title: Molecular mechanisms of GABA(B) receptor activation: new insights from the mechanism of action of CGP7930, a positive allosteric modulator.
abstract: The GABA(B) (gamma-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).
authors.affiliation: Laboratory of Functional Genomics, CNRS UPR-2580, Montpellier, France.
authors.forename: V
authors.initials: V
authors.lastname: Binet
authors.forename: C
authors.initials: C
authors.lastname: Goudet
authors.forename: C
authors.initials: C
authors.lastname: Brajon
authors.forename: L
authors.initials: L
authors.lastname: Le Corre
authors.forename: F
authors.initials: F
authors.lastname: Acher
authors.forename: J-P
authors.initials: JP
authors.lastname: Pin
authors.forename: L
authors.initials: L
authors.lastname: Prézeau
mesh_terms: D000495:Allosteric Site; D001665:Binding Sites; D002460:Cell Line; D006801:Humans; D008954:Models, Biological; D008958:Models, Molecular; D010636:Phenols / Q000737:chemistry*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D018080:Receptors, GABA-B / Q000378:metabolism*
chemical_list: C438607:2,6-di-tert-butyl-4-(3-hydroxy-2,2-dimethylpropyl)phenol; D010636:Phenols; D018080:Receptors, GABA-B