title: ELKS1 localizes the synaptic vesicle priming protein bMunc13-2 to a specific subset of active zones.
abstract: Presynaptic active zones (AZs) are unique subcellular structures at neuronal synapses, which contain a network of specific proteins that control synaptic vesicle (SV) tethering, priming, and fusion. Munc13s are core AZ proteins with an essential function in SV priming. In hippocampal neurons, two different Munc13s-Munc13-1 and bMunc13-2-mediate opposite forms of presynaptic short-term plasticity and thus differentially affect neuronal network characteristics. We found that most presynapses of cortical and hippocampal neurons contain only Munc13-1, whereas ∼10% contain both Munc13-1 and bMunc13-2. Whereas the presynaptic recruitment and activation of Munc13-1 depends on Rab3-interacting proteins (RIMs), we demonstrate here that bMunc13-2 is recruited to synapses by the AZ protein ELKS1, but not ELKS2, and that this recruitment determines basal SV priming and short-term plasticity. Thus, synapse-specific interactions of different Munc13 isoforms with ELKS1 or RIMs are key determinants of the molecular and functional heterogeneity of presynaptic AZs.
authors.affiliation: Department of Molecular Neurobiology, Center for Nanoscale Microscopy and Molecular Physiology of the Brain, Max Planck Institute of Experimental Medicine, 37075 Göttingen, Germany.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kawabe
authors.affiliation: Light Microscopy Facility, Max Planck Institute of Experimental Medicine, 37075 Göttingen, Germany.
authors.forename: Miso
authors.initials: M
authors.lastname: Mitkovski
authors.affiliation: Department of Molecular and Cellular Physiology, Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94305.|Department of Neurobiology, Harvard Medical School, Boston, MA 02115.
authors.forename: Pascal S
authors.initials: PS
authors.lastname: Kaeser
authors.affiliation: Department of Neurogenetics, Max Planck Institute of Experimental Medicine, 37075 Göttingen, Germany.|Carl Ludwig Institute for Physiology, University of Leipzig, 04109 Leipzig, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Hirrlinger
authors.affiliation: Department of Neuro- and Sensory Physiology, University of Göttingen Medical Center, 37073 Göttingen, Germany.|Center for Biostructural Imaging of Neurodegeneration, University of Göttingen Medical Center, 37073 Göttingen, Germany.
authors.forename: Felipe
authors.identifier: 0000-0002-4968-9713
authors.initials: F
authors.lastname: Opazo
authors.affiliation: Department of Molecular Neurobiology, Center for Nanoscale Microscopy and Molecular Physiology of the Brain, Max Planck Institute of Experimental Medicine, 37075 Göttingen, Germany.
authors.forename: Dennis
authors.identifier: 0000-0002-0568-2552
authors.initials: D
authors.lastname: Nestvogel
authors.affiliation: Department of Molecular Neurobiology, Center for Nanoscale Microscopy and Molecular Physiology of the Brain, Max Planck Institute of Experimental Medicine, 37075 Göttingen, Germany.
authors.forename: Stefan
authors.identifier: 0000-0003-4496-5827
authors.initials: S
authors.lastname: Kalla
authors.affiliation: Department of Neurochemistry and Molecular Biology, Leibniz Institute of Neurobiology, 39118 Magdeburg, Germany.|Research Group Presynaptic Plasticity, Leibniz Institute of Neurobiology and Center for Behavioral Brain Sciences, Otto von Guericke University, 39106 Magdeburg, Germany.|Department of Psychiatry and Psychotherapy, University Hospital, Friedrich Alexander University Erlangen-Nuremberg, 91054 Erlangen, Germany.
authors.forename: Anna
authors.initials: A
authors.lastname: Fejtova
authors.affiliation: Department of Neurobiology, Max Planck Institute for Biophysical Chemistry, 37077 Göttingen, Germany.
authors.forename: Sophie E
authors.identifier: 0000-0003-1308-5229
authors.initials: SE
authors.lastname: Verrier
authors.affiliation: Department of Molecular Neurobiology, Center for Nanoscale Microscopy and Molecular Physiology of the Brain, Max Planck Institute of Experimental Medicine, 37075 Göttingen, Germany.
authors.forename: Simon R
authors.identifier: 0000-0002-2880-839X
authors.initials: SR
authors.lastname: Bungers
authors.affiliation: Department of Molecular Neurobiology, Center for Nanoscale Microscopy and Molecular Physiology of the Brain, Max Planck Institute of Experimental Medicine, 37075 Göttingen, Germany.
authors.forename: Benjamin H
authors.initials: BH
authors.lastname: Cooper
authors.affiliation: Department of Molecular Neurobiology, Center for Nanoscale Microscopy and Molecular Physiology of the Brain, Max Planck Institute of Experimental Medicine, 37075 Göttingen, Germany.
authors.forename: Frederique
authors.identifier: 0000-0002-3614-3121
authors.initials: F
authors.lastname: Varoqueaux
authors.affiliation: Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, TX 75390.
authors.forename: Yun
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030.|Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030.
authors.forename: Ralf B
authors.initials: RB
authors.lastname: Nehring
authors.affiliation: Department of Neurochemistry and Molecular Biology, Leibniz Institute of Neurobiology, 39118 Magdeburg, Germany.
authors.forename: Eckart D
authors.identifier: 0000-0001-9377-7414
authors.initials: ED
authors.lastname: Gundelfinger
authors.affiliation: Neuroscience Research Centre and NeuroCure, Charité, University Medicine Berlin, 10117 Berlin, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Rosenmund
authors.affiliation: Department of Neuro- and Sensory Physiology, University of Göttingen Medical Center, 37073 Göttingen, Germany.
authors.forename: Silvio O
authors.initials: SO
authors.lastname: Rizzoli
authors.affiliation: Department of Molecular and Cellular Physiology, Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94305.
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Südhof
authors.affiliation: Department of Molecular Neurobiology, Center for Nanoscale Microscopy and Molecular Physiology of the Brain, Max Planck Institute of Experimental Medicine, 37075 Göttingen, Germany.
authors.forename: Jeong-Seop
authors.initials: JS
authors.lastname: Rhee
authors.affiliation: Department of Molecular Neurobiology, Center for Nanoscale Microscopy and Molecular Physiology of the Brain, Max Planck Institute of Experimental Medicine, 37075 Göttingen, Germany brose@em.mpg.de.
authors.forename: Nils
authors.identifier: 0000-0003-0938-8534
authors.initials: N
authors.lastname: Brose
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D006624:Hippocampus / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D051379:Mice; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism; D020033:Protein Isoforms / Q000378:metabolism; D013569:Synapses / Q000378:metabolism*; D009435:Synaptic Transmission / Q000502:physiology; D013572:Synaptic Vesicles / Q000378:metabolism*; D020692:rab3 GTP-Binding Proteins / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D047908:Intracellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; D020033:Protein Isoforms; C485549:Unc13b protein, mouse; D020692:rab3 GTP-Binding Proteins