1.A.9.2.1
Serotonin (5-hydroxytryptamine)-activated cation-selective receptor/channel, 5-HT3R. Residues in TMS2 and the cytoplasmic loop linking TMSs 3 and 4 influence conductance, selectivity, gating and desensitization (Peters et al., 2010; McKinnon et al., 2011). Resveratrol enhances ion currents (Lee et al., 2011). Rings of charge within the extracellular vestibule influence ion permeation (Livesey et al., 2011).  Based on the 3-d structure, serotonin binding first induces distinct conformational fluctuations at the side chain of W156 in the highly conserved ligand-binding cage, followed by tilting-twisting movements of the extracellular domain which couple to the transmembrane TM2 helices, opening the hydrophobic gate at L260 and forming a continuous transmembrane water pathway (Yuan et al. 2016). There are 5 isoforms of 5-HT3A which include 5-HT3AB, 5-HT3AC, 5-HT3AD, and 5-HT3AE, all of which have similar but distinct pharmacological profiles compared to those of 5-HT3A receptors (Price et al. 2017). Trans-3-(4-methoxyphenyl)-N-(pentan-3-yl)acrylamide (TMPPAA) is a potent agonist with behavior different from that of 5-HT (Gasiorek et al. 2016). Two serotonin-bound structures of the full-length 5-HT3A receptor in distinct conformations reveal the mechanism underlying channel activation (Basak et al. 2018). The trans-cis isomerization of a proline at the interface between the extracellular and transmembrane domain may be the switch between closed and open states of the channel (Crnjar et al. 2019).  SR 57227A is the most commonly used 5-HT3 receptor agonist with the ability to cross the blood brain barrier (Nakamura et al. 2019). Picrotoxin antagonizes serotonin (5-HT)3 receptors in a subunit-dependent fashon (Das and Dillon 2005). It interacts directly with the chaparone protein, Ric-3, (TC# 8.A.71.1.1) (Pirayesh et al. 2019). A nanopore based on the 5-HT3 receptor channel (see TC# 1.A.9.2.1) responds to an electric field than induces wetting of the hydrophobic gate (Klesse et al. 2020). Cholesterol content in the membrane promotes key lipid-protein interactions (Crnjar and Molteni 2021). Triple arginines are molecular determinants for pentameric assembly of the intracellular domain of 5-HT3A receptors (Pandhare et al. 2019). Five different subunits of the human serotonin (5-HT3) receptor exist and these are present in both central and peripheral systems. Different subunits alter the efficacy of 5-HT3 receptor antagonists used to treat diarrhoea predominant-irritable bowel syndrome, chemotherapy induced nausea and vomiting and depression. Cells transfected with either fluorescent protein tagged A or A and C subunits generate whole cell currents in response to 5-HT. The A and C subunits associate forming AC heteromer complexes at or near the cell surface, and a proportion can also form A or C homomers. Both A homomers and AC heteromers contribute to whole cell currents in response to 5-HT with minimal contribution from C homomers (Abad et al. 2020). It is a biomarker for  endometriosis (EM), a common gynecological disorder that often leads to irregular menstruation and infertility (Jiang et al. 2022).Perić et al. 2022 have  summarized information on the location of the components of the serotonin system in the human placenta, their regulation, function, and alterations in pathological pregnancies. Molecular dynamics refinement of open state serotonin 5-HT(3A) receptor structures have been reported (Li et al. 2023). The structures of tetrameric forms of the serotonin-gated 5-HT3_A receptor ion channel have been determined (Introini et al. 2024). The tetrameric structures have near-symmetric transmembrane domains, but asymmetric extracellular domains, and can bind serotonin. The cryo-EM structures were used to decipher the assembly pathway of pentameric 5-HT3R and suggest a potential functional role for the tetrameric receptors (Introini et al. 2024).