Acetylcholine receptor extracellular domain determines sensitivity to nicotine-induced inactivation

We have shown previously that chronic exposure to submicromolar concentrations of nicotine permanently inactivates α4β2 and α7 neuronal nicotinic acetylcholine receptors while α3β2 acetylcholine receptors are resistant to inactivation. Phosphorylation of the large cytoplasmic domain has been proposed to mediate functional inactivation. Chimeric subunits consisting of human α4 sequence from their N-terminus to either the beginning of the first transmembrane domain or the large cytoplasmic domain and α3 sequences thereafter formed acetylcholine receptors with β2 subunits which were as susceptible to nicotine-induced inactivation as wild-type α4 acetylcholine receptors. The converse chimeras, containing the N-terminal parts of the α3 subunit and the C-terminal parts of the α4 subunit, formed acetylcholine receptors with β2 subunits which were as resistant to nicotine-induced inactivation as wild-type α3β2 acetylcholine receptors. Thus, inactivation of acetylcholine receptors produced by chronic exposure to nicotine results primarily from effects of the agonist on the extracellular and transmembrane domains of the α subunit.