Trends in Pharmacological Sciences
ReviewGABAA receptor subtypes: dissecting their pharmacological functions
Section snippets
GABAA 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 GABAA 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 GABAA receptors had indicated that a His to Arg point mutation in the benzodiazepine binding site of GABAA 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 GABAA receptor subtypes holds the promise of increased clinical specificity compared with the classical benzodiazepines, which act indiscriminately on all diazepam-sensitive GABAA 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 GABAA 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
References (44)
- et al.
The benzodiazepine binding site of GABAA receptors
Trends Pharmacol. Sci.
(1997) Long-range interactions in neuronal gene expression: evidence from gene targeting in the GABA(A) receptor β2-α6-α1-γ2- subunit gene cluster
Mol. Cell. Neurosci.
(2000)Normal electrophysiological and behavioral responses to ethanol in mice lacking the long splice variant of the γ2 subunit of the γ-aminobutyrate type A receptor
Neuropharmacology
(1999)Mice lacking the long splice variant of the γ2 subunit of the GABA(A) receptor are more sensitive to benzodiazepines
Pharmacol. Biochem. Behav.
(2000)- et al.
Functional domains of GABAA receptors
Trends Pharmacol. Sci.
(1995) A single histidine in GABAA receptors is essential for benzodiazepine agonist binding
J. Biol. Chem.
(1992)Pharmacology of recombinant γ-aminobutyric acidA receptors rendered diazepam-insensitive by point-mutated α-subunits
FEBS Lett.
(1998)Comparison of the pharmacological profiles of the hypnotic drugs, zaleplon and zolpidem
Eur. J. Pharmacol.
(1996)GABAA-receptor subtypes: a new pharmacology
Curr. Opin. Pharmacol.
(2001)Structure and pharmacology of γ-aminobutyric acidA receptor subtypes
Pharmacol. Rev.
(2000)
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.
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