View source for 5-HT3 receptor

{{DISPLAYTITLE:5-HT<sub>3</sub> receptor}}

The '''5-HT<sub>3</sub> receptor''' is a member of the superfamily of [[ligand-gated ion channel]]s, a superfamily that also includes the neuronal [[nicotinic acetylcholine receptor]]s (nAChRs), and the inhibitory neurotransmitter receptors for [[Gamma-aminobutyric acid|GABA]] (both [[GABA A receptor|GABA<SUB>A</SUB>]] and [[GABAA-rho receptor|GABA<sub>A</sub>-ρ]] receptors) and [[glycine receptor|glycine]].<ref name="Maricq_1991">{{cite journal |author=Maricq AV, Peterson AS, Brake AJ, Myers RM, Julius D|title=Primary structure and functional expression of the 5HT<sub>3</sub> receptor, a serotonin-gated ion channel|journal= Science |volume= 254 |issue= 5030 |pages= 432–7 |year= 1991| doi = 10.1126/science.1718042 |pmid= 1718042}}</ref><ref name="Yakel_2000">{{Cite book | last=Yakel | first=JL | year=2000 | editor-last=Endo | editor-first=M | editor2-last=Kurachi | editor2-first=Y | editor3-last=Mishina | editor3-first=M | title=The 5-HT<sub>3</sub> receptor channel: function, activation and regulation in Pharmacology of Ionic Channel Function: Activators and Inhibitors (Handbook of Experimental Pharmacology) | place=Berlin | publisher=[[Springer-Verlag]] | publication-date= | volume=147 | pages=541–560 | isbn=3540661271 | postscript=<!--None-->}}</ref>  The 5-HT<sub>3</sub> receptor is most closely related by homology to the nicotinic acetylcholine receptor.  

The 5-HT<sub>3</sub> 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-HT<sub>3</sub> receptor opens the channel, which, in turn, leads to an excitatory response in neurons.  The 5-HT<sub>3</sub> receptor differs markedly in structure and mechanism from the other [[5-HT receptor]] subtypes, which are all [[G-protein-coupled receptor|G-protein-coupled]].

== Structure ==

As with other ligand gated ion channels, the 5-HT<sub>3</sub> receptor is composed of five subunits pseudo symmetrically arranged about a central ion conducting pore.   These subunits are proteins encoded by the {{Gene|HTR3A}}, {{Gene|HTR3B}}, {{Gene|HTR3C}}, {{Gene|HTR3D}}, and/or {{Gene|HTR3E}} genes.

A functional channel may be compossed of five identical [[HTR3A|5-HT<sub>3A</sub>]] subunits (homopentameric) or a mixture of 5-HT<sub>3A</sub> and one of the other four 5-HT<sub>3B</sub>,<ref name="van Davies_1999">{{cite journal |author=Davies PA, Pistis M, Hanna MC, Peters JA, Lambert JJ, Hales TG, Kirkness EF|title=The 5-HT<sub>3B</sub> subunit is a major determinant of serotonin-receptor function|journal= Nature |volume= 397 |issue= 6717 |pages= 359–63 |year= 1999| doi = 10.1038/16941 |pmid= 9950429}}</ref><ref name="van Dubin_1999">{{cite journal |author=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|title=The pharmacological and functional characteristics of the serotonin 5-HT<sub>3A</sub> receptor are specifically modified by a 5-HT<sub>3B</sub> receptor subunit|journal= J Biol Chem |volume= 274 |issue= 43 |pages= 30799–810 |year= 1999| doi = 10.1074/jbc.274.43.30799|pmid= 10521471}}</ref><ref name="van Monk_2001">{{cite journal |author=Monk SA, Desai K, Brady CA, Williams JM, Lin L, Princivalle A, Hope AG, Barnes NM|title=Generation of a selective 5-HT<sub>3B</sub> subunit-recognising polyclonal antibody; identification of immunoreactive cells in rat hippocampus|journal= Neuropharmacology |volume= 41 |issue= 8 |pages= 1013–6 |year= 2001| doi = 10.1016/S0028-3908(01)00153-8 |pmid= 11747906}}</ref><ref name="Boyd">{{cite journal |author=Boyd GW, Low P, Dunlop JI, Ward M, Vardy AW, Lambert JJ, Peters J, Conolly CN|title= Assembly and cell surface expression of homomeric and heteromeric 5-HT3 receptors: The role of oligomerisation and chaperone proteins|journal= Mol Cell Neurosci |volume= 21 |issue= 1 |pages= 38–50 |year= 2002 |pmid= 12359150 | doi = 10.1006/mcne.2002.1160(02)}}</ref> 5-HT<sub>3C</sub>, 5-HT<sub>3D</sub>, or 5-HT<sub>3E</sub> subunits (heteropentameric).<ref name="Niesler_2007">{{cite journal |author=Niesler B, Walstab J, Combrink S, Moeller D, Kapeller J, Rietdorf J, Boenisch H, Goethert M, Rappold G, Bruess M|title=Characterization of the Novel Human Serotonin Receptor Subunits 5-HT<sub>3C</sub>, 5- HT<sub>3D</sub> and 5-HT<sub>3E</sub>|journal= Mol Pharmacol |volume= 71 |issue= Mar 28 |pages= Epub ahead of print |year= 2007| doi = 10.1124/mol.106.032144 |pmid= 17392525}}</ref> It appears that only the 5-HT<sub>3A</sub> subunits form functional homopentameric channels.  All other subunit subtypes must heteropentamerize with 5-HT<sub>3A</sub> subunits to form functional channels.

== Tissue distribution ==

The 5-HT<sub>3</sub> receptor is expressed throughout the [[central nervous system|central]] and [[peripheral nervous system]]s and mediates a variety of physiological functions.<ref name="Yakel_2000"/>  On a cellular level, it has been shown that postsynaptic 5-HT<sub>3</sub> receptors mediate fast excitatory synaptic transmission in rat neocortical interneurons and [[amygdala]], and in ferret [[visual cortex]].<ref name="Ferezou_1991">{{cite journal |author=Férézou I, Cauli B, Hill EL, Rossier J, Hamel E, Lambolez B|title=5-HT<sub>3</sub> receptors mediate serotonergic fast synaptic excitation of neocortical vasoactive intestinal peptide/cholecystokinin interneurons|journal= J Neurosci |volume= 22 |issue= 17 |pages= 7389–97 |year= 2002| doi = |pmid= 12196560}}</ref><ref name="Sugita_1992">{{cite journal |author=Sugita S, Shen KZ, North RA|title=5-hydroxytryptamine is a fast excitatory transmitter at 5-HT<sub>3</sub> receptors in rat amygdala|journal= Neuron |volume= 8 |issue= 1 |pages= 199–203 |year= 1992| doi = 10.1016/0896-6273(92)90121-S |pmid= 1346089}}</ref><ref name="Roerig_1997">{{cite journal |author=Roerig B, Nelson DA, Katz LC|title=Fast synaptic signaling by nicotinic acetylcholine and serotonin 5-HT<sub>3</sub> receptors in developing visual cortex|journal= J Neurosci |volume= 17 |issue= 21 |pages= 199–203 |year= 1992| doi = |pmid= 9334409}}</ref>  5-HT<sub>3</sub> receptors are also present on presynaptic nerve terminals, where they are thought to mediate or modulate neurotransmitter release.<ref name="Ronde_1998">{{cite journal |author=Rondé P, Nichols RA|title=High calcium permeability of serotonin 5-HT<sub>3</sub> receptors on presynaptic nerve terminals from rat striatum|journal= J Neurochem |volume= 70 |issue= 3 |pages= 1094–103 |year= 1998| doi = 10.1046/j.1471-4159.1998.70031094.x |pmid= 9489730}}</ref><ref name="Ronde_1997">{{cite journal |author=Rondé P, Nichols RA|title=5-HT<sub>3</sub> receptors induce rises in cytosolic and nuclear calcium in NG108-15 cells via calcium-induced calcium release|journal= Cell Calcium |volume= 22 |issue= 5 |pages= 357–65 |year= 1997| doi = 10.1016/S0143-4160(97)90020-8|pmid= 9448942}}</ref><ref name="van Hooft_2000">{{cite journal |author=van Hooft JA, Vijverberg HP|title=5-HT<sub>3</sub> receptors and neurotransmitter release in the CNS: a nerve ending story?|journal= Trends Neurosci |volume= 23 |issue= 12 |pages= 605–10 |year= 2000| doi = 10.1016/S0166-2236(00)01662-3 |pmid= 11137150}}</ref>

== Effects ==

When the receptor is activated to open the ion channel by agonists, the following effects are observed:
* [[central nervous system|CNS]]: anxiety<ref name="Rang187"/>
* [[peripheral nervous system|PNS]]: neuronal excitation (in autonomic, nociceptive neurons), [[emesis]]<ref name="Rang187"/>

== Agonists ==

Agonists for the receptor include:
* [[2-methyl-5-HT]]
* [[varenicline]]
* [[Chlorophenylbiguanide]]<ref name="Rang187"/>
* [[Quipazine]]
* [[RS-56812]]: potent and selective 5-HT<sub>3</sub> partial agonist, 1000x selectivity over other serotonin receptors
* SR-57227 
* YM-31636<ref>Imanishi N, Iwaoka K, Koshio H, Nagashima SY, Kazuta K, Ohta M, Sakamoto S, Ito H, Akuzawa S, Kiso T, Tsukamoto S, Mase T. New thiazole derivatives as potent and selective 5-hydroxytriptamine 3 (5-HT3) receptor agonists for the treatment of constipation. ''Bioorganic and Medicinal Chemistry''. 2003 Apr 3;11(7):1493-502. PMID 12628674</ref>

== Antagonists ==

See also: [[5-HT3 receptor antagonist:drug discovery and development|5-HT<sub>3</sub> receptor antagonist: Drug discovery and development]]

Antagonists for the receptor (sorted by their respective therapeutic application) include:
* [[Antiemetic]]s
** [[AS-8112]]
** [[Granisetron]]<ref name="Rang187"/>
** [[Ondansetron]]
** [[Tropisetron]]<ref name="Rang187"> {{cite book |author=Rang, H. P. |title=Pharmacology |publisher=Churchill Livingstone |location=Edinburgh |year=2003 |pages= |isbn=0-443-07145-4 |oclc= |doi=}} Page 187 </ref>
* [[Gastroprokinetic]]s
** [[Alosetron]]
** [[Batanopride]]
** [[Metoclopramide]] (high doses)
** [[Renzapride]]
** [[Zacopride]]
* [[Antidepressant]]s
** [[Mianserin]]
** [[Mirtazapine]]
* [[Antipsychotic]]s
** [[Clozapine]]
** [[Olanzapine]]
** [[Quetiapine]]
* Others
** [[Memantine]] ([[Alzheimer's disease]] medication)

== Discovery ==

Identification of the 5-HT<sub>3</sub> receptor did not take place until 1986 because of a lack of selective pharmacological tool.<ref name="Yakel_2000"/> However, with the discovery that the 5-HT<sub>3</sub> receptor plays a prominent role in [[chemotherapy]]- and [[radiotherapy]]-induced [[vomiting]], and the concomitant development of selective [[5-HT3 antagonist|5-HT<sub>3</sub> receptor antagonist]]s to suppress these side effects aroused intense interest from the pharmaceutical industry<ref name="Thompson_2006">{{cite journal |author=Thompson AJ, Lummis SC|title=5-HT<sub>3</sub> receptors|journal= Curr Pharm Des |volume= 12 |issue= 28 |pages= 3615–30 |year= 2006| url = http://www.ingentaconnect.com/content/ben/cpd/2006/00000012/00000028/art00005 | doi =  10.2174/138161206778522029|pmid= 17073663 |pmc=2664614}}</ref><ref name="Thompson_2007">{{cite journal |author=Thompson AJ, Lummis SC|title=The 5-HT<sub>3</sub> receptor as a therapeutic target|journal= Expert Opin Ther Targets |volume= 11 |issue= 4 |pages= 527–40 |year= 2007| doi = 10.1517/14728222.11.4.527 |pmid= 17373882 |pmc=1994432}}</ref> and therefore the identification of 5-HT<sub>3</sub> receptors in cell lines and native tissues quickly followed.<ref name="Yakel_2000"/>

== References ==
{{Reflist|2}}

== External links ==
* {{MeshName|5-HT3+Receptor}}

{{Ligand-gated ion channels}}
{{Serotonergics}}

[[Category:Neurotransmitters]]
[[Category:Ion channels]]
[[Category:Ionotropic receptors]]

[[fr:Récepteur 5-HT3]]
[[Category:2Fix]]