Native GABAB receptors are heteromultimers with a family of auxiliary subunits

GABA B receptor helpers A proteomics study of GABA B receptors, the receptors for γ-aminobutyric acid, the main inhibitory neurotransmitter in the brain, throws new light on the origin of their functional diversity. Rather than being heterodimers of the well-known GABA B1 and GABA B2 subunits, GABA B receptors are shown to be high-molecular-weight complexes of GABA B1 , GABA B2 and four sequence-related members of the KCTD (potassium channel tetramerization domain-containing) family of proteins. The KCTD proteins increase agonist potency and markedly alter the G-protein signalling of the receptors, suggesting that these proteins act as auxiliary subunits of GABA B receptors, determining the pharmacology and kinetics of the receptor response. GABA B receptors are the G-protein-coupled receptors for γ-aminobutyric acid (GABA), the main inhibitory neurotransmitter in the brain. Here, functional proteomics is used to show that GABA B receptors in the brain are complexes of GABA B1 , GABA B2 and members of a subfamily of KCTD proteins. The KCTD proteins increase the potency of agonists and markedly alter the G-protein signalling of the receptors, suggesting that they determine the pharmacology and kinetics of the receptor response. GABA 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 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 , 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 desens