The 5-HT3 receptor is a member of the superfamily of ligand-gated ion channels, a superfamily that also includes the neuronal nicotinic acetylcholine receptors (nAChRs), and the inhibitory neurotransmitter receptors for GABA (both GABAA and GABAA-ρ receptors) and glycine. The 5-HT3 receptor is most closely related by homology to the nicotinic acetylcholine receptor.
The 5-HT3 receptor consists of 5 subunits arranged around a central ion conducting pore, which is permeable to sodium(Na), potassium(K), and calcium(Ca) ions. Binding of the neurotransmitter 5-hydroxytryptamine (serotonin) to the 5-HT3 receptor opens the channel, which, in turn, leads to an excitatory response in neurons. The 5-HT3 receptor differs markedly in structure and mechanism from the other 5-HT receptor subtypes, which are all G-protein-coupled.
As with other ligand gated ion channels, the 5-HT3 receptor is composed of five subunits pseudo symmetrically arranged about a central ion conducting pore. These subunits are proteins encoded by the HTR3A, HTR3B, HTR3C, HTR3D, and/or HTR3E genes.
A functional channel may be composed of five identical 5-HT3A subunits (homopentameric) or a mixture of 5-HT3A and one of the other four 5-HT3B, 5-HT3C, 5-HT3D, or 5-HT3E subunits (heteropentameric). It appears that only the 5-HT3A subunits form functional homopentameric channels. All other subunit subtypes must heteropentamerize with 5-HT3A subunits to form functional channels.
The 5-HT3 receptor gene is located on human chromosomal region 11q23.1-q23.2. It has been 9 exons in the mouse genome and is spread over ~13 kb. Interestingly, four of its introns are exactly in the same position as the introns in the homologous α7-Acetylcholine receptor gene, clearly proving their evolutionary relationship.
The 5-HT3 receptor is expressed throughout the central and peripheral nervous systems and mediates a variety of physiological functions. On a cellular level, it has been shown that postsynaptic 5-HT3 receptors mediate fast excitatory synaptic transmission in rat neocortical interneurons, amygdala, and hippocampus, and in ferret visual cortex. 5-HT3 receptors are also present on presynaptic nerve terminals, where they are thought to mediate or modulate neurotransmitter release.
When the receptor is activated to open the ion channel by agonists, the following effects are observed:
- CNS: nausea and vomiting center in brain stem, anxiety, seizure propensity 
- PNS: neuronal excitation (in autonomic, nociceptive neurons), emesis
Agonists for the receptor include:
- RS-56812: Potent and selective 5-HT3 partial agonist, 1000x selectivity over other serotonin receptors
Antagonists for the receptor (sorted by their respective therapeutic application) include:
Positive Allosteric Modulators
These agents are not agonists at the receptor, but increase the affinity or efficacy of the receptors for an agonist:
- 5-chloroindole 
Identification of the 5-HT3 receptor did not take place until 1986 because of a lack of selective pharmacological tool. However, with the discovery that the 5-HT3 receptor plays a prominent role in chemotherapy- and radiotherapy-induced vomiting, and the concomitant development of selective 5-HT3 receptor antagonists to suppress these side effects aroused intense interest from the pharmaceutical industry and therefore the identification of 5-HT3 receptors in cell lines and native tissues quickly followed.
- Maricq AV, Peterson AS, Brake AJ, Myers RM, Julius D (1991). "Primary structure and functional expression of the 5HT3 receptor, a serotonin-gated ion channel". Science 254 (5030): 432–7.
- Yakel, JL (2000). Endo, M; Kurachi, Y; Mishina, M, eds. The 5-HT3 receptor channel: function, activation and regulation in Pharmacology of Ionic Channel Function: Activators and Inhibitors (Handbook of Experimental Pharmacology) 147. Berlin:
- Davies PA, Pistis M, Hanna MC, Peters JA, Lambert JJ, Hales TG, Kirkness EF (1999). "The 5-HT3B subunit is a major determinant of serotonin-receptor function". Nature 397 (6717): 359–63.
- Dubin AE, Huvar R, D'Andrea MR, Pyati J, Zhu JY, Joy KC, Wilson SJ, Galindo JE, Glass CA, Luo L, Jackson MR, Lovenberg TW, Erlander MG (1999). "The pharmacological and functional characteristics of the serotonin 5-HT3A receptor are specifically modified by a 5-HT3B receptor subunit". J Biol Chem 274 (43): 30799–810.
- Monk SA, Desai K, Brady CA, Williams JM, Lin L, Princivalle A, Hope AG, Barnes NM (2001). "Generation of a selective 5-HT3B subunit-recognising polyclonal antibody; identification of immunoreactive cells in rat hippocampus". Neuropharmacology 41 (8): 1013–6.
- Boyd GW, Low P, Dunlop JI, Ward M, Vardy AW, Lambert JJ, Peters J, Conolly CN (2002). "Assembly and cell surface expression of homomeric and heteromeric 5-HT3 receptors: The role of oligomerisation and chaperone proteins". Mol Cell Neurosci 21 (1): 38–50.
- Niesler B, Walstab J, Combrink S, Moeller D, Kapeller J, Rietdorf J, Boenisch H, Goethert M, Rappold G, Bruess M (2007). "Characterization of the Novel Human Serotonin Receptor Subunits 5-HT3C, 5- HT3D and 5-HT3E". Mol Pharmacol 71 (Mar 28): 8–17.
- Uetz, P; Abdelatty, F; Villarroel, A; Rappold, G; Weiss, B; Koenen, M (1994). "Organisation of the murine 5-HT3 receptor gene and assignment to human chromosome 11". FEBS Letters 339 (3): 302–6.
- Uetz, P. (1992) Das 5HT3-Rezeptorgen der Maus. Diploma Thesis, University of Heidelberg, 143 pp.
- Férézou I, Cauli B, Hill EL, Rossier J, Hamel E, Lambolez B (2002). "5-HT3 receptors mediate serotonergic fast synaptic excitation of neocortical vasoactive intestinal peptide/cholecystokinin interneurons". J Neurosci 22 (17): 7389–97.
- Kazuyoshi Kawa (1994). Receptors in the Rat Hippocampus Dentate Gyrus"3"Distribution and Functional Properties of 5HT. Journal of Neurophysiology 71 (5): 1935–47.
- Sugita S, Shen KZ, North RA (1992). "5-hydroxytryptamine is a fast excitatory transmitter at 5-HT3 receptors in rat amygdala". Neuron 8 (1): 199–203.
- Roerig B, Nelson DA, Katz LC (1992). "Fast synaptic signaling by nicotinic acetylcholine and serotonin 5-HT3 receptors in developing visual cortex". J Neurosci 17 (21): 199–203.
- Rondé P, Nichols RA (1998). "High calcium permeability of serotonin 5-HT3 receptors on presynaptic nerve terminals from rat striatum". J Neurochem 70 (3): 1094–103.
- Rondé P, Nichols RA (1997). "5-HT3 receptors induce rises in cytosolic and nuclear calcium in NG108-15 cells via calcium-induced calcium release". Cell Calcium 22 (5): 357–65.
- van Hooft JA, Vijverberg HP (2000). "5-HT3 receptors and neurotransmitter release in the CNS: a nerve ending story?". Trends Neurosci 23 (12): 605–10.
- Rang, H. P. (2003). Pharmacology. Edinburgh: Churchill Livingstone. Page 187
- Gholipour T, Ghasemi M, Riazi K, Ghaffarpour M, Dehpour AR. (January 2010). "Seizure susceptibility alteration through 5-HT(3) receptor: modulation by nitric oxide". Seizure 19 (1): 17–22.
- Mineur YS, Picciotto MR (December 2010). "Nicotine receptors and depression: revisiting and revising the cholinergic hypothesis". Trends Pharmacol. Sci. 31 (12): 580–6.
- Imanishi, N.; Iwaoka, K.; Koshio, H.; Nagashima, S. Y.; Kazuta, K. I.; Ohta, M.; Sakamoto, S.; Ito, H.; Akuzawa, S.; Kiso, T.; Tsukamoto, S. I.; Mase, T. (2003). "New thiazole derivatives as potent and selective 5-hydroxytriptamine 3 (5-HT3) receptor agonists for the treatment of constipation". Bioorganic & Medicinal Chemistry 11 (7): 1493.
- Ashoor, A.; Nordman, J.; Veltri, D.; Susan Yang, K. -H.; Shuba, Y.; Al Kury, L.; Sadek, B.; Howarth, F. C.; Shehu, A.; Kabbani, N.; Oz, M. (2013). "Menthol Inhibits 5-Ht3 Receptor-Mediated Currents". Journal of Pharmacology and Experimental Therapeutics 347 (2): 398–409.
- Newman, A. S.; Batis, N; Grafton, G; Caputo, F; Brady, C. A.; Lambert, J. J.; Peters, J. A.; Gordon, J; Brain, K. L.; Powell, A. D.; Barnes, N. M. (2013). "5-Chloroindole: A potent allosteric modulator of the 5-HT3 receptor". British Journal of Pharmacology 169 (6): 1228–38.
- Thompson AJ, Lummis SC (2006). "5-HT3 Receptors". Curr Pharm Des 12 (28): 3615–30.
- Thompson AJ, Lummis SC (2007). "The 5-HT3 receptor as a therapeutic target". Expert Opin Ther Targets 11 (4): 527–40.
- 5-HT3 Receptor at the US National Library of Medicine Medical Subject Headings (MeSH)