Current Awareness
Unraveling the function of GABAA receptor subtypes

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Abstract

GABAA receptors are Cl channels that can be opened by GABA and are the major inhibitory neurotransmitter receptors in the CNS. A variety of pharmacologically important drugs, such as benzodiazepines, barbiturates, neuroactive steroids, anesthetics and convulsants, produce at least part of their clinically relevant effects by interacting with distinct allosteric binding sites on GABAA receptors1.

Section snippets

Multiplicity of GABAA receptor subtypes

GABAA receptors are composed of five subunits that can belong to different subunit classes. So far, at least six α-, three β-, three γ-, one δ-, one ϵ-, one π-, one θ- and three ρ-subunits have been cloned from the mammalian nervous system 2., 3., and depending on their subunit composition, receptors exhibit distinct pharmacological and electrophysiological properties 1., 2.. Recent immunocytochemical studies have indicated that individual subunits exhibit a distinct and often widespread

Pharmacological and gene-knockout approaches for studying the function of GABAA receptor subtypes

What is the function of individual GABAA receptor subtypes in the brain? One way to answer this question is to study the effects of a selective pharmacological modulation of a certain receptor subtype. Although a large variety of allosteric binding sites have been identified on GABAA receptors 1, only a few compounds have been discovered so far that exhibit a certain subtype selectivity. Most of these compounds interact with the benzodiazepine binding site of GABAA receptors. Because this site

A novel strategy for investigating the function of GABAA receptor subtypes

In an attempt to identify the function of receptors that contain specific α-subunits, a new genetic approach was developed recently by Rudolph et al. 17. This approach was based on introducing a point mutation (His101Arg) into the α1-subunit of GABAA receptors, rendering α1-containing receptors insensitive to allosteric modulation by diazepam without altering their GABA sensitivity. In the absence of any change in signal intensity produced by the mutated receptors, animals possessing this

Studying effects of diazepam mediated by other GABAA receptor subtypes

Studies investigating the function of α2-, α3- or α5-subunit-containing receptors are underway in both laboratories 17., 18., using mice that carry the appropriate point mutation that renders the respective receptor subtypes diazepam-insensitive. Localization of α2 and α3 receptors in the amygdala and cortical regions point to these subtypes mediating the anxiolytic properties of the benzodiazepines, whereas α5 receptors located in the hippocampus 4., 5. might be involved in the

Concluding remarks

Recent progress in GABAA receptor research suggested the existence of far more receptor subtypes than previously assumed. These subtypes can now be identified by a newly developed method 7 and their regional, cellular and subcellular distribution can be studied by available subunit-specific antibodies 4., 5.. The distinct cellular and subcellular location of individual receptor subtypes 4., 5., 6. suggests that they exhibit specific functions in the brain. This conclusion is supported by the

Note added in proof

A study of mice carrying a point mutation in α2- or α3-subunits has recently been reported in Science 21.

Chemical name
L838417: 3-(2,5-difluorophenyl)-7-(1,1-dimethylethyl)-6-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-1,2,4-triazolo[4,3-b]pyridazine

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