2025
Two successive oligomeric Munc13 assemblies scaffold vesicle docking and SNARE assembly to support neurotransmitter release
Bera M, Grushin K, Kalyana Sundaram R, Hinzen J, Chen J, Chatterjee A, Radhakrishnan A, Lee S, Padmanarayana M, Coleman J, Pincet F, Rothman J, Dittman J. Two successive oligomeric Munc13 assemblies scaffold vesicle docking and SNARE assembly to support neurotransmitter release. Nature Communications 2025, 16: 7222. PMID: 40764329, PMCID: PMC12325603, DOI: 10.1038/s41467-025-62420-7.Peer-Reviewed Original ResearchConceptsVesicle dockingSynaptic vesiclesPriming of synaptic vesiclesPresynaptic plasma membraneFusion in vitroTrans-SNARESNARE assemblyVesicle primingFunction in vivoMunc13Oligomeric assembliesHomo-oligomersInterface mutationsPlasma membraneNeurotransmitter secretionFunctional impactNeurotransmitter releaseVesiclesSnareIn vivoAssemblyIn vitroDockingMutationsSequence
2024
Minimal presynaptic protein machinery governing diverse kinetics of calcium-evoked neurotransmitter release
Bose D, Bera M, Norman C, Timofeeva Y, Volynski K, Krishnakumar S. Minimal presynaptic protein machinery governing diverse kinetics of calcium-evoked neurotransmitter release. Nature Communications 2024, 15: 10741. PMID: 39738049, PMCID: PMC11685451, DOI: 10.1038/s41467-024-54960-1.Peer-Reviewed Original ResearchConceptsSynaptotagmin-7Synaptotagmin-1Protein machinerySNARE complex assemblyFusion clampExocytosis processVesicle fusionVesicular fusionComplex assemblySynaptic vesiclesFusion assayMolecular basisPhysiologically relevant conditionsPresynaptic calcium influxNeurotransmitter releaseVesiclesSnareProteinMachineryCompetitive bindingFusion dynamicsComplexinExocytosisFusionCalcium influxVesicle docking and fusion pore modulation by the neuronal calcium sensor Synaptotagmin-1
Tsemperouli M, Cheppali S, Rivera-Molina F, Chetrit D, Landajuela A, Toomre D, Karatekin E. Vesicle docking and fusion pore modulation by the neuronal calcium sensor Synaptotagmin-1. Biophysical Journal 2024, 124: 1798-1814. PMID: 39719826, PMCID: PMC12256845, DOI: 10.1016/j.bpj.2024.12.023.Peer-Reviewed Original ResearchVesicle dockingSynaptotagmin-1C2 domainFusion triggeringCalcium sensor synaptotagmin 1Neuronal SNARE complexFusion pore dynamicsSensor synaptotagmin-1Domains of Syt1Neuroendocrine cell linePolybasic patchSNARE complexTriggers exocytosisFusion poreFusion eventsDense-core vesiclesSyt1Synaptic vesiclesPlasma membranePore regulationCalcium sensorNegatively charged phospholipidsBind calciumPore dynamicsCell linesQuantitative single-molecule analysis of assembly and Ca2+-dependent disassembly of synaptotagmin oligomers on lipid bilayers
Li F, Coleman J, Redondo-Morata L, Kalyana Sundaram R, Stroeva E, Rothman J, Pincet F. Quantitative single-molecule analysis of assembly and Ca2+-dependent disassembly of synaptotagmin oligomers on lipid bilayers. Communications Biology 2024, 7: 1608. PMID: 39627539, PMCID: PMC11615320, DOI: 10.1038/s42003-024-07317-9.Peer-Reviewed Original ResearchConceptsSyt-1Lipid bilayerRing-like oligomersCa2+-evoked releaseSynaptotagmin-1Single-molecule imaging methodsSynaptic vesiclesBiochemical evidencePhysiological requirementsOligomerizationAnalysis of assembliesBilayerOligomersCa2+LipidAssemblyCa2Classes of oligomersMutationsVesiclesDisassemblyEvoked releaseNeuroinflammatory Stress Exerts Distinct Proteomic Effects on Soma, Synapses and Mitochondria in Excitatory Neurons
Espinosa‐Garcia C, Srivastava U, Kumar P, Tobin B, Xiao H, Cheng L, Bagchi P, Duong D, Seyfried N, Faundez V, Wood L, Rangaraju S. Neuroinflammatory Stress Exerts Distinct Proteomic Effects on Soma, Synapses and Mitochondria in Excitatory Neurons. Alzheimer's & Dementia 2024, 20: e090723. PMCID: PMC11710382, DOI: 10.1002/alz.090723.Peer-Reviewed Original ResearchProteomic effectsLabel-free quantitative mass spectrometryCytoskeleton-related proteinsAlzheimer's disease pathogenesisProteome in vivoIncreased aerobic respirationCellular signaling pathwaysQuantitative mass spectrometryDisease pathogenesisCytoskeleton organizationSubcellular compartmentsOxidoreductase activitySynaptic vesiclesProteomic approachAerobic respirationBiological pathwaysNeuroinflammatory stressSignaling pathwaySynapse-related proteinsMAPK signalingMetabolic processesDifferential centrifugationMitochondriaSomatodendritic compartmentRegulating activityThe p. S178L mutation in Tbc1d24 disrupts endosome‐mediated synaptic vesicle trafficking of cochlear hair cells and leads to hearing impairment in mice
Chen P, Hou S, Li G, Lin Y, Lu J, Song L, Li G, Pang X, Wu H, Yang T. The p. S178L mutation in Tbc1d24 disrupts endosome‐mediated synaptic vesicle trafficking of cochlear hair cells and leads to hearing impairment in mice. Clinical Genetics 2024, 107: 67-77. PMID: 39400345, DOI: 10.1111/cge.14620.Peer-Reviewed Original ResearchNon-syndromic hearing lossSynaptic vesiclesRibbon synapses of cochlear inner hair cellsAutosomal dominant non-syndromic hearing lossDominant non-syndromic hearing lossEndosome-like vacuolesEndosomal membrane traffickingInner hair cellsSynaptic vesicle traffickingHearing lossRibbon synapsesHair cell ribbon synapsesKnock-in mouse modelMutant miceSustained exocytosisVesicle traffickingEndosomal traffickingMembrane traffickingVesicle recyclingIn vitro interactionCochlear inner hair cellsReduced exocytosisWave I amplitudeMild hearing lossAuditory brainstem responseTroriluzole rescues glutamatergic deficits, amyloid and tau pathology, and synaptic and memory impairments in 3xTg‐AD mice
Pfitzer J, Pinky P, Perman S, Redmon E, Cmelak L, Suppiramaniam V, Coric V, Qureshi I, Gramlich M, Reed M. Troriluzole rescues glutamatergic deficits, amyloid and tau pathology, and synaptic and memory impairments in 3xTg‐AD mice. Journal Of Neurochemistry 2024, 169: e16215. PMID: 39214859, DOI: 10.1111/jnc.16215.Peer-Reviewed Original ResearchTau mouse modelsRestore cognitive deficitsAlzheimer's diseaseSynaptic vesiclesSV pool sizeMouse model of ADCognitive deficitsTau-related pathologyGlutamate releasePool sizeModel of ADHippocampal culturesGlutamate-modulating drugsLoss of glutamatergic synapsesBeta-amyloidGlutamate modulator riluzoleTau pathologyPresynaptic vesicular glutamate transporterVesicular glutamate transportersAD pathologyAccumulation of glutamateMouse modelTau modelStages of ADPresynaptic dysfunctionDMXL2 Is Required for Endocytosis and Recycling of Synaptic Vesicles in Auditory Hair Cells
Peng H, Wang L, Gao Y, Liu H, Lin G, Kong Y, Xu P, Liu H, Yuan Q, Liu H, Song L, Yang T, Wu H. DMXL2 Is Required for Endocytosis and Recycling of Synaptic Vesicles in Auditory Hair Cells. Journal Of Neuroscience 2024, 44: e1405232024. PMID: 39147590, PMCID: PMC11411588, DOI: 10.1523/jneurosci.1405-23.2024.Peer-Reviewed Original ResearchEndocytic membrane retrievalSynaptic vesiclesSynaptic exocytosisMembrane retrievalEndocytic compartmentsMolecular machineryRecycling of synaptic vesiclesReserve poolMembrane capacitance measurementsRibbon synapses of inner hair cellsElectron microscopy reconstructionsAuditory synaptopathyMutant miceSynaptic endocytosisCell-specific knockout miceHuman homologMembrane-proximalHair cellsAuditory hair cellsMolecular basisEndocytosisRibbon synapsesInner hair cellsHearing lossDMXL2Overlapping role of synaptophysin and synaptogyrin family proteins in determining the small size of synaptic vesicles
Park D, Fujise K, Wu Y, Luján R, Del Olmo-Cabrera S, Wesseling J, De Camilli P. Overlapping role of synaptophysin and synaptogyrin family proteins in determining the small size of synaptic vesicles. Proceedings Of The National Academy Of Sciences Of The United States Of America 2024, 121: e2409605121. PMID: 38985768, PMCID: PMC11260120, DOI: 10.1073/pnas.2409605121.Peer-Reviewed Original ResearchConceptsSynaptic vesiclesFamily proteinsBiogenesis of synaptic vesiclesClusters of small vesiclesSize of synaptic vesiclesSynaptogyrin familySynaptogyrin-1Vesicle proteinsSynaptogyrinTransmembrane domainOrganismal levelSmall vesiclesProteinMild defectsVesiclesFamily membersBiogenesisSmall sizeFamilyMiceSynapsinCoexpressionAbundanceSynaptoporinMembersDual-Ring SNAREpin Machinery Tuning for Fast Synaptic Vesicle Fusion
Caruel M, Pincet F. Dual-Ring SNAREpin Machinery Tuning for Fast Synaptic Vesicle Fusion. Biomolecules 2024, 14: 600. PMID: 38786007, PMCID: PMC11117985, DOI: 10.3390/biom14050600.Peer-Reviewed Original ResearchThe Structural and Functional Integrity of Rod Photoreceptor Ribbon Synapses Depends on Redundant Actions of Dynamins 1 and 3
Hanke-Gogokhia C, Zapadka T, Finkelstein S, Klingeborn M, Maugel T, Singer J, Arshavsky V, Demb J. The Structural and Functional Integrity of Rod Photoreceptor Ribbon Synapses Depends on Redundant Actions of Dynamins 1 and 3. Journal Of Neuroscience 2024, 44: e1379232024. PMID: 38641407, PMCID: PMC11209669, DOI: 10.1523/jneurosci.1379-23.2024.Peer-Reviewed Original ResearchRod ribbon synapsesDynamin-1Photoreceptor ribbon synapsesDynamin isoformsMembrane scissionRibbon synapsesConventional synapsesReduced synaptic vesicle densitySynaptic vesicle recycling processesEndocytosis of synaptic vesiclesRibbon-type active zonesVesicle densityConditional gene knockout approachGene knockout approachSynaptic vesicle densityVesicle endocytosisVesicle cycleDisrupt endocytosisDynaminSpecialized proteinsSynapse integrityEnlarged vesiclesSynaptic vesiclesKnockout approachRod photoreceptorsTomosyns attenuate SNARE assembly and synaptic depression by binding to VAMP2-containing template complexes
Meijer M, Öttl M, Yang J, Subkhangulova A, Kumar A, Feng Z, van Voorst T, Groffen A, van Weering J, Zhang Y, Verhage M. Tomosyns attenuate SNARE assembly and synaptic depression by binding to VAMP2-containing template complexes. Nature Communications 2024, 15: 2652. PMID: 38531902, PMCID: PMC10965968, DOI: 10.1038/s41467-024-46828-1.Peer-Reviewed Original ResearchConceptsSynaptobrevin-2/VAMP2SNARE assemblySNARE motifC-terminal polybasic regionSNAP-25 bindingSNARE complex assemblyTemplate complexStructure-function analysisMunc18-1Syntaxin-1Polybasic regionTomosynSNAP-25Membrane fusionSynaptic vesiclesSingle-molecule force measurementsEssential intermediateSnareMotifInhibitory functionAssemblyMouse modelMunc18Synaptic transmissionSynaptic strength
2023
The release of inhibition model reproduces kinetics and plasticity of neurotransmitter release in central synapses
Norman C, Krishnakumar S, Timofeeva Y, Volynski K. The release of inhibition model reproduces kinetics and plasticity of neurotransmitter release in central synapses. Communications Biology 2023, 6: 1091. PMID: 37891212, PMCID: PMC10611806, DOI: 10.1038/s42003-023-05445-2.Peer-Reviewed Original ResearchConceptsFusion clampSV exocytosisSynaptic vesiclesNeurotransmitter releaseSNARE complexSNARE proteinsSV fusionPhysiological timescalesSynaptotagmin-1Synergistic regulationMolecular biochemistryComplete assemblyPresynaptic proteinsSynaptotagmin-7Molecular architectureCalcium bindingExocytosisDual bindingProteinCentral synapsesBindingPlasticitySynaptotagminSnareVesiclesTurbocharging synaptic transmission
Rothman J, Grushin K, Bera M, Pincet F. Turbocharging synaptic transmission. FEBS Letters 2023, 597: 2233-2249. PMID: 37643878, DOI: 10.1002/1873-3468.14718.Peer-Reviewed Original ResearchImpaired pre-synaptic plasticity and visual responses in auxilin-knockout mice
Cheng X, Tang Y, Vidyadhara D, Li B, Zimmerman M, Pak A, Nareddula S, Edens P, Chandra S, Chubykin A. Impaired pre-synaptic plasticity and visual responses in auxilin-knockout mice. IScience 2023, 26: 107842. PMID: 37766983, PMCID: PMC10520332, DOI: 10.1016/j.isci.2023.107842.Peer-Reviewed Original ResearchParkinson's diseasePyramidal cell synapsesVisual cortical functionSilicon probe recordingsPrimary visual cortexShort-term facilitationFamilial Parkinson's diseaseCortical dysfunctionMotor deficitsMotor symptomsCell synapsesCortical functionRepetitive stimulationVisual cortexOptokinetic responseReleasable poolProlonged stimulationLayer 4Visual responsesMiceSynaptic vesiclesEye movementsOrientation selectivityDysfunctionFunction mutationsStudying Membrane Protein–Lipid Specificity through Direct Native Mass Spectrometric Analysis from Tunable Proteoliposomes
Panda A, Brown C, Gupta K. Studying Membrane Protein–Lipid Specificity through Direct Native Mass Spectrometric Analysis from Tunable Proteoliposomes. Journal Of The American Society For Mass Spectrometry 2023, 34: 1917-1927. PMID: 37432128, PMCID: PMC10932607, DOI: 10.1021/jasms.3c00110.Peer-Reviewed Original ResearchConceptsIntegral membrane proteinsMembrane proteinsNative mass spectrometryTrafficking pathwaysPlasma membraneEukaryotic integral membrane proteinsEndoplasmic reticulumBiophysical propertiesMembrane protein assemblySynaptic vesiclesCellular trafficking pathwaysOrganellar membranesLipid specificityTransmembrane proteinProtein assembliesMembrane contextMass spectrometric analysisProteinNative mass spectrometric analysesVAMP2Lipid compositionExogenous ligandsLipid membranesIndividual lipidsMembraneThe active zone protein CLA-1 (Clarinet) bridges two subsynaptic domains to regulate presynaptic sorting of ATG-9
Xuan Z, Colón-Ramos D. The active zone protein CLA-1 (Clarinet) bridges two subsynaptic domains to regulate presynaptic sorting of ATG-9. Autophagy 2023, 19: 2807-2808. PMID: 37389488, PMCID: PMC10472863, DOI: 10.1080/15548627.2023.2229227.Peer-Reviewed Original ResearchConceptsATG-9Forward genetic screenAdaptor protein complexesIntegral synaptic vesicle proteinsActive zone proteinsSynaptic vesicle cycleCLA-1Synaptic vesicle proteinsGenetic screenPeriactive zoneAutophagosome biogenesisProtein complexesVesicle cycleVesicle proteinsLong isoformNovel roleSubsynaptic domainsZone proteinNeuronal synapsesSynaptic vesiclesProteinDistinct mechanismsVesiclesMutantsPresynaptic localizationcAMP−EPAC−PKCε−RIM1α signaling regulates presynaptic long-term potentiation and motor learning
Wang X, Zhou L, Dong B, Xu F, Wang D, Shen E, Cai X, Wang Y, Wang N, Ji S, Chen W, Schonewille M, Zhu J, De Zeeuw C, Shen Y. cAMP−EPAC−PKCε−RIM1α signaling regulates presynaptic long-term potentiation and motor learning. ELife 2023, 12: e80875. PMID: 37159499, PMCID: PMC10171863, DOI: 10.7554/elife.80875.Peer-Reviewed Original ResearchConceptsPresynaptic long-term potentiationSignaling cascadesPresynaptic plasticityRelease of synaptic vesiclesLong-term potentiationThreonine phosphorylationSynaptic vesiclesFunctional relevancePurkinje cell synapsesMotor behaviorPresynaptic formLearning mechanismCerebellar learning mechanismsCascadeLearningCell synapsesBasic performanceMotor learningThreonineMotor skillsSignalVesiclesThe active zone protein Clarinet regulates synaptic sorting of ATG-9 and presynaptic autophagy
Xuan Z, Yang S, Clark B, Hill S, Manning L, Colón-Ramos D. The active zone protein Clarinet regulates synaptic sorting of ATG-9 and presynaptic autophagy. PLOS Biology 2023, 21: e3002030. PMID: 37053235, PMCID: PMC10101500, DOI: 10.1371/journal.pbio.3002030.Peer-Reviewed Original ResearchConceptsATG-9Presynaptic autophagyAdaptor protein complexesZone proteinActive zone proteinsC. elegans neuronsSynaptic vesicle proteinsGenetic screenPeriactive zoneAutophagosome biogenesisCellular homeostasisProtein complexesVesicle proteinsGenetic analysisLong isoformNovel roleSynaptic vesiclesAutophagyDistinct mechanismsProteinVesiclesSortingCLA-1Abnormal accumulationActive zone
2022
Synaptotagmin rings as high-sensitivity regulators of synaptic vesicle docking and fusion
Zhu J, McDargh ZA, Li F, Krishnakumar SS, Rothman JE, O’Shaughnessy B. Synaptotagmin rings as high-sensitivity regulators of synaptic vesicle docking and fusion. Proceedings Of The National Academy Of Sciences Of The United States Of America 2022, 119: e2208337119. PMID: 36103579, PMCID: PMC9499556, DOI: 10.1073/pnas.2208337119.Peer-Reviewed Original ResearchConceptsVesicle dockingPlasma membrane domainsSynaptic vesiclesCalcium sensor synaptotagminSynaptic vesicle dockingInhibitor of fusionFusion clampSensor synaptotagminMembrane domainsTrigger fusionPlasma membraneC2AB domainAnionic phospholipid bilayersNeuronal synapsesMembrane compositionPhospholipid monolayersATP levelsVesiclesExocytotic releaseDockingPhospholipid bilayers
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