PMID: 22660477

 

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Title : Structure and functional interaction of the extracellular domain of human GABA(B) receptor GBR2

Abstract :

1. Inhibitory neurotransmission is mediated primarily by GABA
2. The metabotropic GABA(B) receptor is a G protein-coupled receptor central to mammalian brain function
3. Malfunction of GABA(B) receptor has been implicated in several neurological disorders
4. GABA(B) receptor functions as a heterodimeric assembly of GBR1 and GBR2 subunits , where GBR1 is responsible for ligand-binding and GBR2 is responsible for G protein coupling
5. Here we demonstrate that the GBR2 ectodomain directly interacts with the GBR1 ectodomain to increase agonist affinity by selectively stabilizing the agonist-bound conformation of GBR1
6. We present the crystal structure of the GBR2 ectodomain , which reveals a polar heterodimeric interface
7. We also identify specific heterodimer contacts from both subunits , and GBR1 residues involved in ligand recognition
8. Lastly, our structural and functional data indicate that the GBR2 ectodomain adopts a constitutively open conformation, suggesting a structural asymmetry in the active state of GABA(B) receptor that is unique to the GABAergic system