Functional Domains of GABAA RECEPTORS

Functional domains of GABAA RECEPTORS

G.B. Smith and R. W. Olsen. TIPS 16:162-167.

This review discusses recent advances in the field of gamma aminobutyric acid-A (GABAA) receptors and their pharmacology. The authors summarize all current information on the molecular biology and pharmacology of the structure of GABAA receptors, the GABA binding site, the benzodiazepine binding site and ion channels. A convincing argument is developed for using information gathered on one member of the transmitter-gated ion channel receptors as models for other members of the superfamily. The authors conclude by presenting and justifying a model describing the functional domain of a transmitter-gated ion channel based on data collected for the GABAA receptor.

GABAA receptors mediate the majority of inhibitory synaptic transmissions in the central nervous system (CNS) and are members of the superfamily of transmitter-gated ion channels that include nicotinic acetylcholine receptors and inhibitory glycine receptors. GABAA receptors contain recognition sites that bind with gamma aminobutyric acid (GABA) - the most ubiquitous neurotransmitter in the brain - and many important neuroactive drugs including benzodiazepines, barbiturates, steroids, general anesthetics and possibly alcohol. These binding sites are directly or indirectly involved in mediating the gating properties of integral Cl- channels.

GABAA receptors - and other members of the superfamily - are heteropentameric pseudo-symm

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, Thr244, Tyr247, Tyr200 and Try241 are critical for channel opening, closing and desensitization kinetics. In addition to the specific residues that have been identified as being actively involved in agonist and antagonist binding, transmitter-gated ion channel receptors may have agonist binding sites at the interface between two dissimilar subunits. Photoaffinity labeling has revealed binding activity at the (-( subunit interface and the (-( subunit interface. Interestingly, the active residues at the interfaces of the ( and ( subunits of nicotinic acetylcholine receptors are located in the region that is homologous with the previously mentioned Phe64 in the GABAA receptor (1 subunit. In recombinant GABAA receptors it has been shown that multiple combinations of subunits can express channels, however a minimal composition of ( and ( subunits are required for the reconstruction of agonist-dependent gating. The interaction of GABAA receptors and the clinically relevant compounds known as benzodiazepines is highly complex. Benzodiazepines act by increasing the probability of Cl- channel opening in the presence of GABA, but cannot open Cl- channels alone. Photoaffinity labeling has revealed that benzodiazepines bind to distinc

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