Consequence of the presence of two different beta subunit isoforms in a GABA(A) receptor

The major isoforms of GABA(A) receptors are thought to be composed of two alpha, two beta and one gamma subunit(s). GABA(A) receptors containing two beta1 subunits respond differently to the anticonvulsive compound loreclezole and the general anaesthetic etomidate than receptors containing two beta2...

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Bibliographic Details
Published in:Journal of neurochemistry 2005-12, Vol.95 (6), p.1724-1731
Main Authors: Boulineau, Nathalie, Baur, Roland, Minier, Frédéric, Sigel, Erwin
Format: Article
Language:English
Subjects:
Animals
DNA - biosynthesis
Dose-Response Relationship, Drug
Electrophysiology
Etomidate - pharmacology
GABA Agonists - pharmacology
gamma-Aminobutyric Acid - pharmacology
Hypnotics and Sedatives - pharmacology
Isomerism
Membrane Potentials - drug effects
Oocytes - metabolism
Patch-Clamp Techniques
Rats
Receptors, GABA-A - biosynthesis
Receptors, GABA-A - drug effects
Triazoles - pharmacology
Xenopus
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Summary:The major isoforms of GABA(A) receptors are thought to be composed of two alpha, two beta and one gamma subunit(s). GABA(A) receptors containing two beta1 subunits respond differently to the anticonvulsive compound loreclezole and the general anaesthetic etomidate than receptors containing two beta2 subunits. Receptors containing beta2 subunits show a much larger allosteric stimulation by these agents than those containing beta1 subunits. We were interested to know how receptors containing both beta1 and beta2 subunits, in different positions respond to loreclezole and etomidate. To answer this question, subunits were fused at the DNA level to form dimeric and trimeric subunits. Concatenated receptors (alpha1-beta1-alpha1/gamma2-beta1, alpha1-beta2-alpha1/gamma2-beta1, alpha1-beta1-alpha1/gamma2-beta2 and alpha1-beta2-alpha1/gamma2-beta2) were expressed in Xenopus ooctyes and functionally compared in their response to the agonist GABA and to the positive allosteric modulators, loreclezole and etomidate. We have shown that (I) in the presence of both beta1 and beta2 subunits in the same pentamer (mixed receptors) direct gating by etomidate is similar to exclusively beta1 containing receptors; (II) In mixed receptors, stimulation by etomidate assumed characteristics intermediate to exclusively beta1 or beta2 containing receptors, but the values for the concentrations < 10 microM were always much closer to those observed in alpha1-beta1-alpha1/gamma2-beta1 receptors; and (III) mixed receptors show no positional effects.
ISSN:0022-3042
1471-4159
DOI:10.1111/j.1471-4159.2005.03495.x