5-HT3 receptor

protein
Name=5-hydroxytryptamine (serotonin) receptor 3A
caption=


width=
HGNCid=5297
Symbol=HTR3A
AltSymbols=HTR3
EntrezGene=3359
OMIM=182139
RefSeq=NM_000869
UniProt=P46098
PDB=
ECnumber=
Chromosome=11
Arm=q
Band=23.1
LocusSupplementaryData=-23.2
protein
Name=5-hydroxytryptamine (serotonin) receptor 3B
caption=


width=
HGNCid=5298
Symbol=HTR3B
AltSymbols=
EntrezGene=9177
OMIM=604654
RefSeq=NM_006028
UniProt=O95264
PDB=
ECnumber=
Chromosome=11
Arm=q
Band=23.1
LocusSupplementaryData=
protein
Name=5-hydroxytryptamine (serotonin) receptor 3C
caption=


width=
HGNCid= 24003
Symbol=HTR3C
AltSymbols=
EntrezGene= 170572
OMIM= 610121
RefSeq= NM_130770
UniProt= A2RRR5
PDB=
ECnumber=
Chromosome=3
Arm=q
Band=27
LocusSupplementaryData=
protein
Name=5-hydroxytryptamine (serotonin) receptor 3D
caption=


width=
HGNCid= 24004
Symbol=HTR3D
AltSymbols=
EntrezGene= 200909
OMIM= 610122
RefSeq= NM_182537
UniProt= Q70Z44
PDB=
ECnumber=
Chromosome=3
Arm=q
Band=27
LocusSupplementaryData=
protein
Name=5-hydroxytryptamine (serotonin) receptor 3E
caption=


width=
HGNCid= 24005
Symbol=HTR3E
AltSymbols=
EntrezGene= 285242
OMIM= 610123
RefSeq= NM_182589
UniProt= Q495G3
PDB=
ECnumber=
Chromosome=3
Arm=q
Band=27
LocusSupplementaryData=

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 GABAC receptors) and glycine.cite journal |author=Maricq AV, Peterson AS, Brake AJ, Myers RM, Julius D|title=Primary structure and functional expression of the 5HT3 receptor, a serotonin-gated ion channel|journal= Science |volume= 254 |issue= 5030 |pages= 432–7 |year= 1991| doi = 10.1126/science.1718042 |pmid= 1718042] Citation | 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-HT3 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] 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.

tructure

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 Gene|HTR3A, Gene|HTR3B, Gene|HTR3C, Gene|HTR3D, and/or Gene|HTR3E genes.

Functional channels may be comprised of five identical 5-HT3A subunits (homopentameric) or a mixture of 5-HT3A and one of the other four 5-HT3B,cite journal |author=Davies PA, Pistis M, Hanna MC, Peters JA, Lambert JJ, Hales TG, Kirkness EF|title=The 5-HT3B 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] 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-HT3A receptor are specifically modified by a 5-HT3B receptor subunit|journal= J Biol Chem |volume= 274 |issue= 43 |pages= 30799–810 |year= 1999| doi = |pmid= 10521471] 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-HT3B 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] 5-HT3C, 5-HT3D, or 5-HT3E subunits (heteropentameric).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-HT3C, 5- HT3D and 5-HT3E|journal= Mol Pharmacol |volume= 71 |issue= Mar 28 |pages= Epub ahead of print |year= 2007| doi = 10.1124/mol.106.032144 |pmid= 17392525] 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. 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.cite journal |author=Férézou I, Cauli B, Hill EL, Rossier J, Hamel E, Lambolez B|title=5-HT3 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] cite journal |author=Sugita S, Shen KZ, North RA|title=5-hydroxytryptamine is a fast excitatory transmitter at 5-HT3 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] cite journal |author=Roerig B, Nelson DA, Katz LC|title=Fast synaptic signaling by nicotinic acetylcholine and serotonin 5-HT3 receptors in developing visual cortex|journal= J Neurosci |volume= 17 |issue= 21 |pages= 199–203 |year= 1992| doi = |pmid= 9334409] 5-HT3 receptors are also present on presynaptic nerve terminals, where they are thought to mediate or modulate neurotransmitter release.cite journal |author=Rondé P, Nichols RA|title=High calcium permeability of serotonin 5-HT3 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] cite journal |author=Rondé P, Nichols RA|title=5-HT3 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 = |pmid= 9448942] cite journal |author=van Hooft JA, Vijverberg HP|title=5-HT3 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]

Effects

When the receptor is activated to open the ion channel by agonists, the following effects are observed:
* CNS: anxiety
* PNS: neuronal excitation (in autonomic, nociceptive neurons), emesis

Agonists

Agonists (channel openers) for the receptor include:
* Quipazine
* 2-methyl-5-HT
* chlorophenylbiguanide

Antagonists

Antagonists (channel closers) for the receptor (sorted by their respective therapeutic application) include:
* IBS medications
** metoclopramide (high doses)
** renzapride
** alosetron
* antiemetics
** ondansetron
** tropisetron 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 ]
** granisetron
* mirtazapine (antidepressant)
* memantine (in Alzheimer disease)

Discovery

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 industrycite journal |author=Thompson AJ, Lummis SC|title=5-HT3 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 = |pmid= 17073663] cite journal |author=Thompson AJ, Lummis SC|title=The 5-HT3 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] and therefore the identification of 5-HT3 receptors in cell lines and native tissues quickly followed.

References

External links

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