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Positioning of the α-Subunit Isoforms Confers a Functional Signature to γ-Aminobutyric Acid Type A Receptors
Frédéric Minier, Erwin Sigel and Arthur Karlin
Proceedings of the National Academy of Sciences of the United States of America
Vol. 101, No. 20 (May 18, 2004), pp. 7769-7774
Published by: National Academy of Sciences
Stable URL: http://www.jstor.org/stable/3372269
Page Count: 6
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Fast synaptic inhibitory transmission in the CNS is mediated by γ-aminobutyric acid type A ( GABA A) 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, α 1 and α 6, in a single pentamer. For this purpose, we used concatenated subunit receptors in which subunit arrangement is predefined. The resulting receptors were expressed in Xenopus oocytes and analyzed by using the two-electrode voltage-clamp technique. Thus, we have characterized γ 2β 2α 1β 2α 1, γ 2β 2α 6β 2α 6, γ 2β 2α 1β 2α 6, and γ 2β 2α 6β 2α 1 GABA A receptors. 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 α 6-subunit is sufficient to confer high furosemide sensitivity, and that the diazepam efficacy is determined exclusively by the α-subunit neighboring the γ 2-subunit. By using this diagnostic tool, it should become possible to determine the subunit arrangement of receptors expressed in vivo that contain α 1- and α 6-subunits. This method may also be applied to the study of other ion channels.
Proceedings of the National Academy of Sciences of the United States of America © 2004 National Academy of Sciences