1.A.9.2.3
The 5-hydroxytryptamine (serotonin) receptor-3A receptor/cation-selective ion channel, 5-HT3AR, of 454 aas.  The channel is activated by the binding of serotonin to an extracellular orthosteric site, located at the interface of two adjacent receptor subunits. A variety of compounds modulate agonist-evoked responses of 5-HT3ARs and other Cys-loop receptors by binding to distinct allosteric sites (Lansdell et al. 2014).  Alternative intersubunit pathways may exist for ion translocation at the interface between the extracellular and the transmembrane domains, in addition to the one along the channel main axis. An arginine triplet located in the intracellular domain may determine the characteristic low conductance properties of the channel (Di Maio et al. 2015). The 12 Å resolution structure of the protein in a lipid bilayer (cryo EM) reveals topological features (Kudryashev et al. 2016).  A  chimeric receptor consisting of the extracellular domain of the 5-HT3A receptor and the transmembrane domain of a prokaryotic homologue, ELIC has been constructed (Price and Lummis 2018). The resulting receptor responds to 5-HT. Partial agonists and competitive antagonists activate and inhibit the chimera. Examination of a range of receptor modulators including ethanol, thymol, 5-hydroxyindole, and 5-chloroindole suggest that these compounds act via the transmembrane domain, except for 5-hydroxyindole, which can compete with 5-HT at the orthosteric binding site (Price and Lummis 2018). The receptor has 4 TMSs, M1 - M4, and Y441 in M4 interacts with D238 in M1, W459 in M4 interacts with F144 in the Cys loop, and D434 in M4 interacts with R251 in M2 according to the residue numbering system of Mesoy et al. 2019. This suggests that M4 helicies in LIC receptors interact with other parts of these receptors differently. Amino acid residues involved in agonist binding, linked to channel gating, that are proximal to the transmembrane domain for halothane modulation have been identified (Kim et al. 2009). Microsecond-timescale simulations suggest 5-HT mediates preactivation of the 5-HT3A serotonin receptor (Guros et al. 2019). Minimal structural rearrangement of the cytoplasmic pore occur during activation (Panicker et al. 2004). The intracellular domain starts with a short loop after the third TMS, followed by a short alpha-helical segment, a large unstructured loop, and finally, the membrane-associated MA-helix that continues into the last TMS (Stuebler and Jansen 2020). The MA-helices from all five subunits form the extension of the transmembrane ion channel and shape what has been described as a "closed vestibule," with the lateral portals obstructed by loops and their cytosolic ends forming a tight hydrophobic constriction. Although conformational changes associated with gating promote cross-linking for I409C/R410C, which in turn decreases channel currents, cross-linking of L402C/L403C is functionally silent in macroscopic currents. These results support the hypothesis that concerted conformational changes open the lateral portals for ion conduction, rendering ion conduction through the vertical portal unlikely (Stuebler and Jansen 2020).