Paradoxical allosteric effects of competitive inhibitors on neuronal α7 nicotinic receptor mutants


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Abstract

MUTATION of the conserved leucine residue, in the second transmembrane domain of the neuronal α7 acetylcholine receptor to a threonine (L247T) causes pleiotropic alterations of receptor properties. In this study we examined the effects of competitive inhibitors on the α7-L247T physiological responses. While the α7 competitive inhibitor dihydro-β-erythroidine evoked a current comparable to that induced by ACh, other inhibitors such as methyllycaconitine (MLA) and α-bungarotoxin (α-Bgt) caused a blockade of α7-L247T to ACh activation. When applied in the absence of ACh, MLA or α-Bgt reduced the cell leakage current, showing that α7-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 α-Bgt stabilize the closed, resting state.

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