Journal Article

Modular composition and dynamics of native GABAB receptors identified by high-resolution proteomics

Pérez-Garci, Enrique, Hanuschkin, Alexander, Schulte, Uwe, Klingauf, Jürgen, Schwenk, Jochen, Schneider, Andy, Raveh, Adi, Gauthier-Kemper, Anne, Fakler, Bernd, Kollewe, Astrid, Bildl, Wolfgang, Bettler, Bernhard, Fritzius, Thorsten, Dinamarca, Margarita C, Gassmann, Martin

2016

Overview

GABA B receptors are the most abundant inhibitory G protein–coupled receptors in the mammalian brain. Using high-resolution proteomics, the authors show that native GABA B receptors are macromolecular complexes with previously unknown complexity in subunit composition. This molecular diversity in structure and assembly encodes the diversity of GABA B physiology in the CNS. GABA B 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 GABA B receptors are macromolecular complexes with defined architecture, but marked diversity in subunit composition: the receptor core is assembled from GABA B1a/b , GABA B2 , 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 GABA B1a . Our results unravel the molecular diversity of GABA B receptors and their postnatal assembly dynamics and provide a roadmap for studying the cellular signaling of this inhibitory neurotransmitter receptor.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 14 / 14/19 / 38 / 631/378/1697/1691 / 631/378/340 / 82 / 82/58 / 82/83 / 9/74 / 96 / Amyloid beta-Protein Precursor - genetics / Animal Genetics and Genomics / Animals / Behavioral Sciences / Biological Techniques / Biomedicine / Biophysics / Brain / Caveolin 2 - genetics / Cell Membrane - genetics / Cell Membrane - metabolism / Epitopes / Mass spectrometry / Mice / Mice, Inbred BALB C / Mice, Knockout / Neurobiology / Neurosciences / Physiology / Proteins / Proteomics / Proteomics - methods / Rats / Rats, Wistar / Receptors, G-Protein-Coupled / Receptors, GABA-B - genetics / Receptors, GABA-B - metabolism / Scientific imaging / Signal Transduction - physiology