Subunit interfaces contribute differently to activation and allosteric modulation of neuronal nicotinic acetylcholine receptors

摘要: Abstract Neuronal nicotinic acetylcholine receptors (nAChRs) are widely distributed in the nervous system and implicated many normal pathological processes. The structural determinants of allostery nAChRs not well understood. One class nAChR allosteric modulators, including small molecule morantel (Mor), acts from a site that is structurally homologous to canonical agonist but exists β(+)/α(−) subunit interface. We hypothesized all subunits move with respect each other during channel activation modulation. therefore studied five pairs residues predicted span interfaces α3β2 receptors, one at interface four modulator Substituting cysteines these positions, we used disulfide trapping perturb receptor function. pair α3Y168–β2D190, involving C loop region β2 subunit, mediates modulation activation, because evoked currents were reduced up 50% following oxidation (H 2 O ) treatment. α3S125–β2Q39, below site, also involved accord previous studies muscle-type receptor; however, differentially sensitive ACh Mor (currents decreased 60% 80%, respectively). α3Q37–β2A127 α3E173–β2R46, both non-canonical interface, showed increased oxidation, suggesting movements symmetrical. Together, our results further mutation analysis indicate movement important for nAChRs, two types contribute unequally activation.