5‐HT3 Receptors


The 5‐HT3 receptor is a cation‐selective member of the pentameric ligand‐gated ion channel (pLGIC) family. It differs both structurally and functionally from the other six classes of 5‐HT receptors, which are G‐protein coupled receptors. 5‐HT3 receptors are pentamers, and five different subunits have been identified (5‐HT3A–E). These are widely distributed, both in the nervous system and in other tissues, although the stoichiometry of most functional heteromeric receptors is still not known. 5‐HT3 receptor activation opens a nonselective cation channel, causing depolarisation in postsynaptic cells; receptor function can be modulated by a wide range of compounds including anaesthetics, opioids and alcohols. 5‐HT3 receptors play a major role in the vomiting reflex, regulate gut motility, secretion and peristalsis in the enteric nervous system, and are involved in information transfer in the gastrointestinal tract. Disturbances within the 5‐HT3 receptor system may contribute to the pathogenesis of a range of neurological, gastrointestinal and immunological disorders.

Key Concepts

  • 5‐HT3 receptors are members of the pentameric ligand‐gated ion channel family of neurotransmitter receptors.
  • 5‐HT3 receptors have a bullet‐shaped structure, with extracellular, transmembrane and intracellular domains.
  • 5‐HT3 receptor activation opens a cation channel resulting in cell depolarisation.
  • 5‐HT3 receptor function can be modulated by a wide range of compounds including anaesthetics, opioids and alcohols.
  • 5‐HT3 receptors are involved in the function of both the central and peripheral nervous systems, including specific roles in the vomiting reflex and in the gastrointestinal tract.
  • Disturbances within the 5‐HT3 receptor system may contribute to the pathogenesis of a range of neurological, gastrointestinal and immunological disorders.
  • 5‐HT3 receptor antagonists are effective at treating nausea, emesis and irritable bowel syndrome, and have potential in a range of other disorders.

Keywords: serotonin; ligand‐gated ion channel; neurotransmitter receptor; Cys‐loop; pentamer

Figure 1. The 5‐HT3 receptor. (a): Image of the 5‐HT3A receptor (from 4PIR) showing the five subunits and the locations of the extracellular domain (ECD) transmembrane domain (TMD), which is in the lipid bilayer, and the intracellular domain (ICD), which is not complete in this image. (b): Enlarged image showing the orthosteric (agonist) binding site, which is located between two adjacent subunits in the ECD, and is rich in aromatic amino acids. (c): The orientation of 5‐HT and granisetron have been revealed in 5‐HTBP, a version of AChBP whose binding site has been modified to resemble that in the 5‐HT3 receptor. Black = 5‐HTBP residues, red = the equivalent residues in the 5‐HT3A subunit. Reprinted from Kesters et al. 2012 with permission from EMBO J.
Figure 2. Diversity in the 5‐HT3 receptor family. There are five 5‐HT3 receptor subunits in humans, and receptor heterogeneity may be achieved at many levels. Differential expression could be because of differences in transcription and/or translation (e.g. because of different promoters), while different splice variants and mutations (e.g. at places marked with stars) will yield subunits with different properties. There is also potential variation in the level of posttranslational modifications such as glycosylation and phosphorylation, and in the combinations of subunits that form functional receptors, which is currently poorly understood.
Figure 3. Schematic representation of binding sites in the 5‐HT3 receptor. Only two of the five subunits are shown. The expanded orthosteric binding site illustrates that six regions of the protein (loops A–F) contribute to agonist binding. The sites of all modulatory compounds have not yet been fully defined, but there are known examples that bind in the extracellular or the transmembrane domain.
Figure 4. The roles of 5‐HT3 receptors in diseases. Disturbances of 5‐HT3 receptors in the forebrain are relevant in neuropsychiatric disorders such as depression, schizophrenia and autism. 5‐HT3 receptors in the brain stem and dorsal root ganglia, activated by 5‐HT released after visceral stimuli, can trigger nausea and vomiting, and antagonists are especially potent against chemotherapy‐induced nausea and vomiting (CINV), radiotherapy‐induced nausea and vomiting (RINV), and postoperative nausea and vomiting. In addition, 5‐HT released in the gut stimulates 5‐HT3 receptors in the gastrointestinal (GI) tract, and their malfunction is involved in functional GI disorders such as irritable bowel syndrome (IBS) and gastroesophageal reflux disease (GERD) as well as eating disorders. 5‐HT3 receptor subunits implicated in the disorders are shown in red.


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Further Reading

Bouzat C (2012) New insights into the structural bases of activation of Cys‐loop receptors. Journal of Physiology, Paris 106 (1‐2): 23–33.

Lummis SC (2015) 5‐HT3 receptors. In: Zheng J and Trudeau M (eds) Handbook of Ion Channels, pp. 331–344. Florida, USA: CRC Press.

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Nys M, Kesters D and Ulens C (2013) Structural insights into Cys‐loop receptor function and ligand recognition. Biochemical Pharmacology 86 (8): 1042–1053.

Peters JA, Hales TG and Lambert JJ (2005) Molecular determinants of single‐channel conductance and ion selectivity in the Cys‐loop family: insights from the 5‐HT3 receptor. Trends in Pharmacological Sciences 26: 587–594.

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Lummis, Sarah(Jan 2018) 5‐HT3 Receptors. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0027709]