title: Gating characteristics control glutamate receptor distribution and trafficking in vivo.
abstract: Glutamate-releasing synapses dominate excitatory release in the brain. Mechanisms governing their assembly are of major importance for circuit development and long-term plasticity underlying learning and memory. AMPA/Kainate-type glutamate receptors (GluRs) are tetrameric ligand-gated ion channels that open their ion-conducting pores in response to binding of the neurotransmitter. Changes in subunit composition of postsynaptic GluRs are highly relevant for plasticity and development of glutamatergic synapses [1-4]. To date, posttranslational modifications, mostly operating via the intracellular C-terminal domains (CTDs) of GluRs, are presumed to be the major regulator of trafficking [5]. In recent years, structural and electrophysiological analyses have improved our understanding of GluR gating mechanism [6-11]. However, whether conformational changes subsequent to glutamate binding may per se be able to influence GluR trafficking has remained an unaddressed question. Using a Drosophila system allowing for extended visualization of GluR trafficking in vivo, we here provide evidence that mutations changing the gating behavior alter GluR distribution and trafficking. GluR mutants associated with reduced charge transfer segregated from coexpressed wild-type GluRs on the level of individual postsynaptic densities. Segregation was lost upon blocking of evoked glutamate release. Photobleaching experiments suggested increased mobility of mutants with reduced charge transfer, which accumulated prematurely during early steps of synapse assembly, but failed to further increase their level in accordance with assembly of the presynaptic scaffold. In summary, gating characteristics seem to be a new variable for the understanding of GluR trafficking relevant to both development and plasticity.
authors.affiliation: Neurogenetik, Institut für Biologie, Freie Universität Berlin, 14195 Berlin, Germany; Cluster of Excellence NeuroCure, Charité-Universitätsmedizin Berlin, 10117 Berlin, Germany.
authors.forename: Astrid G
authors.initials: AG
authors.lastname: Petzoldt
authors.affiliation: Institute for Theoretical Biology, Humboldt University, 10115 Berlin, Germany.
authors.forename: Yü-Hien
authors.initials: YH
authors.lastname: Lee
authors.affiliation: Neurogenetik, Institut für Biologie, Freie Universität Berlin, 14195 Berlin, Germany; Cluster of Excellence NeuroCure, Charité-Universitätsmedizin Berlin, 10117 Berlin, Germany.
authors.forename: Omid
authors.initials: O
authors.lastname: Khorramshahi
authors.affiliation: Neurogenetik, Institut für Biologie, Freie Universität Berlin, 14195 Berlin, Germany; Cluster of Excellence NeuroCure, Charité-Universitätsmedizin Berlin, 10117 Berlin, Germany.
authors.forename: Eric
authors.initials: E
authors.lastname: Reynolds
authors.affiliation: Cluster of Excellence NeuroCure, Charité-Universitätsmedizin Berlin, 10117 Berlin, Germany; Leibniz Institut für Molekulare Pharmakologie, Berlin 13125, Germany.
authors.forename: Andrew J R
authors.initials: AJ
authors.lastname: Plested
authors.affiliation: Institute for Theoretical Biology, Humboldt University, 10115 Berlin, Germany. Electronic address: h.herzel@biologie.hu-berlin.de.
authors.forename: Hanspeter
authors.initials: H
authors.lastname: Herzel
authors.affiliation: Neurogenetik, Institut für Biologie, Freie Universität Berlin, 14195 Berlin, Germany; Cluster of Excellence NeuroCure, Charité-Universitätsmedizin Berlin, 10117 Berlin, Germany. Electronic address: stephan.sigrist@fu-berlin.de.
authors.forename: Stephan J
authors.initials: SJ
authors.lastname: Sigrist
mesh_terms: D000818:Animals; D029721:Drosophila Proteins / Q000235:genetics* / Q000378:metabolism; D004331:Drosophila melanogaster / Q000235:genetics* / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism; D015640:Ion Channel Gating; D009154:Mutation; D021381:Protein Transport; D017470:Receptors, Glutamate / Q000235:genetics* / Q000378:metabolism
chemical_list: D029721:Drosophila Proteins; D017470:Receptors, Glutamate; D018698:Glutamic Acid