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

Sonia Bertrand (1) , Anne Devillers-Thiéry (2) , Eleonora Palma (1) , Bruno Buisson (1) , Stuart J. Edelstein (1) , Pierre-Jean Corringer (2) , Jean-Pierre Changeux (2, 3) , Daniel Bertrand (1)

1 CMU - Centre médical universitaire de Genève
2 Neurobiologie moléculaire
3 RC - Récepteurs et Cognition

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.

Domains: Life Sciences [q-bio]; Neurons and Cognition [q-bio.NC]

Sonia Bertrand, Anne Devillers-Thiéry, Eleonora Palma, Bruno Buisson, Stuart J. Edelstein, et al.. Paradoxical allosteric effects of competitive inhibitors on neuronal alpha7 nicotinic receptor mutants. NeuroReport, 1997, 8 (16), pp.3591-6. ⟨pasteur-01718282⟩