1.A.9.1.9
The cation-selective pentameric nicotinic acetylcholine receptor, nAChR, with α (461 aas; P02710), β (493 aas; P02712), γ (506 aas; P02714) and δ (522 aas; P02718) subunits.  The transmembrane domain of the uncoupled nAChR adopts a conformation distinct from that of the resting or desensitized state (Sun et al. 2016).  Studies with this receptor have been reviewed (Unwin 2013).  Many small molecules interact with nAChRs including d-tubocurarine, snake venom protein α-bungarotoxin (α-Bgt), and α-conotoxins, neurotoxic peptides from Conus snails. Various more recently discovered compounds of different structural classes also interact with nAChRs including the low-molecular weight alkaloids, pibocin, varacin and makaluvamines C and G. 6-Bromohypaphorine from the mollusk Hermissenda crassicornis does not bind to Torpedo nAChR but behaves as an agonist on human α7 nAChR (Kudryavtsev et al. 2015). Dimethylaniline mimics the low potency and non-competitive actions of lidocaine on nAChRs, as opposed to the high potency and voltage-dependent block by lidocaine (Alberola-Die et al. 2016).  Cholesterol is a potent modulator of the Torpedo nAChR (Baenziger et al. 2017). Cholesterol may play a mechanical role by conferring local rigidity to the membrane so that there is productive coupling between the extracellular and membrane domains, leading to opening of the channel (Unwin 2017). 11beta-(p-azidotetrafluorobenzoyloxy)allopregnanolone (F4N3Bzoxy-AP), a general anesthetic, a photoreactive allopregnanolone analog and a potent GABAAR PAM,was used to characterize steroid binding sites in the Torpedo nAChR in its native membrane environment (Yu et al. 2019). The steroid-binding site in the nAChR ion channel was identified, and additional steroid-binding sites could also be occupied by other lipophilic nAChR antagonists. Structural features of the αM4 TMS determine how lipid dependent changes in alphaM4 structure may ultimately modify nAChR function (Thompson et al. 2020). The positive allosteric modulators (PAMs) of the alpha7 nicotinic receptor, N-(5-Cl-2-hydroxyphenyl)-N'-[2-Cl-5-(trifluoromethyl)phenyl]-urea (NS-1738) and (E)-3-(furan-2-yl)-N-(p-tolyl)-acrylamide (PAM-2) potentiate the alpha1beta2gamma2L GABA(A) receptor through interactions with the classic anesthetic binding sites located at intersubunit interfaces in the transmembrane domain of the receptor. Pierce et al. 2023 employed mutational analysis to investigate the involvement and contributions made by the individual intersubunit interfaces to receptor modulation by NS-1738 and PAM-2. They showed that mutations to each of the anesthetic-binding intersubunit interfaces (beta+/alpha-, alpha+/beta-, and gamma+/beta-), as well as the orphan alpha+/gamma- interface, modify receptor potentiation by NS-1738 and PAM-2. Mutations to any single interface can fully abolish potentiation by the alpha7-PAMs (Pierce et al. 2023).