Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

The 5-HT3 Receptor

Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_647


Historical Background

5-Hydroxytryptamine (5-HT), also known as serotonin, was initially identified as a potent vasoconstrictor present in blood serum (Rapport et al. 1947), but it has become obvious over the years that 5-HT has a multitude of functions, including activation or inhibition of muscle, exocrine and endocrine glands, central and peripheral neurons, and cells of the hematopoietic and immune systems. 5-HT initiates its actions by binding to specific receptor proteins in the cell membrane. These 5-HT receptors were initially subdivided into D and M subtypes, based on their sensitivity to dibenyline or morphine (Gaddum and Picarelli 1957). This was an oversimplification, and currently 5-HT receptors are divided into seven major families (5-HT1–7) based on transduction and structural characteristics. All of these receptors exert their effects via G proteins, except for the 5-HT3 receptor which is a ligand-gated ion channel (LGIC), and, indeed, it is this receptor which is the original M subtype.


The 5-HT3 receptor is a cation-selective member of the Cys-loop family of pentameric ligand-gated ion channels (pLGIC). The receptors are located primarily in the central and peripheral nervous systems, but also present in a wide range of other tissues, including peripheral and sensory ganglia, the gastrointestinal tract, and immune cells such as monocytes, chondrocytes, T-cells, synovial tissue, and platelets, suggesting a physiological importance in many body regions (Barnes et al. 2009; Lummis 2012). The structure of the mouse 5-HT3 receptor has been resolved (Hassaine et al. 2014) and confirms earlier work which showed that this protein is closely related to other pLGIC, including the nACh receptor, the glycine receptor, the GluCl receptor, and the bacterial Cys-loop receptor homologues GLIC and ELIC (see Lummis 2012; Nys et al. 2013; Thompson et al. 2010 for reviews). Activation by 5-HT and other agonists opens an integral cation-selective channel. The receptor is inhibited by a wide range of antagonists, some of which are useful therapeutic agents, and is also modulated by a wide range of substances, including alcohols, steroids, and anesthetics (Barnes et al. 2009; Davies 2011; Lummis 2012; Niesler 2011; Machu 2011).

Receptor Heterogeneity

The functional receptor is a pentamer (Fig. 1), and five 5-HT3 receptor subunits have been identified (5-HT3A–E). Only the A subunit can form functional homomeric receptors, while subunits B–E function as heteromeric receptors in combination with the A subunit (Holbrooke et al. 2009; Niesler et al. 2003, 2007). Homomeric 5-HT3A and heteromeric 5-HT3AB receptors have been extensively characterized (Thompson and Lummis 2013; Davies et al. 1999). 5-HT3AB receptors have an increased single channel conductance, reduced Ca2+ permeability, faster kinetics, increased EC50s, and decreased Hill slopes compared to 5-HT3A receptors. There are also some differences in the potency of noncompetitive antagonists. Data from functional expression of 5-HT3A with either 5-HT3 C, D, or E subunits suggest their characteristics are similar to those of homomeric 5-HT3A receptors, but there may be some differences in expression levels (Holbrook et al. 2009; Niesler et al. 2007).
The 5-HT3 Receptor, Fig. 1

(a) An image of the 5-HT3 receptor (pdb id 4PIR) showing the predominantly β-sheet constitution of the extracellular domain and the α-helical constitution of the transmembrane domains (the approx. location of the lipid bilayer is also shown). The intracellular domain has not been fully resolved, although α-helices which protrude into the cell can be seen. The five subunits, shown here in different colors, surround the ion pore as is shown in (b), which is a view from above. All the subunits are 5-HT3A receptor subunits, although four other subunits also exist (B–E)

Receptor Structure

The five subunits surround a central ion-conducting pore (Fig. 1). The extracellular (N-terminal) part is mostly β-sheet, with an immunoglobulin-like fold. This region contains the ligand-binding site, which lies at the interface of two adjacent subunits and is formed by three loops (A–C) from the “principal” subunit and three β-strands (D–F) from the adjacent or “complementary” subunit (Fig. 2). A number of studies have identified key residues that are involved in both agonist and antagonist binding (Fig. 3). A comprehensive review of the 5-HT3 ligand-binding site can be found in Thompson and Lummis (2006).
The 5-HT3 Receptor, Fig. 2

A model of the extracellular domain of two adjacent subunits of the 5-HT3 receptor showing the location of three loops (A–C) from one (the principal) subunit and three loops (D–F) from the adjacent (complementary) subunit, all of which contribute to the ligand-binding pocket. 5-HT (green) and granisetron (brown) can be seen nestled in this binding pocket

The 5-HT3 Receptor, Fig. 3

A close-up of the binding pocket (from 4PIR) showing some of the residues that are known to contribute to the binding ligand. The principal subunit is shown in purple and the complementary in yellow; both contribute residues to the binding site, although those on the principal face have a stronger influence on ligand binding

The transmembrane region contains four membrane-spanning α-helices (M1–M4); M2 from each subunit lines the pore and contains regions responsible for channel gating and ion selectivity. Pore opening results in a rapidly activating and then desensitizing inward current, which is primarily carried by Na+ and K+ ions, although divalent and small organic cations are also permeable. Various compounds are known to block the pore, e.g., picrotoxin, diltiazem, morphine, and quinine. Many of these also act in the pore of other pLGIC, highlighting the common mechanisms that many of these drugs share and also the promiscuity of these compounds. Other modulators, such as alcohols, anesthetics, antidepressants, cannabinoids, opioids, and steroids, may bind in an inter-subunit binding cavity at the top of the transmembrane region, although details are not yet clear.

The long loop between M3 and M4 forms the intracellular domain (ICD); its structure has only been partially resolved, but reveals part of it forms an α-helical region that lines opening (portals) on the intracellular side on the protein (Fig 1). Functionally, the ICD has a role in modulation, interacting with intracellular proteins, confirmation of which has been provided by insertion of this region into a pLGIC that has no intracellular domain that results in modulation by RIC-3 (Goyal et al. 2011). The ICD also contributes to channel conductance: altering charged amino acids that face into the portals alters the conductance. These data explain the large difference in single channel conductance for homomeric 5-HT3A and heteromeric 5-HT3AB receptors; the latter display a much larger conductance (9–17 pS) than the former (sub-pS) due to the presence of three Arg residues in the 5-HT3 A subunit (Kelley et al. 2003; Peters et al. 2010)


5-HT3 receptor antagonists are in use clinically, primarily for controlling chemotherapy and radiotherapy-induced nausea and vomiting and in postoperative nausea and vomiting, but also in a range of gastrointestinal disorders (Machu 2011; Mawe and Hoffman 2013; Niesler 2011). In addition, studies have revealed a diversity of potential disease targets that might be amenable to alleviation by 5-HT3 receptor selective compounds; these include addiction, pruritis, emesis, fibromyalgia, migraine, rheumatic diseases, and neurological phenomena such as anxiety, psychosis, nociception, and cognitive function (Niesler 2011; Thompson and Lummis 2007).)


The 5-HT3 receptor is the only 5-HT receptor that is a ligand-gated ion channel. It is a member of the Cys-loop family of neurotransmitter-gated ion channels, which also includes nACh, glycine, and GABAA receptors. It is a pentamer, and five subunits (A–E) can contribute to a functional receptor, as long as A subunits are present. The large extracellular domain contains the neurotransmitter-binding site which is located between two adjacent subunits. The transmembrane pore is lined by α-helices, and the intracellular domain has a role in channel conductance and receptor modulation. A range of neurological and gastrointestinal diseases may be amenable to treatment with 5-HT3 receptor antagonists, and some compounds are currently in clinical use.


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© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Department of BiochemistryUniversity of CambridgeCambridgeUK