DOI: 10.1073/pnas.0400220101. Positioning of the α-subunit isoforms confers a functional signature to γ-aminobutyric acid type A receptors

Positioning of the α-subunit isoforms confers a functional signature to γ-aminobutyric acid type A receptors

10.1073/pnas.0400220101

Crossref journal-article

Proceedings of the National Academy of Sciences

Proceedings of the National Academy of Sciences (341)

Abstract

Fast synaptic inhibitory transmission in the CNS is mediated by γ-aminobutyric acid type A (GABAA) receptors. They belong to the ligand-gated ion channel receptor superfamily, and are constituted of five subunits surrounding a chloride channel. Their clinical interest is highlighted by the number of therapeutic drugs that act on them. It is well established that the subunit composition of a receptor subtype determines its pharmacological properties. We have investigated positional effects of two different α-subunit isoforms, α1and α6, in a single pentamer. For this purpose, we used concatenated subunit receptors in which subunit arrangement is predefined. The resulting receptors were expressed inXenopusoocytes and analyzed by using the two-electrode voltage-clamp technique. Thus, we have characterized γ2β2α1β2α1, γ2β2α6β2α6, γ2β2α1β2α6, and γ2β2α6β2α1GABAAreceptors. We investigated their response to the agonist GABA, to the partial agonist piperidine-4-sulfonic acid, to the noncompetitive inhibitor furosemide and to the positive allosteric modulator diazepam. Each receptor isoform is characterized by a specific set of properties. In this case, subunit positioning provides a functional signature to the receptor. We furthermore show that a single α6-subunit is sufficient to confer high furosemide sensitivity, and that the diazepam efficacy is determined exclusively by the α-subunit neighboring the γ2-subunit. By using this diagnostic tool, it should become possible to determine the subunit arrangement of receptors expressedin vivothat contain α1- and α6-subunits. This method may also be applied to the study of other ion channels.

Bibliography

Minier, F., & Sigel, E. (2004). Positioning of the Î±-subunit isoforms confers a functional signature to Î³-aminobutyric acid type A receptors. Proceedings of the National Academy of Sciences, 101(20), 7769â7774.

Authors 2

Frédéric Minier (first)
Erwin Sigel (additional)

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Dates

Type	When
Created	21 years, 3 months ago (May 10, 2004, 9:04 p.m.)
Deposited	1 year, 7 months ago (Jan. 13, 2024, 5:28 a.m.)
Indexed	1 month, 4 weeks ago (July 3, 2025, 12:03 p.m.)
Issued	21 years, 3 months ago (May 10, 2004)
Published	21 years, 3 months ago (May 10, 2004)
Published Online	21 years, 3 months ago (May 10, 2004)
Published Print	21 years, 3 months ago (May 18, 2004)

Funders 0

None

BibTeX

@article{Minier_2004, title={Positioning of the α-subunit isoforms confers a functional signature to γ-aminobutyric acid type A receptors}, volume={101}, ISSN={1091-6490}, url={http://dx.doi.org/10.1073/pnas.0400220101}, DOI={10.1073/pnas.0400220101}, number={20}, journal={Proceedings of the National Academy of Sciences}, publisher={Proceedings of the National Academy of Sciences}, author={Minier, Frédéric and Sigel, Erwin}, year={2004}, month=may, pages={7769–7774} }

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