Fishing for allosteric sites on GABA(A) receptors

Biochem Pharmacol. 2004 Oct 15;68(8):1675-84. doi: 10.1016/j.bcp.2004.07.026.


GABA(A) receptors have structural and functional homology with a super-family of cys-loop ligand-gated ion channel receptors including the nicotinic acetylcholine receptors. Amino acid residues involved in ligand-binding pockets are homologous among super-family members, leading to the multiple-loop model of binding sites situated at subunit interfaces, validated by structural studies on the nicotinic acetylcholine receptor and water-soluble snail acetylcholine binding protein. This article will briefly review the literature on the agonist binding sites on the receptor super-family, and then describe the current situation for attempts to identify sites for allosteric modulators on the GABA(A) receptors. A combination of mutagenesis and photoaffinity labeling with anesthetic ligands has given some leads in this endeavor. Current work by others and ourselves focuses on three putative sites for modulators: (1) within the ion channel domain TM2, near the extracellular end; (2) the agonist binding sites and homologous pockets at other subunit interfaces of the pentameric receptor; and (3) on the linker region stretching from the agonist site loop C to the top of the TM1 region. It is likely that concrete structural information will be forthcoming soon.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Allosteric Site
  • Amino Acid Sequence
  • Anesthetics / pharmacology*
  • Binding Sites
  • Ethanol / pharmacology*
  • Ligands
  • Models, Molecular
  • Molecular Sequence Data
  • Protein Conformation
  • Receptors, GABA-A / chemistry*
  • Receptors, GABA-A / drug effects
  • Receptors, GABA-A / genetics
  • Receptors, GABA-A / metabolism


  • Anesthetics
  • Ligands
  • Receptors, GABA-A
  • Ethanol