Abstract
The gamma-aminobutyric acid, type B (GABA(B)) receptor is well recognized as being composed of two subunits, GABA(B1) and GABA(B2). Both subunits share structural homology with other class-III G-protein-coupled receptors. They are composed of two main domains: a heptahelical domain (HD) typical of all G-protein-coupled receptors and a large extracellular domain (ECD). Although GABA(B1) binds GABA, GABA(B2) is required for GABA(B1) to reach the cell surface. However, it is still not demonstrated whether the association of these two subunits is always required for function in the brain. Indeed, GABA(B2) plays a major role in the coupling of the heteromer to G-proteins, such that it is possible that GABA(B2) can transmit a signal in the absence of GABA(B1). Today only ligands interacting with GABA(B1) ECD have been identified. Thus, the compounds acting exclusively on the GABA(B2) subunit will be helpful in analyzing the specific role of this subunit in the brain. Here, we explored the mechanism of action of CGP7930, a compound described as a positive allosteric regulator of the GABA(B) receptor. We showed that it activates the wild type GABA(B) receptor but with a low efficacy. The GABA(B2) HD is necessary for this effect, although one cannot exclude that CGP7930 could also bind to GABA(B1). Of interest, CGP7930 could activate GABA(B2) expressed alone and is the first described agonist of GABA(B2). Finally, we show that CGP7930 retains its agonist activity on a GABA(B2) subunit deleted of its ECD. This demonstrates that the HD of GABA(B2) behaves similar to a rhodopsin-like receptor, because it can reach the cell surface alone, can couple to G-protein, and be activated by agonists. These data open new strategies for studying the mechanism of activation of GABA(B) receptor and examine any possible role of homomeric GABA(B2) receptors.
Highlights
The ␥-aminobutyric acid, type B (GABAB)1 receptor is a G-protein-coupled receptor (GPCR) activated by the most abun
In support of a functional role of GABAB2 in the absence of GABAB1, homodimeric GABAB2 receptors have been observed at the surface of heterologous cells [24] and homodimeric GABAB2 heptahelical domain (HD) are capable of activating G-proteins [20, 21]
We explored the mechanism of action of CGP7930, one of the first described positive allosteric modulators of the GABAB receptor [44]
Summary
The ␥-aminobutyric acid, type B (GABAB) receptor is a G-protein-coupled receptor (GPCR) activated by the most abun-. GPCRs have been identified for calcium-sensing and mGlu receptors (29 –31) Such compounds act either as non-competitive antagonists [32,33,34] or as positive allosteric modulators [35,36,37,38,39,40]. In each case, these compounds have been shown to bind within the HD of their targeted receptor [34, 41,42,43].
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