The GABAB (γ-aminobutyric acid-B) receptor is composed of two subunits, GABAB1 and GABAB2. 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, GABAB2 plays a major role in coupling with G-proteins, and GABAB1 has been shown to bind GABA. To date, only ligands interacting with GABAB1-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 GABAB receptor. We have shown that it can weakly activate the wild-type GABAB receptor, but also the GABAB2 expressed alone, thus being the first described agonist of GABAB2. CGP7930 retains its weak agonist activity on a GABAB2 subunit deleted of its ECD. Thus the heptahelical domain of GABAB2 behaves similar to a rhodopsin-like receptor. These results open new strategies for studying the mechanism of activation of GABAB receptor and examine any possible role of GABAB2.
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November 2004
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Conference Article|
October 26 2004
Molecular mechanisms of GABAB receptor activation: new insights from the mechanism of action of CGP7930, a positive allosteric modulator
V. Binet;
V. Binet
*Laboratory of Functional Genomics, CNRS UPR-2580, Montpellier, France
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C. Goudet;
C. Goudet
*Laboratory of Functional Genomics, CNRS UPR-2580, Montpellier, France
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C. Brajon;
C. Brajon
*Laboratory of Functional Genomics, CNRS UPR-2580, Montpellier, France
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L. Le Corre;
L. Le Corre
†Laboratory of Pharmacological and Toxicological Chemistry and Biochemistry, UMR 8601, University Paris-V, Paris, France
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F. Acher;
F. Acher
†Laboratory of Pharmacological and Toxicological Chemistry and Biochemistry, UMR 8601, University Paris-V, Paris, France
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J.-P. Pin;
J.-P. Pin
*Laboratory of Functional Genomics, CNRS UPR-2580, Montpellier, France
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L. Prézeau
L. Prézeau
1
*Laboratory of Functional Genomics, CNRS UPR-2580, Montpellier, France
1To whom correspondence should be addressed (email Laurent.Prezeau@ccipe.cnrs.fr).
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Publisher: Portland Press Ltd
Received:
July 06 2004
Online ISSN: 1470-8752
Print ISSN: 0300-5127
© 2004 The Biochemical Society
2004
Biochem Soc Trans (2004) 32 (5): 871–872.
Article history
Received:
July 06 2004
Citation
V. Binet, C. Goudet, C. Brajon, L. Le Corre, F. Acher, J.-P. Pin, L. Prézeau; Molecular mechanisms of GABAB receptor activation: new insights from the mechanism of action of CGP7930, a positive allosteric modulator. Biochem Soc Trans 1 November 2004; 32 (5): 871–872. doi: https://doi.org/10.1042/BST0320871
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