Molecular mechanisms of GABA_B receptor activation: new insights from the mechanism of action of CGP7930, a positive allosteric modulator

The GABA_B (γ-aminobutyric acid-B) receptor is composed of two subunits, GABA_B1 and GABA_B2. Both subunits share structural homology with other class-III G-protein-coupled receptors. They contain two main domains, a heptahelical domain typical of all G-protein-coupled receptors and a large ECD (extracellular domain). It has not been demonstrated whether the association of these two subunits is always required for function. However, GABA_B2 plays a major role in coupling with G-proteins, and GABA_B1 has been shown to bind GABA. To date, only ligands interacting with GABA_B1-ECD have been identified. In the present study, we explored the mechanism of action of CGP7930, a compound described as a positive allosteric regulator of the GABA_B receptor. We have shown that it can weakly activate the wild-type GABA_B receptor, but also the GABA_B2 expressed alone, thus being the first described agonist of GABA_B2. CGP7930 retains its weak agonist activity on a GABA_B2 subunit deleted of its ECD. Thus the heptahelical domain of GABA_B2 behaves similar to a rhodopsin-like receptor. These results open new strategies for studying the mechanism of activation of GABA_B receptor and examine any possible role of GABA_B2.