S. Bertrand et al., PARADOXICAL ALLOSTERIC EFFECTS OF COMPETITIVE INHIBITORS ON NEURONAL ALPHA-7 NICOTINIC RECEPTOR MUTANTS, NeuroReport, 8(16), 1997, pp. 3591-3596
MUTATION of the conserved leucine residue, in the second transmembrane
domain of the neuronal alpha 7 acetylcholine receptor to a threonine
(L247T) causes pleiotropic alterations of receptor properties. In this
study we examined the effects of competitive inhibitors on the alpha
7-L247T physiological responses. While the alpha 7 competitive inhibit
or dihydro-beta-erythroidine evoked a current comparable to that induc
ed by ACh, other inhibitors such as methyllycaconitine (MLA) and alpha
-bungarotoxin (alpha-Bgt) caused a blockade of alpha 7-L247T to ACh ac
tivation. When applied in the absence of ACh, MLA or alpha-Bgt reduced
the cell leakage current, showing that alpha 7-L247T displays a signi
ficant fraction (10%) of spontaneously open channels. These data can b
e interpreted in terms of an allosteric model, assuming that the L247T
mutant possesses a low isomerization constant L and that MLA and alph
a-Bgt stabilize the closed, resting state.