PMID: 9177245Jun 10, 1997Paper

Agonist-induced closure of constitutively open gamma-aminobutyric acid channels with mutated M2 domains

Proceedings of the National Academy of Sciences of the United States of America
Z H PanS A Lipton

Abstract

Ligand-gated ion channels display a fundamental property-channels remain virtually closed at rest and open upon agonist binding. Here we show that substituting alanines for either of two amino acid residues (T314 or L317) in the M2 region of the gamma-aminobutyric acid (GABA) rho1 subunit results in spontaneous channel opening in the absence of ligand. Surprisingly, for two single point mutants (T314A or L317A), application of very low concentrations of agonist partially suppressed this spontaneous current, while higher concentrations re-activated the receptors. When both of these sites were mutated (T314A/L317A), GABA nearly completely suppressed the constitutive current and did not re-activate the current even at very high concentrations. This study provides important new insights into the structure-function relationship of ligand-gated ion channels, where modification of the structure of the channel pore region not only alters the allosteric transition of the receptor protein but also reverses the polarity of agonist regulation of channel gating. Our results suggest that the sites where these two residues are located are structurally critical for channel gating.

References

Apr 1, 1991·Proceedings of the National Academy of Sciences of the United States of America·G R CuttingG R Uhl
Apr 1, 1986·Proceedings of the National Academy of Sciences of the United States of America·J GiraudatJ P Changeux
Dec 1, 1974·Proceedings of the National Academy of Sciences of the United States of America·S R ZukinS H Snyder
Jun 1, 1984·Proceedings of the National Academy of Sciences of the United States of America·M B Jackson
Jan 31, 1995·Proceedings of the National Academy of Sciences of the United States of America·K OhnoA G Engel
Aug 1, 1993·Proceedings of the National Academy of Sciences of the United States of America·D BertrandJ P Changeux
Jan 14, 1993·Nature·H Qian, J E Dowling
Feb 20, 1993·Journal of Molecular Biology·N Unwin
Dec 5, 1995·Proceedings of the National Academy of Sciences of the United States of America·D ZhangS A Lipton
Feb 7, 1996·Biochimica Et Biophysica Acta·T Ogurusu, R Shingai
Mar 5, 1996·Proceedings of the National Academy of Sciences of the United States of America·J L GalziJ Changeux
Aug 29, 1957·The Journal of Physiology·B KATZ, S THESLEFF
May 1, 1965·Journal of Molecular Biology·J MONODJ P CHANGEUX

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Citations

Mar 10, 2001·Trends in Pharmacological Sciences·D ZhangS A Lipton
Jun 16, 2000·Neuroscience·Z H PanS A Lipton
May 16, 2009·Acta Pharmacologica Sinica·Yong-chang ChangYao Huang
Aug 24, 1999·British Journal of Pharmacology·S A ThompsonK A Wafford
Oct 2, 2002·Journal of Neurochemistry·Michael J BecksteadS John Mihic
Oct 29, 2011·The Journal of Biological Chemistry·Timothy LynaghJoseph W Lynch
Dec 10, 2013·Psychopharmacology·Megan M EatonGustav Akk
Nov 17, 2015·ACS Chemical Neuroscience·Cecilia M BorgheseR Adron Harris
May 15, 2007·Progress in Brain Research·Mark Farrant, Kai Kaila
Dec 18, 1998·Neuron·J P Changeux, S J Edelstein
Dec 3, 1999·The Journal of Physiology·V E WotringD S Weiss
Jan 21, 2004·British Journal of Pharmacology·Juan D Goutman, Daniel J Calvo
Sep 5, 2001·FEBS Letters·V Itier, D Bertrand
Nov 19, 2004·The Journal of Biological Chemistry·Anna SedelnikovaYongchang Chang
Dec 14, 2017·Scientific Reports·Alfredo Alaniz-Palacios, Ataulfo Martínez-Torres
May 31, 2013·The Journal of Biological Chemistry·Shawnalea J FrazierHenry A Lester
Oct 13, 2000·The European Journal of Neuroscience·A GrekaD Zhang

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