Format

Send to

Choose Destination
Biochem Pharmacol. 2004 Oct 15;68(8):1675-84.

Fishing for allosteric sites on GABA(A) receptors.

Author information

1
Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, Room CHS 23-120, 650 Young Drive South, Los Angeles, CA 90095-1735, USA. rolsen@mednet.ucla.edu

Abstract

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.

PMID:
15451411
DOI:
10.1016/j.bcp.2004.07.026
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center