Gamma-aminobutyric acidA receptor structure and function.

Abstract

The major type of receptor for the most important inhibitory neurotransmitter y-aminobutyric acid (GABA)' in the mammalian central nervous system is the GABAA receptor.The far reaching functional significance of GABA suggests a role for GABAA receptors in human neurological and psychiatric disorders (1) and in the mechanism of action of numerous clinically important drugs (2).The GABAA receptor is a member of a gene superfamily of ligand-gated ion channel receptors which are typified by a hetero-oligomeric complex that spans the membrane to form an ion channel.Binding of a specific neurotransmitter ligand to the receptor protein controls the opening and closing of the ion channel (3, 4).The GABAA receptor channel is constituted from a family of 15 or so genes encoding for related but different polypeptides.Homologous sequence domains among members of the family and superfamily are believed to have conserved structural and functional features.This article will briefly summarize the latest information available on the GABAA receptor-ion channel complex.The literature cited is illustrative, not exhaustive. GABA Receptor Physiology and PharmacologyThe GABAA receptor is a macromolecular complex, the GABA-benzodiazepine receptor/chloride channel protein (2, 4).The complex consists of five major binding domains: sites for GABA, benzodiazepines, barbiturates, picrotoxin, and the anesthetic steroids.These binding domains serve to modulate the receptor's response to GABA activation.An integral part of this complex is the chloride channel.GABA analogs such as muscimol, an ingredient of the hallucinogenic mushroom Amanita muscaria, act as agonists, binding to the GABA site and opening the C1-channel.The plant-derived convulsant bicuculline is considered the definitive competitive antagonist of GABAA receptors (2).Electrophysiological investigations of GABAA receptor function including single channel recording indicate that it mediates an increase in membrane chloride permeability, resulting in inhibition of electrical activity of the postsynaptic cell (5, 6).Ion channel activation involves complex kinetics of opening and closing on a millisecond time scale and desensitizes in the continuing presence of GABA.36Cl-flux studies NS22071, NS28772, AA07680, and HD06576.