Leonard Kaczmarek, PhD
Professor of Pharmacology and of Cellular And Molecular PhysiologyCards
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About
Titles
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
Tamas Horvath, DVM, PhD
Yalan Zhang, PhD
Milan Stoiljkovic, MD, PhD
Akiko Iwasaki, PhD
Ion Channels
Pharmacology
Memory
Learning
Publications
2024
GABAA 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 PMID: 39642883, DOI: 10.1016/j.molcel.2024.11.016.Peer-Reviewed Original ResearchConceptsExtracellular 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 ResearchConceptsWild-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 ResearchConceptsInhibitory 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 ResearchConceptsPFC 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 ResearchMeSH 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 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 ResearchMeSH Keywords and ConceptsConceptsNervous 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 ResearchMeSH Keywords and ConceptsConceptsPotassium 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 ResearchMeSH Keywords
News
News
- April 04, 2019Source: Medicine@Yale
Endowment to Support Student Research at Woods Hole
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Endowment to support student research
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