5-HT3 receptor

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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 receptors) and glycine.[1][2] 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, potassium, and calcium 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 compossed of five identical 5-HT3A subunits (homopentameric) or a mixture of 5-HT3A and one of the other four 5-HT3B,[3][4][5][6] 5-HT3C, 5-HT3D, or 5-HT3E subunits (heteropentameric).[7] 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.

Tissue distribution

The 5-HT3 receptor is expressed throughout the central and peripheral nervous systems and mediates a variety of physiological functions.[2] On a cellular level, it has been shown that postsynaptic 5-HT3 receptors mediate fast excitatory synaptic transmission in rat neocortical interneurons and amygdala, and in ferret visual cortex.[8][9][10] 5-HT3 receptors are also present on presynaptic nerve terminals, where they are thought to mediate or modulate neurotransmitter release.[11][12][13]




Agonists for the receptor include:




Identification of the 5-HT3 receptor did not take place until 1986 because of a lack of selective pharmacological tool.[2] 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[16][17] and therefore the identification of 5-HT3 receptors in cell lines and native tissues quickly followed.[2]


  1. 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. doi:10.1126/science.1718042. PMID 1718042.
  2. 2.0 2.1 2.2 2.3 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: Springer-Verlag. pp. 541–560. ISBN 3540661271.
  3. 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. doi:10.1038/16941. PMID 9950429.
  5. 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. doi:10.1016/S0028-3908(01)00153-8. PMID 11747906.
  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. doi:10.1006/mcne.2002.1160(02). PMID 12359150.
  7. 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): Epub ahead of print. doi:10.1124/mol.106.032144. PMID 17392525.
  8. 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. PMID 12196560.
  9. 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. doi:10.1016/0896-6273(92)90121-S. PMID 1346089.
  10. 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. PMID 9334409.
  11. 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. doi:10.1046/j.1471-4159.1998.70031094.x. PMID 9489730.
  12. 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. doi:10.1016/S0143-4160(97)90020-8. PMID 9448942.
  13. 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. doi:10.1016/S0166-2236(00)01662-3. PMID 11137150.
  14. 14.0 14.1 14.2 14.3 14.4 Rang, H. P. (2003). Pharmacology. Edinburgh: Churchill Livingstone. ISBN 0-443-07145-4. Page 187
  15. Imanishi, N; Iwaoka, K; Koshio, H; Nagashima, SY; Kazuta, K; Ohta, M; Sakamoto, S; Ito, H; Akuzawa, S (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): 1493–502. PMID 12628674.
  16. Thompson AJ, Lummis SC (2006). "5-HT3 receptors". Curr Pharm Des. 12 (28): 3615–30. doi:10.2174/138161206778522029. PMC 2664614. PMID 17073663.
  17. Thompson AJ, Lummis SC (2007). "The 5-HT3 receptor as a therapeutic target". Expert Opin Ther Targets. 11 (4): 527–40. doi:10.1517/14728222.11.4.527. PMC 1994432. PMID 17373882.

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