Activation mechanism of the heterodimeric GABA(B) receptor

Biochem Pharmacol. 2004 Oct 15;68(8):1565-72. doi: 10.1016/j.bcp.2004.06.035.

Abstract

The GABA(B) receptor was the first heteromeric G-protein coupled receptor (GPCR) identified. Indeed, both GABA(B1) and GABA(B2) subunits appear necessary to get a functional GABA(B) receptor. Soon after the cloning of both subunits, it was demonstrated that GABA(B2) was required for GABA(B1) to reach the cell surface. However, even a mutated GABA(B1) able to reach the cell surface is not functional alone despite its ability to bind GABA(B) ligands. This clearly demonstrated that GABA(B2) is not only required for the correct trafficking of GABA(B1) but also for the correct functioning of the receptor. In the present review article, we will summarize our actual knowledge of the specific role of each subunit in ligand recognition, intramolecular transduction, G-protein activation and allosteric modulation. We will show that the GABA(B) receptor is an heterodimer (not an hetero-oligomer), that agonists bind in GABA(B1), whereas GABA(B2) controls agonist affinity and is responsible for G-protein coupling. Finally, we will show that the recently identified positive allosteric modulator CGP7930 acts as a direct activator of the heptahelical domain of GABA(B2), being therefore the first GABA(B2) ligand identified so far.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Allosteric Regulation
  • Animals
  • Baclofen / pharmacology
  • Dimerization
  • GABA Agonists / pharmacology
  • GTP-Binding Proteins / metabolism
  • Humans
  • Protein Binding
  • Protein Structure, Tertiary
  • Protein Subunits
  • Receptors, G-Protein-Coupled / metabolism
  • Receptors, GABA-B / drug effects
  • Receptors, GABA-B / metabolism*
  • gamma-Aminobutyric Acid / metabolism*

Substances

  • GABA Agonists
  • Protein Subunits
  • Receptors, G-Protein-Coupled
  • Receptors, GABA-B
  • gamma-Aminobutyric Acid
  • GTP-Binding Proteins
  • Baclofen