Journal
NATURE
Volume 465, Issue 7295, Pages 231-U121Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nature08964
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Funding
- Deutsche Forschungsgemeinschaft [SFB 746/TP16, SFB 780/A3, EXC294, SFB 780/A2]
- Wellcome Trust (ISRF)
- EU Synapse
- GACR [309/06/1304]
- Swiss Science Foundation [3100A0-117816]
- Fridericus Stiftung
- European Community [FP7/2007-2013, 201714]
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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(1). Molecular cloning revealed that functional GABA(B) receptors are formed by the heteromeric assembly of GABA(B1) with GABA(B2) subunits(2-5). However, cloned GABA(B(1,2)) receptors failed to reproduce the functional diversity observed with native GABA(B) receptors(6-8). 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.
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