Native GABAB receptors are heteromultimers with a family of auxiliary subunits

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

GABA_B 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 (Ca_v) and inward-rectifier potassium (K_ir) channels¹. Molecular cloning revealed that functional GABA_B receptors are formed by the heteromeric assembly of GABA_B1 with GABA_B2 subunits^{2, 3, 4, 5}. However, cloned GABA_B(1,2) receptors failed to reproduce the functional diversity observed with native GABA_B receptors^{6, 7, 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.