GABAA receptor subtypes: dissecting their pharmacological functions

doi:10.1016/S0165-6147(00)01646-1

Trends in Pharmacological Sciences

Volume 22, Issue 4, 1 April 2001, Pages 188-194

https://doi.org/10.1016/S0165-6147(00)01646-1 Get rights and content

Abstract

The enhancement of GABA-mediated synaptic transmission underlies the pharmacotherapy of various neurological and psychiatric disorders. GABA_A receptors are pluripotent drug targets that display an extraordinary structural heterogeneity: they are assembled from a repertoire of at least 18 subunits (α1–6, β1–3, γ1–3, δ, ε, θ, ρ1–3). However, differentiating defined GABA_A receptor subtypes on the basis of function has had to await recent progress in the genetic dissection of receptor subtypes in vivo. Evidence that the various actions of allosteric modulators of GABA_A receptors, in particular the benzodiazepines, can be attributed to specific GABA_A receptor subtypes will be discussed. Such discoveries could open up new avenues for drug development.

Section snippets

GABA_A receptors analyzed by gene-knockout strategies

In gene-knockout strategies, ablation of a particular receptor subunit would be expected to perturb the structure of a defined group of GABA_A receptors and cause a corresponding alteration in the physiology and pharmacology of the mutant mice. The best studied examples of this are mice with targeted mutations of the genes encoding α6-, β3-, δ- or γ2-subunits 4, 5.

Distinction of receptor subtypes by knock-in point mutations

The term knock-in point mutation refers to the replacement of a single amino acid codon in a defined gene in vivo. Studies on recombinant GABA_A receptors had indicated that a His to Arg point mutation in the benzodiazepine binding site of GABA_A receptors abolished binding of classical benzodiazpines but it apparently did not affect receptor assembly and sensitivity to GABA (Refs 26, 27). Thus, the corresponding knock-in point mutation is not expected to be susceptible to appreciable changes in

Subtype-selective ligands of the benzodiazepine site

These new insights into the subtype-specificity of benzodiazepine actions provide precise guidelines for the development of novel drugs with more selective actions and fewer side-effects than those currently in clinical use. A major factor in anxiolytic profiling is the avoidance of a response at α1-containing receptors in favor of α2-, α3- and α5-containing receptors. The novel ligand L838417, developed and characterized by McKernan et al.³², is a breakthrough in this direction. L838417 binds

Concluding remarks

Targeting drugs to GABA_A receptor subtypes holds the promise of increased clinical specificity compared with the classical benzodiazepines, which act indiscriminately on all diazepam-sensitive GABA_A receptors. In addition, subtype-selective drugs are expected to display fewer side-effects, such as tolerance and dependence liability, because they affect only a small population of GABA_A receptors. Furthermore, subtype-specific ligands might be useful for the treatment of neuropsychiatric

Acknowledgements

We would like to thank Dietmar Benke and Jean-Marc Fritschy for critical reading of the manuscript and for the immunohistochemical and autoradiographical illustrations.

Glossary

Ro154513: ethyl 8-acido-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-α][1,4]benzodiazepine-3-carboxylate

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Trends in Pharmacological Sciences

ReviewGABAA receptor subtypes: dissecting their pharmacological functions

Abstract

Section snippets

GABAA receptors analyzed by gene-knockout strategies

Distinction of receptor subtypes by knock-in point mutations

Subtype-selective ligands of the benzodiazepine site

Concluding remarks

Acknowledgements

Glossary

Trends Pharmacol. Sci.

Mol. Cell. Neurosci.

Neuropharmacology

Pharmacol. Biochem. Behav.

Trends Pharmacol. Sci.

J. Biol. Chem.

FEBS Lett.

Eur. J. Pharmacol.

Curr. Opin. Pharmacol.

Structure and pharmacology of γ-aminobutyric acidA receptor subtypes

Pharmacol. Rev.

International Union of Pharmacology. XV. Subtypes of γ-aminobutyric acidA receptors: classification on the basis of subunit structure and receptor function

Pharmacol. Rev.

Function of GABAA-receptors: insights from mutant and knockout mice

Pharmacology and pathophysiology of GABAA-receptor subtypes

Gene knockout of the α6 subunit of the γ-aminobutyric acid type A receptor: lack of effect on responses to ethanol, pentobarbital, and general anesthetics

Mol. Pharmacol.

Cerebellar granule-cell-specific GABAA receptors attenuate benzodiazepine-induced ataxia: evidence from α6-subunit-deficient mice

Eur. J. Neurosci.

Ligand-gated ion channel subunit partnerships: GABAA receptor α6 subunit gene inactivation inhibits δ subunit expression

J. Neurosci.

Alterations in the expression of GABAA receptor subunits in cerebellar granule cells after the disruption of the α6 subunit gene

Eur. J. Neurosci.

Adaptive regulation of neuronal excitability by a voltage-independent potassium conductance

Nature

GABAA-receptor heterogeneity in the adult rat brain: differential regional and cellular distribution of seven major subunits

J. Comp. Neurol.

Mice devoid of γ-aminobutyrate type A receptor β3 subunit have epilepsy, cleft palate, and hypersensitive behavior

Proc. Natl. Acad. Sci. USA

Sensory thresholds and the antinociceptive effects of GABA receptor agonists in mice lacking the β3 subunit of the GABAA receptor

Neuroscience

Mice lacking the β3 subunit of the GABAA receptor have the epilepsy phenotype and many of the behavioral characteristics of Angelman syndrome

J. Neurosci.

Review
GABA_A receptor subtypes: dissecting their pharmacological functions

GABA_A receptors analyzed by gene-knockout strategies

Structure and pharmacology of γ-aminobutyric acid_A receptor subtypes

International Union of Pharmacology. XV. Subtypes of γ-aminobutyric acid_A receptors: classification on the basis of subunit structure and receptor function

Function of GABA_A-receptors: insights from mutant and knockout mice

Pharmacology and pathophysiology of GABA_A-receptor subtypes

Cerebellar granule-cell-specific GABA_A receptors attenuate benzodiazepine-induced ataxia: evidence from α6-subunit-deficient mice

Ligand-gated ion channel subunit partnerships: GABA_A receptor α6 subunit gene inactivation inhibits δ subunit expression

Alterations in the expression of GABA_A receptor subunits in cerebellar granule cells after the disruption of the α6 subunit gene

GABA_A-receptor heterogeneity in the adult rat brain: differential regional and cellular distribution of seven major subunits

Sensory thresholds and the antinociceptive effects of GABA receptor agonists in mice lacking the β3 subunit of the GABA_A receptor

Mice lacking the β3 subunit of the GABA_A receptor have the epilepsy phenotype and many of the behavioral characteristics of Angelman syndrome