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Auxiliary GABAB receptor subunits uncouple G protein betagamma subunits from effector channels to induce desensitization
JournalArticle (Originalarbeit in einer wissenschaftlichen Zeitschrift)
 
ID 4374377
Author(s) Turecek, Rostislav; Schwenk, Jochen; Fritzius, Thorsten; Ivankova, Klara; Zolles, Gerd; Adelfinger, Lisa; Jacquier, Valérie; Besseyrias, Valérie; Gassmann, Martin; Schulte, Uwe; Fakler, Bernd; Bettler, Bernhard
Author(s) at UniBasel Bettler, Bernhard
Year 2014
Title Auxiliary GABAB receptor subunits uncouple G protein betagamma subunits from effector channels to induce desensitization
Journal Neuron
Volume 82
Number 5
Pages / Article-Number 1032-44
Keywords Animals; Brain/metabolism; CHO Cells; Cricetulus; G Protein-Coupled Inwardly-Rectifying Potassium Channels/*metabolism; GTP-Binding Protein beta Subunits/*metabolism; GTP-Binding Protein gamma Subunits/*metabolism; HEK293 Cells; Humans; Intracellular Signaling Peptides and Proteins/metabolism; Mice; Receptors, GABA/*metabolism; Receptors, GABA-B/chemistry/*metabolism
Mesh terms Animals; Brain, metabolism; CHO Cells; Cricetulus; G Protein-Coupled Inwardly-Rectifying Potassium Channels, metabolism; GTP-Binding Protein beta Subunits, metabolism; GTP-Binding Protein gamma Subunits, metabolism; HEK293 Cells; Humans; Intracellular Signaling Peptides and Proteins, metabolism; Mice; Receptors, GABA, metabolism; Receptors, GABA-B, metabolism
Abstract Activation of K(+) channels by the G protein betagamma subunits is an important signaling mechanism of G-protein-coupled receptors. Typically, receptor-activated K(+) currents desensitize in the sustained presence of agonists to avoid excessive effects on cellular activity. The auxiliary GABAB receptor subunit KCTD12 induces fast and pronounced desensitization of the K(+) current response. Using proteomic and electrophysiological approaches, we now show that KCTD12-induced desensitization results from a dual interaction with the G protein: constitutive binding stabilizes the heterotrimeric G protein at the receptor, whereas dynamic binding to the receptor-activated Gbetagamma subunits induces desensitization by uncoupling Gbetagamma from the effector K(+) channel. While receptor-free KCTD12 desensitizes K(+) currents activated by other GPCRs in vitro, native KCTD12 is exclusively associated with GABAB receptors. Accordingly, genetic ablation of KCTD12 specifically alters GABAB responses in the brain. Our results show that GABAB receptors are endowed with fast and reversible desensitization by harnessing KCTD12 that intercepts Gbetagamma signaling.
Publisher Elsevier
ISSN/ISBN 0896-6273 ; 1097-4199
edoc-URL https://edoc.unibas.ch/61408/
Full Text on edoc No
Digital Object Identifier DOI 10.1016/j.neuron.2014.04.015
PubMed ID http://www.ncbi.nlm.nih.gov/pubmed/24836506
ISI-Number WOS:000337359800011
Document type (ISI) Journal Article
 
   

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