Jochen Schwenk, Michaela Metz, Gerd Zolles, Rostislav Turecek, Thorsten Fritzius, Wolfgang Bildl, Etsuko Tarusawa, Akos Kulik, Andreas Unger, Klara Ivankova, Riad Seddik, Jim Y. Tiao, Mathieu Rajalu, Johana Trojanova, Volker Rohde, Martin Gassmann, Uwe Schulte, Bernd Fakler & Bernhard Bettler
GABAB receptors are the G-protein-coupled receptors for ?-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 (Cav) and inward-rectifier potassium (Kir) channels1. Molecular cloning revealed that functional GABAB receptors are formed by the heteromeric assembly of GABAB1 with GABAB2 subunits2, 3, 4, 5. However, cloned GABAB(1,2) receptors failed to reproduce the functional diversity observed with native GABAB receptors6, 7, 8. Here we show by functional proteomics that GABAB receptors in the brain are high-molecular-mass complexes of GABAB1, GABAB2 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 GABAB2 as tetramers. This co-assembly changes the properties of the GABAB(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 GABAB receptors that determine the pharmacology and kinetics of the receptor response.