Role of the Putative Transmembrane Segment M3 in Gating of Neuronal Nicotinic Receptors

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Abstract
The involvement of some structural domains in the gating of the neuronal nicotinic acetylcholine receptor (AChR) was studied by expressing functional α7/α3 chimeric subunits in Xenopus oocytes. Substitution of the M3 transmembrane segment in the α7 subunit modifies the kinetic properties of the chimeric AChRs as follows: (a) a 6-fold reduction in the maximal current evoked by nicotinic agonists, (b) a 10-fold decrease in the macroscopic desensitization rate, (c) an increase of almost 1 order of magnitude in the apparent affinity for acetylcholine and nicotine, and (d) a decrease in the affinity for α-bungarotoxin. Computer simulations showed that the first three effects could be accounted for by a simple kinetic model in which chimeric AChRs presented a smaller ratio of the gating rates, β/α, and a slightly slower desensitization rate. It is concluded that the M3 domain influences the gating of neuronal AChRs.