1b channel, which is required for high-frequency firing in many neurons and the Slack and Slick genes that underlie Na+-activated K+ channels. Our work was the first to show directly that rapid changes in the phosphorylation state of ion channels and in the synthesis of new channels occur in vivo in response to changes in an animal’s environment. Most recently, we have found that the Slack protein interacts with the Fragile X Mental Retardation Protein FMRP and that human mutations in Slack produce very severe epilepsy and developmental delay. This is now a major focus of our laboratory.
Medical Research Interests
ORCID
0000-0001-5128-6326- View Lab Website
Kaczmarek Lab
Research at a Glance
Yale Co-Authors
Publications Timeline
Research Interests
Elizabeth Jonas, MD
Imran Quraishi, MD, PhD
Yalan Zhang, PhD
Tamas Horvath, DVM, PhD
Milan Stoiljkovic, MD, PhD
Akiko Iwasaki, PhD
Ion Channels
Pharmacology
Memory
Learning
Publications
2025
Neuronal potassium channel activity triggers initiation of mRNA translation through binding of translation regulators
Malone T, Wu J, Zhang Y, Licznerski P, Chen R, Nahiyan S, Pedram M, Jonas E, Kaczmarek L. Neuronal potassium channel activity triggers initiation of mRNA translation through binding of translation regulators. Science Advances 2025, 11: eadv3140. PMID: 40435242, PMCID: PMC12118559, DOI: 10.1126/sciadv.adv3140.Peer-Reviewed Original ResearchAltmetricMeSH Keywords and ConceptsConceptsMRNA translationTranslational regulationInitiation of mRNA translationInitiation of translationSevere intellectual disabilityRegulation of translationMRNA translation regulationNeurites of cortical neuronsB-actinChannel activityIntellectual disabilityPotassium channel activityNeuronal activityMolecular mechanismsInhibit initiationMutationsCell linesPharmacological stimulationCortical neuronsMRNABindingRegulationTranslationEIF4ECYFIP1Activation of a Potassium Channel Mutation That Causes Spinocerebellar Ataxia Promotes Aggregation of the RhoGEF Domain‐Containing Protein Plekhg4
Zhang Y, Andrawis A, Kaczmarek L. Activation of a Potassium Channel Mutation That Causes Spinocerebellar Ataxia Promotes Aggregation of the RhoGEF Domain‐Containing Protein Plekhg4. The FASEB Journal 2025, 39: e70552. PMID: 40249242, DOI: 10.1096/fj.202402809rr.Peer-Reviewed Original ResearchMeSH Keywords and ConceptsConceptsGuanine nucleotide exchange factorKv3.3 channelsNucleation of actin filamentsPlasma membraneNucleotide exchange factorPurkinje neuronsRegulating Rac1 activitySpinocerebellar ataxiaPotassium channel mutationsAuditory brainstem neuronsCerebellar Purkinje neuronsActin nucleationPurkinje cell activityWild-type channelsExchange factorActin filamentsPotential new therapeutic approachCytoplasmic proteinsTreatment of spinocerebellar ataxiaRac1 activationHAX-1Cytoplasmic aggregatesRegulate excitabilityBrainstem neuronsCHO cellsMultiple Neuronal Processes, Including the Mauthner Axon, Form a Multi‐Axial Fiber Within a Common Myelin Sheath in the Central Nervous System of Adult Lungfishes, Protopterus annectens, Lepidosiren paradoxa, and Neoceratodus forsteri
Zottoli S, Kaczmarek L, Faber D. Multiple Neuronal Processes, Including the Mauthner Axon, Form a Multi‐Axial Fiber Within a Common Myelin Sheath in the Central Nervous System of Adult Lungfishes, Protopterus annectens, Lepidosiren paradoxa, and Neoceratodus forsteri. Journal Of Morphology 2025, 286: e70042. PMID: 40145734, DOI: 10.1002/jmor.70042.Peer-Reviewed Original ResearchAltmetricMeSH Keywords and Concepts
2024
Molecular mechanism governing the plasticity of use-dependent spike broadening in dorsal root ganglion neurons
Alexander T, Tymanskyj S, Kennedy K, Kaczmarek L, Covarrubias M. Molecular mechanism governing the plasticity of use-dependent spike broadening in dorsal root ganglion neurons. Proceedings Of The National Academy Of Sciences Of The United States Of America 2024, 122: e2411033121. PMID: 39739796, PMCID: PMC11725888, DOI: 10.1073/pnas.2411033121.Peer-Reviewed Original ResearchCitationsAltmetricMeSH Keywords and ConceptsConceptsN-terminal inactivation domainDorsal root ganglionDorsal root ganglion neuronsSpike broadeningCumulative inactivationVoltage-gated K<sup>+</sup>Rat dorsal root ganglionViral vector approachPain modulationRoot ganglionGanglion neuronsKv3.4AP widthAction potentialsDynamic clampMechanosensory transductionInactivation domainNeuronsMolecular mechanismsFast recoveryInactivationSlow recoveryPhosphorylationPainRepolarizationGABAA receptor π forms channels that stimulate ERK through a G-protein-dependent pathway
Wang Y, Zhang Y, Li W, Salovska B, Zhang J, Li T, Li H, Liu Y, Kaczmarek L, Pusztai L, Klein D. GABAA receptor π forms channels that stimulate ERK through a G-protein-dependent pathway. Molecular Cell 2024, 85: 166-176.e5. PMID: 39642883, PMCID: PMC11698630, DOI: 10.1016/j.molcel.2024.11.016.Peer-Reviewed Original ResearchAltmetricConceptsExtracellular regulated kinaseStimulated extracellular regulated kinaseExtracellular-regulated kinase signalingG-protein-dependent pathwayG protein-coupled pathwayUncharacterized pathwayGrowth signalsSignaling functionsCryoelectron microscopyCryo-EMSignaling mechanismsGABRPFunctional assaysNative nanodiscsPathwayStimulate growthPhysiological concentrationsAbsence of GABATargeted inhibitionType A receptorConcentrations of GABAMetabotropic receptorsIonotropic activitySignalGABA bindingMolecular 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. PMID: 39595574, PMCID: PMC11591899, DOI: 10.3390/biom14111397.Peer-Reviewed Original ResearchCitationsConceptsWild-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 ResearchCitationsAltmetricConceptsInhibitory 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 ResearchCitations
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 ResearchCitationsConceptsPFC 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 ResearchCitationsAltmetricMeSH Keywords and ConceptsConceptsBest 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 targets
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