Fishing for allosteric sites on GABA A receptors

• Published in: Biochemical pharmacology Vol. 68; no. 8; pp. 1675 - 1684
• Main Authors: Olsen, Richard W., Chang, Chang-Sheng S., Li, Guodong, Hanchar, H. Jacob, Wallner, Martin
• Format: Journal Article
• Language: English
• Published: England Elsevier Inc 15.10.2004
• Subjects: 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
• ISSN: 0006-2952; 1873-2968
• 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.