Structure, Pharmacology, and Function of GABAA Receptor Subtypes

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Publisher Summary

This chapter describes the structure, pharmacology, and function of γ‐aminobutyric acid type A (GABAA) receptor subtypes. GABAA receptors are the most important inhibitory transmitter receptors in the central nervous system (CNS). They are chloride channels that can be opened by GABA and modulated by a variety of different drugs, such as benzodiazepines, barbiturates, neuroactive steroids, anesthetics, and convulsants. These receptors are composed of five subunits that can belong to different subunit classes, giving rise to a large variety of distinct receptor subtypes. Depending on their subunit composition, these receptor subtypes exhibit distinct pharmacological and electrophysiological properties. The chapter reviews new compounds interacting with these receptors and novel receptor subtype‐selective compounds are discussed. The evidence for the function of distinct GABAA receptor subtypes in the brain is also summarized in the chapter. The information on the molecular structure of the extracellular and transmembrane domain of GABAA receptors based on the X‐ray crystallographic structure of the acetylcholine binding protein and on the cryo‐electronmicroscopic structure of the nicotinic acetylcholine receptor is provided in the chapter. This structure contains multiple solvent accessible cavities that are used by a variety of allosteric modulators for their interaction with GABAA receptors, explaining the rich pharmacology of the important receptors.

Section snippets

Chapter Overview

Gamma‐aminobutyric acid type A (GABAA) receptors are the most important inhibitory transmitter receptors in the central nervous system (CNS). They are chloride channels that can be opened by GABA and modulated by a variety of different drugs such as benzodiazepines, barbiturates, neuroactive steroids, anesthetics, and convulsants. These receptors are composed of five subunits that can belong to different subunit classes, giving rise to a large variety of distinct receptor subtypes. Depending on

Heterogeneity of GABAA Receptors

GABAA receptors are composed of five subunits that consist of a large N‐terminal extracellular domain, four transmembrane (TM) domains, and a large intracellular loop between TM3 and TM4 (Nayeem 1994, Schofield 1987, Tretter 1997). So far, a total of six α, three β, three γ, one δ, one ɛ, one π, one θ, and three ρ subunits of GABAA receptors have been cloned and sequenced from the mammalian nervous system, and for several of these subunits splice variants have been identified (Barnard 1998,

Pharmacology of GABAA Receptors

GABAA receptors not only can be directly activated or inhibited via their GABA binding site but can also be allosterically modulated by benzodiazepines, barbiturates, steroids, anesthetics, convulsants, and many other drugs, the number of which is constantly increasing (Korpi 2002, Sieghart 1995). Currently, only three distinct binding sites present on GABAA receptors can be directly investigated by appropriate radioligand binding studies: the GABA/muscimol‐, the benzodiazepine‐, and the

Function of GABAA Receptor Subtypes in the Brain

The large number of different GABAA receptor subtypes existing in the brain and the striking segregation of some of these subtypes in functionally different neuronal populations raise the possibility that a selective modulation of certain receptor subtypes will precipitate quite specific pharmacological effects and will make it possible to study the function of the respective receptors in the brain. So far, however, no pharmacological tools are available that can address a certain receptor

GABAA Receptor Structure

The GABAA receptor is a member of the superfamily of pentameric ligand‐gated ion channels that also includes the nACh receptor, the 5‐hydroxytryptamine type 3 receptor, and the glycine receptor. So far, no receptor belonging to this superfamily has been characterized structurally by X‐ray crystallography. In 2001, however, the X‐ray crystallographic structure of a soluble remote homolog of the N‐terminal domain of nACh receptor subunits, the acetylcholine binding protein (AChBP), has been

Acknowledgments

Work in the author's laboratory was supported by the Austrian Science Fund.

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