title: Modular composition and dynamics of native GABAB receptors identified by high-resolution proteomics.
abstract: GABAB receptors, the most abundant inhibitory G protein-coupled receptors in the mammalian brain, display pronounced diversity in functional properties, cellular signaling and subcellular distribution. We used high-resolution functional proteomics to identify the building blocks of these receptors in the rodent brain. Our analyses revealed that native GABAB receptors are macromolecular complexes with defined architecture, but marked diversity in subunit composition: the receptor core is assembled from GABAB1a/b, GABAB2, four KCTD proteins and a distinct set of G-protein subunits, whereas the receptor's periphery is mostly formed by transmembrane proteins of different classes. In particular, the periphery-forming constituents include signaling effectors, such as Cav2 and HCN channels, and the proteins AJAP1 and amyloid-β A4, both of which tightly associate with the sushi domains of GABAB1a. Our results unravel the molecular diversity of GABAB receptors and their postnatal assembly dynamics and provide a roadmap for studying the cellular signaling of this inhibitory neurotransmitter receptor.
authors.affiliation: Institute of Physiology, University of Freiburg, Freiburg, Germany.|Center for Biological Signaling Studies (BIOSS), Freiburg, Germany.
authors.forename: Jochen
authors.initials: J
authors.lastname: Schwenk
authors.affiliation: Department of Biomedicine, Institute of Physiology, Pharmazentrum, University of Basel, Basel, Switzerland.
authors.forename: Enrique
authors.initials: E
authors.lastname: Pérez-Garci
authors.affiliation: Institute of Physiology, University of Freiburg, Freiburg, Germany.
authors.forename: Andy
authors.initials: A
authors.lastname: Schneider
authors.affiliation: Institute of Physiology, University of Freiburg, Freiburg, Germany.
authors.forename: Astrid
authors.initials: A
authors.lastname: Kollewe
authors.affiliation: Department of Cellular Biophysics, Institute of Medical Physics and Biophysics, University of Münster, Münster, Germany.
authors.forename: Anne
authors.initials: A
authors.lastname: Gauthier-Kemper
authors.affiliation: Department of Biomedicine, Institute of Physiology, Pharmazentrum, University of Basel, Basel, Switzerland.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Fritzius
authors.affiliation: Department of Biomedicine, Institute of Physiology, Pharmazentrum, University of Basel, Basel, Switzerland.
authors.forename: Adi
authors.initials: A
authors.lastname: Raveh
authors.affiliation: Department of Biomedicine, Institute of Physiology, Pharmazentrum, University of Basel, Basel, Switzerland.
authors.forename: Margarita C
authors.initials: MC
authors.lastname: Dinamarca
authors.affiliation: Optophysiology Lab, Department of Biology, University of Freiburg, Freiburg, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Hanuschkin
authors.affiliation: Institute of Physiology, University of Freiburg, Freiburg, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Bildl
authors.affiliation: Department of Cellular Biophysics, Institute of Medical Physics and Biophysics, University of Münster, Münster, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Klingauf
authors.affiliation: Department of Biomedicine, Institute of Physiology, Pharmazentrum, University of Basel, Basel, Switzerland.
authors.forename: Martin
authors.identifier: http://orcid.org/0000-0001-6201-3032
authors.initials: M
authors.lastname: Gassmann
authors.affiliation: Institute of Physiology, University of Freiburg, Freiburg, Germany.|Center for Biological Signaling Studies (BIOSS), Freiburg, Germany.|Logopharm GmbH, Freiburg, Germany.
authors.forename: Uwe
authors.initials: U
authors.lastname: Schulte
authors.affiliation: Department of Biomedicine, Institute of Physiology, Pharmazentrum, University of Basel, Basel, Switzerland.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Bettler
authors.affiliation: Institute of Physiology, University of Freiburg, Freiburg, Germany.|Center for Biological Signaling Studies (BIOSS), Freiburg, Germany.
authors.forename: Bernd
authors.initials: B
authors.lastname: Fakler
mesh_terms: D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D051243:Caveolin 2 / Q000235:genetics; D002462:Cell Membrane / Q000235:genetics / Q000378:metabolism; D000939:Epitopes; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D040901:Proteomics / Q000379:methods*; D051381:Rats; D017208:Rats, Wistar; D043562:Receptors, G-Protein-Coupled; D018080:Receptors, GABA-B / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology
chemical_list: D016564:Amyloid beta-Protein Precursor; C495545:Cav2 protein, mouse; D051243:Caveolin 2; D000939:Epitopes; D043562:Receptors, G-Protein-Coupled; D018080:Receptors, GABA-B