Paradoxical allosteric effects of competitive inhibitors on neuronal alpha7 nicotinic receptor mutants

Neuroreport
S BertrandD Bertrand

Abstract

Mutation of the conserved leucine residue, in the second transmembrane domain of the neuronal alpha7 acetylcholine receptor to a threonine (L247T) causes pleiotropic alterations of receptor properties. In this study we examined the effects of competitive inhibitors on the alpha7-L247T physiological responses. While the alpha7 competitive inhibitor dihydro-beta-erythroidine evoked a current comparable to that induced by ACh, other inhibitors such as methyllycaconitine (MLA) and alpha-bungarotoxin (alpha-Bgt) caused a blockade of alpha7-L247T to ACh activation. When applied in the absence of ACh, MLA or alpha-Bgt reduced the cell leakage current, showing that alpha7-L247T displays a significant fraction (10%) of spontaneously open channels. These data can be interpreted in terms of an allosteric model, assuming that the L247T mutant possesses a low isomerization constant L and that MLA and alpha-Bgt stabilize the closed, resting state.

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Citations

May 20, 1998·Comptes rendus de l'Académie des sciences. Série III, Sciences de la vie·S J EdelsteinJ P Changeux
Jun 12, 2001·Current Opinion in Neurobiology·J Changeux, S J Edelstein
Jun 14, 2001·The European Journal of Neuroscience·R J LukasD Bertrand
Mar 26, 2011·Proceedings of the National Academy of Sciences of the United States of America·Jaskiran K GillNeil S Millar
Jun 9, 2000·Annual Review of Neuroscience·H A Lester, A Karschin
Jun 3, 2000·Annual Review of Pharmacology and Toxicology·P J CorringerJ P Changeux
Mar 1, 2006·Proceedings of the National Academy of Sciences of the United States of America·Chris UlensTitia K Sixma
Nov 11, 1999·Proceedings of the National Academy of Sciences of the United States of America·E PalmaF Eusebi
Feb 28, 2001·Proceedings of the National Academy of Sciences of the United States of America·C LabarcaH A Lester
Mar 14, 2002·Proceedings of the National Academy of Sciences of the United States of America·Eleonora PalmaRicardo Miledi
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Jul 14, 2012·Trends in Pharmacological Sciences·Juan DuHuan-Xiang Zhou
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