View source for 5-HT4 receptor

{{DISPLAYTITLE:5-HT<sub>4</sub> receptor}}
{{Infobox_gene}}
'''5-Hydroxytryptamine receptor 4''' is a [[protein]] that in humans is encoded by the ''HTR4'' [[gene]].<ref name="pmid9371406">{{cite journal | vauthors = Claeysen S, Faye P, Sebben M, Lemaire S, Bockaert J, Dumuis A, Taviaux S | title = Assignment of 5-hydroxytryptamine receptor (HTR4) to human chromosome 5 bands q31-->q33 by in situ hybridization | journal = Cytogenetics and Cell Genetics | volume = 78 | issue = 2 | pages = 133–4 | date = December 1997 | pmid = 9371406 | pmc =  | doi = 10.1159/000134646 }}</ref><ref name="pmid9276448">{{cite journal | vauthors = Blondel O, Vandecasteele G, Gastineau M, Leclerc S, Dahmoune Y, Langlois M, Fischmeister R | title = Molecular and functional characterization of a 5-HT4 receptor cloned from human atrium | journal = FEBS Letters | volume = 412 | issue = 3 | pages = 465–74 | date = August 1997 | pmid = 9276448 | pmc =  | doi = 10.1016/S0014-5793(97)00820-X }}</ref>

== Function ==

This gene is a member of the family of human [[serotonin]] receptors, which are [[G protein-coupled receptors]] that stimulate [[cyclic adenosine monophosphate|cAMP]] production in response to serotonin (5-hydroxytryptamine). The gene product is a glycosylated transmembrane protein that functions in both the peripheral and central nervous system to modulate the release of various [[neurotransmitters]]. Multiple transcript variants encoding proteins with distinct C-terminal sequences have been described, but the full-length nature of some transcript variants has not been determined.<ref name="entrez">{{cite web| title = Entrez Gene: HTR4 5-hydroxytryptamine (serotonin) receptor 4| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=3360| accessdate = }}</ref>

== Location ==
The receptor is located in the [[alimentary tract]], [[urinary bladder]], [[heart]] and [[adrenal gland]] as well as the [[central nervous system]] (CNS).<ref>{{cite journal | vauthors = Hegde SS, Eglen RM | title = Peripheral 5-HT4 receptors | journal = FASEB Journal | volume = 10 | issue = 12 | pages = 1398–407 | date = October 1996 | pmid = 8903510 }}</ref>
In the CNS the receptor appears in the [[putamen]], [[caudate nucleus]], [[nucleus accumbens]], [[globus pallidus]], and [[substantia nigra]], and to a lesser extent in the [[neocortex]], [[raphe nuclei|raphe]], [[pontine nuclei]], and some areas of the [[thalamus]].
It has not been found in the cerebellum.<ref>{{cite journal | vauthors = Varnäs K, Halldin C, Pike VW, Hall H | title = Distribution of 5-HT4 receptors in the postmortem human brain--an autoradiographic study using [125I]SB 207710 | journal = European Neuropsychopharmacology | volume = 13 | issue = 4 | pages = 228–34 | date = August 2003 | pmid = 12888181 | doi = 10.1016/S0924-977X(03)00009-9 }}</ref>

==Isoforms==
Internalization is isoform-specific.<ref>{{cite journal | vauthors = Mnie-Filali O, Amraei MG, Benmbarek S, Archer-Lahlou E, Peñas-Cazorla R, Vilaró MT, Boye SM, Piñeyro G | title = Serotonin 4 receptor (5-HT4R) internalization is isoform-specific: effects of 5-HT and RS67333 on isoforms A and B | journal = Cellular Signalling | volume = 22 | issue = 3 | pages = 501–9 | date = March 2010 | pmid = 19922792 | doi = 10.1016/j.cellsig.2009.11.004 }}</ref>

==Ligands==
Several drugs that act as 5-HT<sub>4</sub> selective agonists have recently been introduced into use in both scientific research and clinical medicine. Some drugs that act as 5-HT<sub>4</sub> agonists are also active as 5-HT<sub>3</sub> antagonists, such as mosapride, metoclopramide, renzapride, and zacopride, and so these compounds cannot be considered highly selective. Research in this area is ongoing.<ref name="pmid19168624">{{cite journal | vauthors = Pellissier LP, Sallander J, Campillo M, Gaven F, Queffeulou E, Pillot M, Dumuis A, Claeysen S, Bockaert J, Pardo L | title = Conformational toggle switches implicated in basal constitutive and agonist-induced activated states of 5-hydroxytryptamine-4 receptors | journal = Molecular Pharmacology | volume = 75 | issue = 4 | pages = 982–90 | date = April 2009 | pmid = 19168624 | doi = 10.1124/mol.108.053686 }}</ref>

[[SB-207,145]] radiolabeled with [[carbon-11]] is used as a [[radioligand]] for 5-HT<sub>4</sub> in [[positron emission tomography]] pig<ref>{{cite journal | vauthors = Kornum BR, Lind NM, Gillings N, Marner L, Andersen F, Knudsen GM | title = Evaluation of the novel 5-HT4 receptor PET ligand [11C]SB207145 in the Göttingen minipig | journal = Journal of Cerebral Blood Flow and Metabolism | volume = 29 | issue = 1 | pages = 186–96 | date = January 2009 | pmid = 18797470 | doi = 10.1038/jcbfm.2008.110 }}</ref>
and human<ref name="pmid19470850">{{cite journal | vauthors = Marner L, Gillings N, Comley RA, Baaré WF, Rabiner EA, Wilson AA, Houle S, Hasselbalch SG, Svarer C, Gunn RN, Laruelle M, Knudsen GM | title = Kinetic modeling of 11C-SB207145 binding to 5-HT4 receptors in the human brain in vivo | journal = Journal of Nuclear Medicine | volume = 50 | issue = 6 | pages = 900–8 | date = June 2009 | pmid = 19470850 | doi = 10.2967/jnumed.108.058552 }}</ref>
studies.

=== Agonists ===
* [[BIMU-8]]
* [[Cisapride]]
* [[CJ-033,466]] - partial agonist
* [[ML-10302]]<ref name="pmid21239110">{{cite journal | vauthors = Godínez-Chaparro B, Barragán-Iglesias P, Castañeda-Corral G, Rocha-González HI, Granados-Soto V | title = Role of peripheral 5-HT(4), 5-HT(6), and 5-HT(7) receptors in development and maintenance of secondary mechanical allodynia and hyperalgesia | journal = Pain | volume = 152 | issue = 3 | pages = 687–97 | date = March 2011 | pmid = 21239110 | doi = 10.1016/j.pain.2010.12.020 }}</ref>
* [[Mosapride]]
* [[Prucalopride]]
* [[Renzapride]]
* RS-67506
* [[RS-67333]] - partial agonist
* [[SL65.0155]] - partial agonist
* [[Tegaserod]]
* [[Zacopride]]
* [[Metoclopramide]]
* [[Sulpiride]]

=== Antagonists ===
* [[Piboserod]]
* [[GR-113,808]] (1-methyl-1H-indole-3-carboxylic acid, [1-[2-[(methylsulfonyl)amino]ethyl]-4-piperidinyl]methyl ester)<ref>{{cite journal | vauthors = Gale JD, Grossman CJ, Whitehead JW, Oxford AW, Bunce KT, Humphrey PP | title = GR113808: a novel, selective antagonist with high affinity at the 5-HT4 receptor | journal = British Journal of Pharmacology | volume = 111 | issue = 1 | pages = 332–8 | date = January 1994 | pmid = 8012715 | pmc = 1910004 | doi = 10.1111/j.1476-5381.1994.tb14064.x }}</ref>
* GR-125,487
* RS-39604 (1-[4-Amino-5-chloro-2-(3,5-dimethoxyphenyl)methyloxy]-3-[1-[2-methylsulphonylamino]piperidin-4-yl]propan-1-one)
* SB-203,186
* [[SB-204,070]]
*([Methoxy-<sup>11</sup>C]1-butylpiperidin-4-yl)methyl 4-amino-3-methoxybenzoate<ref>{{cite journal | vauthors = Xu R, Hong J, Morse CL, Pike VW | title = Synthesis, structure-affinity relationships, and radiolabeling of selective high-affinity 5-HT4 receptor ligands as prospective imaging probes for positron emission tomography | journal = Journal of Medicinal Chemistry | volume = 53 | issue = 19 | pages = 7035–47 | date = October 2010 | pmid = 20812727 | pmc = 2951497 | doi = 10.1021/jm100668r }}</ref>
* Chamomile (ethanol extract)<ref>{{cite journal | vauthors = Simmen U, Kelber O, Okpanyi SN, Jaeggi R, Bueter B, Weiser D | year = 2006| title = Binding of STW 5 (Iberogast) and its components to intestinal 5-HT, muscarinic M3, and opioid receptors | url = | journal = Phytomedicine| volume =  13 Suppl 5| issue = | pages =  51–5| pmid = 16973340 | doi=10.1016/j.phymed.2006.03.012}}</ref>

== See also ==
* [[5-HT receptor]]
* [[5-HT1 receptor|5-HT<sub>1</sub> receptor]]
* [[5-HT2 receptor|5-HT<sub>2</sub> receptor]]
* [[5-HT3 receptor|5-HT<sub>3</sub> receptor]]
* [[5-HT5 receptor|5-HT<sub>5</sub> receptor]]
* [[5-HT6 receptor|5-HT<sub>6</sub> receptor]]
* [[5-HT7 receptor|5-HT<sub>7</sub> receptor]]

== References ==
{{Reflist|33em}}

== Further reading ==
{{Refbegin|33em}}
* Licht CL, 2009, ''Changes in the 5-HT<sub>4</sub> receptor in [[animal models of depression]] and antidepressant treatment'', PhD thesis, [[University of Copenhagen]].
* {{cite journal | vauthors = Ullmer C, Schmuck K, Kalkman HO, Lübbert H | title = Expression of serotonin receptor mRNAs in blood vessels | journal = FEBS Letters | volume = 370 | issue = 3 | pages = 215–21 | date = August 1995 | pmid = 7656980 | doi = 10.1016/0014-5793(95)00828-W }}
* {{cite journal | vauthors = Blondel O, Vandecasteele G, Gastineau M, Leclerc S, Dahmoune Y, Langlois M, Fischmeister R | title = Molecular and functional characterization of a 5-HT4 receptor cloned from human atrium | journal = FEBS Letters | volume = 412 | issue = 3 | pages = 465–74 | date = August 1997 | pmid = 9276448 | doi = 10.1016/S0014-5793(97)00820-X }}
* {{cite journal | vauthors = Van den Wyngaert I, Gommeren W, Verhasselt P, Jurzak M, Leysen J, Luyten W, Bender E | title = Cloning and expression of a human serotonin 5-HT4 receptor cDNA | journal = Journal of Neurochemistry | volume = 69 | issue = 5 | pages = 1810–9 | date = November 1997 | pmid = 9349523 | doi = 10.1046/j.1471-4159.1997.69051810.x }}
* {{cite journal | vauthors = Claeysen S, Faye P, Sebben M, Lemaire S, Bockaert J, Dumuis A | title = Cloning and expression of human 5-HT4S receptors. Effect of receptor density on their coupling to adenylyl cyclase | journal = NeuroReport | volume = 8 | issue = 15 | pages = 3189–96 | date = October 1997 | pmid = 9351641 | doi = 10.1097/00001756-199710200-00002 }}
* {{cite journal | vauthors = Blondel O, Gastineau M, Dahmoune Y, Langlois M, Fischmeister R | title = Cloning, expression, and pharmacology of four human 5-hydroxytryptamine 4 receptor isoforms produced by alternative splicing in the carboxyl terminus | journal = Journal of Neurochemistry | volume = 70 | issue = 6 | pages = 2252–61 | date = June 1998 | pmid = 9603189 | doi = 10.1046/j.1471-4159.1998.70062252.x }}
* {{cite journal | vauthors = Cichon S, Kesper K, Propping P, Nöthen MM | title = Assignment of the human serotonin 4 receptor gene (HTR4) to the long arm of chromosome 5 (5q31-q33) | journal = Molecular Membrane Biology | volume = 15 | issue = 2 | pages = 75–8 | year = 1998 | pmid = 9724925 | doi = 10.3109/09687689809027521 }}
* {{cite journal | vauthors = Claeysen S, Sebben M, Becamel C, Bockaert J, Dumuis A | title = Novel brain-specific 5-HT4 receptor splice variants show marked constitutive activity: role of the C-terminal intracellular domain | journal = Molecular Pharmacology | volume = 55 | issue = 5 | pages = 910–20 | date = May 1999 | pmid = 10220570 | doi =  }}
* {{cite journal | vauthors = Bender E, Pindon A, van Oers I, Zhang YB, Gommeren W, Verhasselt P, Jurzak M, Leysen J, Luyten W | title = Structure of the human serotonin 5-HT4 receptor gene and cloning of a novel 5-HT4 splice variant | journal = Journal of Neurochemistry | volume = 74 | issue = 2 | pages = 478–89 | date = February 2000 | pmid = 10646498 | doi = 10.1046/j.1471-4159.2000.740478.x }}
* {{cite journal | vauthors = Mialet J, Berque-Bestel I, Eftekhari P, Gastineau M, Giner M, Dahmoune Y, Donzeau-Gouge P, Hoebeke J, Langlois M, Sicsic S, Fischmeister R, Lezoualc'h F | title = Isolation of the serotoninergic 5-HT4(e) receptor from human heart and comparative analysis of its pharmacological profile in C6-glial and CHO cell lines | journal = British Journal of Pharmacology | volume = 129 | issue = 4 | pages = 771–81 | date = February 2000 | pmid = 10683202 | pmc = 1571890 | doi = 10.1038/sj.bjp.0703101 }}
* {{cite journal | vauthors = Bach T, Syversveen T, Kvingedal AM, Krobert KA, Brattelid T, Kaumann AJ, Levy FO | title = 5HT4(a) and 5-HT4(b) receptors have nearly identical pharmacology and are both expressed in human atrium and ventricle | journal = Naunyn-Schmiedeberg's Archives of Pharmacology | volume = 363 | issue = 2 | pages = 146–60 | date = February 2001 | pmid = 11218067 | doi = 10.1007/s002100000299 }}
* {{cite journal | vauthors = Medhurst AD, Lezoualc'h F, Fischmeister R, Middlemiss DN, Sanger GJ | title = Quantitative mRNA analysis of five C-terminal splice variants of the human 5-HT4 receptor in the central nervous system by TaqMan real time RT-PCR | journal = Brain Research. Molecular Brain Research | volume = 90 | issue = 2 | pages = 125–34 | date = June 2001 | pmid = 11406291 | doi = 10.1016/S0169-328X(01)00095-X }}
* {{cite journal | vauthors = Hiroi T, Hayashi-Kobayashi N, Nagumo S, Ino M, Okawa Y, Aoba A, Matsui H | title = Identification and characterization of the human serotonin-4 receptor gene promoter | journal = Biochemical and Biophysical Research Communications | volume = 289 | issue = 2 | pages = 337–44 | date = November 2001 | pmid = 11716477 | doi = 10.1006/bbrc.2001.5979 }}
* {{cite journal | vauthors = Vilaró MT, Doménech T, Palacios JM, Mengod G | title = Cloning and characterization of a novel human 5-HT4 receptor variant that lacks the alternatively spliced carboxy terminal exon. RT-PCR distribution in human brain and periphery of multiple 5-HT4 receptor variants | journal = Neuropharmacology | volume = 42 | issue = 1 | pages = 60–73 | date = January 2002 | pmid = 11750916 | doi = 10.1016/S0028-3908(01)00154-X }}
* {{cite journal | vauthors = López-Rodríguez ML, Murcia M, Benhamú B, Olivella M, Campillo M, Pardo L | title = Computational model of the complex between GR113808 and the 5-HT4 receptor guided by site-directed mutagenesis and the crystal structure of rhodopsin | journal = Journal of Computer-Aided Molecular Design | volume = 15 | issue = 11 | pages = 1025–33 | date = November 2001 | pmid = 11989623 | doi = 10.1023/A:1014895611874 }}
* {{cite journal | vauthors = Ohtsuki T, Ishiguro H, Detera-Wadleigh SD, Toyota T, Shimizu H, Yamada K, Yoshitsugu K, Hattori E, Yoshikawa T, Arinami T | title = Association between serotonin 4 receptor gene polymorphisms and bipolar disorder in Japanese case-control samples and the NIMH Genetics Initiative Bipolar Pedigrees | journal = Molecular Psychiatry | volume = 7 | issue = 9 | pages = 954–61 | year = 2003 | pmid = 12399948 | doi = 10.1038/sj.mp.4001133 }}
* {{cite journal | vauthors = Norum JH, Hart K, Levy FO | title = Ras-dependent ERK activation by the human G(s)-coupled serotonin receptors 5-HT4(b) and 5-HT7(a) | journal = The Journal of Biological Chemistry | volume = 278 | issue = 5 | pages = 3098–104 | date = January 2003 | pmid = 12446729 | doi = 10.1074/jbc.M206237200 }}
* {{cite journal | vauthors = Cartier D, Lihrmann I, Parmentier F, Bastard C, Bertherat J, Caron P, Kuhn JM, Lacroix A, Tabarin A, Young J, Vaudry H, Lefebvre H | title = Overexpression of serotonin4 receptors in cisapride-responsive adrenocorticotropin-independent bilateral macronodular adrenal hyperplasia causing Cushing's syndrome | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 88 | issue = 1 | pages = 248–54 | date = January 2003 | pmid = 12519861 | doi = 10.1210/jc.2002-021107 }}
* {{cite journal | vauthors = Manzke T, Guenther U, Ponimaskin EG, Haller M, Dutschmann M, Schwarzacher S, Richter DW | title = 5-HT4(a) receptors avert opioid-induced breathing depression without loss of analgesia | journal = Science | volume = 301 | issue = 5630 | pages = 226–9 | date = July 2003 | pmid = 12855812 | doi = 10.1126/science.1084674 }}
{{Refend}}

== External links ==
* {{cite web| url = http://www.iuphar-db.org/GPCR/ReceptorDisplayForward?receptorID=2329| title = 5-HT<sub>4</sub>| accessdate =| date =| format =| work = IUPHAR Database of Receptors and Ion Channels| publisher = International Union of Basic and Clinical Pharmacology| pages =| language =| archiveurl =| archivedate =| quote = }}
* {{UCSC gene info|HTR4}}

{{NLM content}}

{{G protein-coupled receptors}}
{{Serotonergics}}

{{Use dmy dates|date=February 2011}}

{{DEFAULTSORT:5-Ht4 Receptor}}
[[Category:Biology of bipolar disorder]]
[[Category:Serotonin receptors]]