title: Differential compartmentalization and distinct functions of GABAB receptor variants.
abstract: GABAB receptors are the G protein-coupled receptors for the main inhibitory neurotransmitter in the brain, gamma-aminobutyric acid (GABA). Molecular diversity in the GABAB system arises from the GABAB1a and GABAB1b subunit isoforms that solely differ in their ectodomains by a pair of sushi repeats that is unique to GABAB1a. Using a combined genetic, physiological, and morphological approach, we now demonstrate that GABAB1 isoforms localize to distinct synaptic sites and convey separate functions in vivo. At hippocampal CA3-to-CA1 synapses, GABAB1a assembles heteroreceptors inhibiting glutamate release, while predominantly GABAB1b mediates postsynaptic inhibition. Electron microscopy reveals a synaptic distribution of GABAB1 isoforms that agrees with the observed functional differences. Transfected CA3 neurons selectively express GABAB1a in distal axons, suggesting that the sushi repeats, a conserved protein interaction motif, specify heteroreceptor localization. The constitutive absence of GABAB1a but not GABAB1b results in impaired synaptic plasticity and hippocampus-dependent memory, emphasizing molecular differences in synaptic GABAB functions.
authors.affiliation: Department of Clinical-Biological Sciences, Institute of Physiology, Pharmazentrum, University of Basel, CH-4056 Basel, Switzerland.
authors.forename: Réjan
authors.initials: R
authors.lastname: Vigot
authors.forename: Samuel
authors.initials: S
authors.lastname: Barbieri
authors.forename: Hans
authors.initials: H
authors.lastname: Bräuner-Osborne
authors.forename: Rostislav
authors.initials: R
authors.lastname: Turecek
authors.forename: Ryuichi
authors.initials: R
authors.lastname: Shigemoto
authors.forename: Yan-Ping
authors.initials: YP
authors.lastname: Zhang
authors.forename: Rafael
authors.initials: R
authors.lastname: Luján
authors.forename: Laura H
authors.initials: LH
authors.lastname: Jacobson
authors.forename: Barbara
authors.initials: B
authors.lastname: Biermann
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Fritschy
authors.forename: Claire-Marie
authors.initials: CM
authors.lastname: Vacher
authors.forename: Matthias
authors.initials: M
authors.lastname: Müller
authors.forename: Gilles
authors.initials: G
authors.lastname: Sansig
authors.forename: Nicole
authors.initials: N
authors.lastname: Guetg
authors.forename: John F
authors.initials: JF
authors.lastname: Cryan
authors.forename: Klemens
authors.initials: K
authors.lastname: Kaupmann
authors.forename: Martin
authors.initials: M
authors.lastname: Gassmann
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Oertner
authors.forename: Bernhard
authors.initials: B
authors.lastname: Bettler
mesh_terms: D000818:Animals; D015152:Blotting, Northern; D019706:Excitatory Postsynaptic Potentials / Q000502:physiology; D006624:Hippocampus / Q000378:metabolism* / Q000648:ultrastructure; D007150:Immunohistochemistry; D008568:Memory / Q000502:physiology; D051379:Mice; D008817:Mice, Mutant Strains; D018613:Microscopy, Confocal; D046529:Microscopy, Electron, Transmission; D009473:Neuronal Plasticity / Q000502:physiology*; D009474:Neurons / Q000378:metabolism*; D020033:Protein Isoforms / Q000235:genetics; D018080:Receptors, GABA-B / Q000235:genetics / Q000378:metabolism*; D013569:Synapses / Q000378:metabolism* / Q000648:ultrastructure; D014162:Transfection
chemical_list: D020033:Protein Isoforms; D018080:Receptors, GABA-B