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, 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, 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 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 and amygdala, 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:
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:
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. doi:10.1126/science.1718042. PMID 1718042.
- 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.
- 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.
- 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. doi:10.1074/jbc.274.43.30799. PMID 10521471.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- Rang, H. P. (2003). Pharmacology. Edinburgh: Churchill Livingstone. ISBN 0-443-07145-4. Page 187
- 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.
- Thompson AJ, Lummis SC (2006). "5-HT3 receptors". Curr Pharm Des. 12 (28): 3615–30. doi:10.2174/138161206778522029. PMC 2664614. PMID 17073663.
- Thompson AJ, Lummis SC (2007). "The 5-HT3 receptor as a therapeutic target". Expert Opin Ther Targets. 11 (4): 527–40. doi:10.1517/14728126.96.36.1997. PMC 1994432. PMID 17373882.