Publication Date:
2010-04-20
Description:
GABA(B) receptors are the G-protein-coupled receptors for gamma-aminobutyric acid (GABA), the main inhibitory neurotransmitter in the brain. They are expressed in almost all neurons of the brain, where they regulate synaptic transmission and signal propagation by controlling the activity of voltage-gated calcium (Ca(v)) and inward-rectifier potassium (K(ir)) channels. Molecular cloning revealed that functional GABA(B) receptors are formed by the heteromeric assembly of GABA(B1) with GABA(B2) subunits. However, cloned GABA(B(1,2)) receptors failed to reproduce the functional diversity observed with native GABA(B) receptors. Here we show by functional proteomics that GABA(B) receptors in the brain are high-molecular-mass complexes of GABA(B1), GABA(B2) and members of a subfamily of the KCTD (potassium channel tetramerization domain-containing) proteins. KCTD proteins 8, 12, 12b and 16 show distinct expression profiles in the brain and associate tightly with the carboxy terminus of GABA(B2) as tetramers. This co-assembly changes the properties of the GABA(B(1,2)) core receptor: the KCTD proteins increase agonist potency and markedly alter the G-protein signalling of the receptors by accelerating onset and promoting desensitization in a KCTD-subtype-specific manner. Taken together, our results establish the KCTD proteins as auxiliary subunits of GABA(B) receptors that determine the pharmacology and kinetics of the receptor response.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Schwenk, Jochen -- Metz, Michaela -- Zolles, Gerd -- Turecek, Rostislav -- Fritzius, Thorsten -- Bildl, Wolfgang -- Tarusawa, Etsuko -- Kulik, Akos -- Unger, Andreas -- Ivankova, Klara -- Seddik, Riad -- Tiao, Jim Y -- Rajalu, Mathieu -- Trojanova, Johana -- Rohde, Volker -- Gassmann, Martin -- Schulte, Uwe -- Fakler, Bernd -- Bettler, Bernhard -- Wellcome Trust/United Kingdom -- England -- Nature. 2010 May 13;465(7295):231-5. doi: 10.1038/nature08964. Epub 2010 Apr 18.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institute of Physiology II, University of Freiburg, Engesserstrasse 4, 79108 Freiburg, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20400944" target="_blank"〉PubMed〈/a〉
Keywords:
Animals
;
CHO Cells
;
Cricetinae
;
Cricetulus
;
Electric Conductivity
;
GABA-B Receptor Agonists
;
Heterotrimeric GTP-Binding Proteins/metabolism
;
Kinetics
;
Mice
;
Multiprotein Complexes/*chemistry/*metabolism
;
Neurons/metabolism
;
Oocytes/metabolism
;
Potassium/metabolism
;
Potassium Channels/metabolism
;
*Protein Multimerization
;
Protein Structure, Tertiary
;
Protein Subunits/*chemistry/*metabolism
;
Rats
;
Rats, Wistar
;
Receptors, GABA-B/*chemistry/*metabolism
;
Signal Transduction
;
Xenopus
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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