You are not currently logged in.
Access your personal account or get JSTOR access through your library or other institution:
If You Use a Screen ReaderThis content is available through Read Online (Free) program, which relies on page scans. Since scans are not currently available to screen readers, please contact JSTOR User Support for access. We'll provide a PDF copy for your screen reader.
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
Since scans are not currently available to screen readers, please contact JSTOR User Support for access. We'll provide a PDF copy for your screen reader.
Preview not available
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