Native [GABA.sub.B] receptors are heteromultimers with a family of auxiliary subunits

[GABA.sub.B] receptors are the G-protein-coupled receptors for γ-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.sub.v]) and inward-rectifier potassium ([K.sub.ir]) channels (1). Molecular cloning revealed that functional [GABA.sub.B] receptors are formed by the heteromeric assembly of [GABA.sub.B1] with [GABA.sub.B2] subunits (2-5). However, cloned [GABA.sub.B(12)] receptors failed to reproduce the functional diversity observed with native [GABA.sub.B] receptors (6-8). Here we show by functional proteomics that [GABA.sub.B] receptors in the brain are high-molecular-mass complexes of [GABA.sub.B1], [GABA.sub.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.sub.B2] as tetramers. This co-assembly changes the properties of the [GABA.sub.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.sub.B] receptors that determine the pharmacology and kinetics of the receptor response.