5-HT4 receptor explained

5-Hydroxytryptamine receptor 4 is a protein that in humans is encoded by the HTR4 gene.^{[1] [2]}

Function

This gene is a member of the family of human serotonin receptors, which are G protein-coupled receptors that stimulate 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.^[3]

Location

The receptor is located in the alimentary tract, urinary bladder, heart and adrenal gland as well as the central nervous system (CNS).^[4] 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, pontine nuclei, and some areas of the thalamus.It has not been found in the cerebellum.^[5]

Isoforms

Internalization is isoform-specific.^[6]

Ligands

Several drugs that act as 5-HT₄ selective agonists have recently been introduced into use in both scientific research and clinical medicine. Some drugs that act as 5-HT₄ agonists are also active as 5-HT₃ antagonists, such as mosapride, metoclopramide, renzapride, and zacopride, and so these compounds cannot be considered highly selective. Research in this area is ongoing.^[7] Amongst these agonists prucalopride has >150-fold higher affinity for 5-HT4 receptors than for other receptors.

SB-207,145 radiolabeled with carbon-11 is used as a radioligand for 5-HT₄ in positron emission tomography pig^[8] and human^[9] studies.

Agonists

• Tropisetron^[10] partial agonist
• BIMU-8
• Cisapride
• CJ-033,466 partial agonist
• ML-10302^[11]
• Mosapride
• Prucalopride
• Renzapride
• RS-67506
• RS-67333 partial agonist
• SL65.0155 partial agonist
• Tegaserod
• Zacopride
• Metoclopramide
• Sulpiride
• Naronapride

Antagonists

• L-lysine
• Piboserod
• GR-113,808 (1-methyl-1H-indole-3-carboxylic acid, [1-[2-[(methylsulfonyl)amino]ethyl]-4-piperidinyl]methyl ester)^[12]
• 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-¹¹C]1-butylpiperidin-4-yl)methyl 4-amino-3-methoxybenzoate^[13]
• Chamomile (ethanol extract)^[14]

See also

• 5-HT receptor
• 5-HT₁ receptor
• 5-HT₂ receptor
• 5-HT₃ receptor
• 5-HT₅ receptor
• 5-HT₆ receptor
• 5-HT₇ receptor

Further reading

• Licht CL, 2009, Changes in the 5-HT₄ receptor in animal models of depression and antidepressant treatment, PhD thesis, University of Copenhagen.
• Ullmer C, Schmuck K, Kalkman HO, Lübbert H . Expression of serotonin receptor mRNAs in blood vessels . FEBS Letters . 370 . 3 . 215–21 . August 1995 . 7656980 . 10.1016/0014-5793(95)00828-W . 9015835 . free .
• Blondel O, Vandecasteele G, Gastineau M, Leclerc S, Dahmoune Y, Langlois M, Fischmeister R . Molecular and functional characterization of a 5-HT4 receptor cloned from human atrium . FEBS Letters . 412 . 3 . 465–74 . August 1997 . 9276448 . 10.1016/S0014-5793(97)00820-X . 23714426 . free .
• Van den Wyngaert I, Gommeren W, Verhasselt P, Jurzak M, Leysen J, Luyten W, Bender E . Cloning and expression of a human serotonin 5-HT4 receptor cDNA . Journal of Neurochemistry . 69 . 5 . 1810–9 . November 1997 . 9349523 . 10.1046/j.1471-4159.1997.69051810.x . 25269904 . free .
• Claeysen S, Faye P, Sebben M, Lemaire S, Bockaert J, Dumuis A . Cloning and expression of human 5-HT4S receptors. Effect of receptor density on their coupling to adenylyl cyclase . NeuroReport . 8 . 15 . 3189–96 . October 1997 . 9351641 . 10.1097/00001756-199710200-00002 . 20624532 .
• Blondel O, Gastineau M, Dahmoune Y, Langlois M, Fischmeister R . Cloning, expression, and pharmacology of four human 5-hydroxytryptamine 4 receptor isoforms produced by alternative splicing in the carboxyl terminus . Journal of Neurochemistry . 70 . 6 . 2252–61 . June 1998 . 9603189 . 10.1046/j.1471-4159.1998.70062252.x . 24203530 . 8 April 2022 . 10 June 2023 . https://web.archive.org/web/20230610072158/https://hal-universite-paris-saclay.archives-ouvertes.fr/hal-03617007/file/Version%20HAL.pdf . dead .
• Cichon S, Kesper K, Propping P, Nöthen MM . Assignment of the human serotonin 4 receptor gene (HTR4) to the long arm of chromosome 5 (5q31-q33) . Molecular Membrane Biology . 15 . 2 . 75–8 . 1998 . 9724925 . 10.3109/09687689809027521 .
• Claeysen S, Sebben M, Becamel C, Bockaert J, Dumuis A . Novel brain-specific 5-HT4 receptor splice variants show marked constitutive activity: role of the C-terminal intracellular domain . Molecular Pharmacology . 55 . 5 . 910–20 . May 1999 . 10220570 .
• Bender E, Pindon A, van Oers I, Zhang YB, Gommeren W, Verhasselt P, Jurzak M, Leysen J, Luyten W . Structure of the human serotonin 5-HT4 receptor gene and cloning of a novel 5-HT4 splice variant . Journal of Neurochemistry . 74 . 2 . 478–89 . February 2000 . 10646498 . 10.1046/j.1471-4159.2000.740478.x . 33817190 .
• 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 . 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 . British Journal of Pharmacology . 129 . 4 . 771–81 . February 2000 . 10683202 . 1571890 . 10.1038/sj.bjp.0703101 .
• Bach T, Syversveen T, Kvingedal AM, Krobert KA, Brattelid T, Kaumann AJ, Levy FO . 5HT4(a) and 5-HT4(b) receptors have nearly identical pharmacology and are both expressed in human atrium and ventricle . Naunyn-Schmiedeberg's Archives of Pharmacology . 363 . 2 . 146–60 . February 2001 . 11218067 . 10.1007/s002100000299 . 27504006 .
• Medhurst AD, Lezoualc'h F, Fischmeister R, Middlemiss DN, Sanger GJ . 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 . Brain Research. Molecular Brain Research . 90 . 2 . 125–34 . June 2001 . 11406291 . 10.1016/S0169-328X(01)00095-X .
• Hiroi T, Hayashi-Kobayashi N, Nagumo S, Ino M, Okawa Y, Aoba A, Matsui H . Identification and characterization of the human serotonin-4 receptor gene promoter . Biochemical and Biophysical Research Communications . 289 . 2 . 337–44 . November 2001 . 11716477 . 10.1006/bbrc.2001.5979 .
• Vilaró MT, Doménech T, Palacios JM, Mengod G . 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 . Neuropharmacology . 42 . 1 . 60–73 . January 2002 . 11750916 . 10.1016/S0028-3908(01)00154-X . 10261/112650 . 23722311 . free .
• López-Rodríguez ML, Murcia M, Benhamú B, Olivella M, Campillo M, Pardo L . Computational model of the complex between GR113808 and the 5-HT4 receptor guided by site-directed mutagenesis and the crystal structure of rhodopsin . Journal of Computer-Aided Molecular Design . 15 . 11 . 1025–33 . November 2001 . 11989623 . 10.1023/A:1014895611874 . 2001JCAMD..15.1025L . 23478175 .
• Ohtsuki T, Ishiguro H, Detera-Wadleigh SD, Toyota T, Shimizu H, Yamada K, Yoshitsugu K, Hattori E, Yoshikawa T, Arinami T . Association between serotonin 4 receptor gene polymorphisms and bipolar disorder in Japanese case-control samples and the NIMH Genetics Initiative Bipolar Pedigrees . Molecular Psychiatry . 7 . 9 . 954–61 . 2003 . 12399948 . 10.1038/sj.mp.4001133 . 21064320 .
• Norum JH, Hart K, Levy FO . Ras-dependent ERK activation by the human G(s)-coupled serotonin receptors 5-HT4(b) and 5-HT7(a) . The Journal of Biological Chemistry . 278 . 5 . 3098–104 . January 2003 . 12446729 . 10.1074/jbc.M206237200 . free .
• Cartier D, Lihrmann I, Parmentier F, Bastard C, Bertherat J, Caron P, Kuhn JM, Lacroix A, Tabarin A, Young J, Vaudry H, Lefebvre H . Overexpression of serotonin4 receptors in cisapride-responsive adrenocorticotropin-independent bilateral macronodular adrenal hyperplasia causing Cushing's syndrome . The Journal of Clinical Endocrinology and Metabolism . 88 . 1 . 248–54 . January 2003 . 12519861 . 10.1210/jc.2002-021107 . free .
• Manzke T, Guenther U, Ponimaskin EG, Haller M, Dutschmann M, Schwarzacher S, Richter DW . 5-HT4(a) receptors avert opioid-induced breathing depression without loss of analgesia . Science . 301 . 5630 . 226–9 . July 2003 . 12855812 . 10.1126/science.1084674 . 2003Sci...301..226M . 13641423 .

External links

• Web site: 5-HT₄. IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology. 25 November 2008. 5 June 2016. https://web.archive.org/web/20160605115442/http://www.iuphar-db.org/GPCR/ReceptorDisplayForward?receptorID=2329. dead.

Notes and References

1. Claeysen S, Faye P, Sebben M, Lemaire S, Bockaert J, Dumuis A, Taviaux S . Assignment of 5-hydroxytryptamine receptor (HTR4) to human chromosome 5 bands q31→q33 by in situ hybridization . Cytogenetics and Cell Genetics . 78 . 2 . 133–4 . December 1997 . 9371406 . 10.1159/000134646 .
2. Blondel O, Vandecasteele G, Gastineau M, Leclerc S, Dahmoune Y, Langlois M, Fischmeister R . Molecular and functional characterization of a 5-HT4 receptor cloned from human atrium . FEBS Letters . 412 . 3 . 465–74 . August 1997 . 9276448 . 10.1016/S0014-5793(97)00820-X . 23714426 . free .
3. Web site: Entrez Gene: HTR4 5-hydroxytryptamine (serotonin) receptor 4.
4. Hegde SS, Eglen RM . Peripheral 5-HT4 receptors . FASEB Journal . 10 . 12 . 1398–407 . October 1996 . 8903510 . 10.1096/fasebj.10.12.8903510 . free . 21596751 .
5. Varnäs K, Halldin C, Pike VW, Hall H . Distribution of 5-HT4 receptors in the postmortem human brain--an autoradiographic study using [125I]SB 207710 . European Neuropsychopharmacology . 13 . 4 . 228–34 . August 2003 . 12888181 . 10.1016/S0924-977X(03)00009-9 . 27945284 .
6. Mnie-Filali O, Amraei MG, Benmbarek S, Archer-Lahlou E, Peñas-Cazorla R, Vilaró MT, Boye SM, Piñeyro G . Serotonin 4 receptor (5-HT4R) internalization is isoform-specific: effects of 5-HT and RS67333 on isoforms A and B . Cellular Signalling . 22 . 3 . 501–9 . March 2010 . 19922792 . 10.1016/j.cellsig.2009.11.004 .
7. Pellissier LP, Sallander J, Campillo M, Gaven F, Queffeulou E, Pillot M, Dumuis A, Claeysen S, Bockaert J, Pardo L . Conformational toggle switches implicated in basal constitutive and agonist-induced activated states of 5-hydroxytryptamine-4 receptors . Molecular Pharmacology . 75 . 4 . 982–90 . April 2009 . 19168624 . 10.1124/mol.108.053686 . 17957338 .
8. Kornum BR, Lind NM, Gillings N, Marner L, Andersen F, Knudsen GM . Evaluation of the novel 5-HT4 receptor PET ligand [11C]SB207145 in the Göttingen minipig . Journal of Cerebral Blood Flow and Metabolism . 29 . 1 . 186–96 . January 2009 . 18797470 . 10.1038/jcbfm.2008.110 . free .
9. Marner L, Gillings N, Comley RA, Baaré WF, Rabiner EA, Wilson AA, Houle S, Hasselbalch SG, Svarer C, Gunn RN, Laruelle M, Knudsen GM . Kinetic modeling of 11C-SB207145 binding to 5-HT4 receptors in the human brain in vivo . Journal of Nuclear Medicine . 50 . 6 . 900–8 . June 2009 . 19470850 . 10.2967/jnumed.108.058552 . free .
10. Costall B, Naylor RJ . The pharmacology of the 5-HT4 receptor . International Clinical Psychopharmacology . 8 Suppl 2 . Suppl 2 . 11–18 . November 1993 . 8201242 . 10.1097/00004850-199311002-00002 . 36692776 .
11. Godínez-Chaparro B, Barragán-Iglesias P, Castañeda-Corral G, Rocha-González HI, Granados-Soto V . Role of peripheral 5-HT(4), 5-HT(6), and 5-HT(7) receptors in development and maintenance of secondary mechanical allodynia and hyperalgesia . Pain . 152 . 3 . 687–97 . March 2011 . 21239110 . 10.1016/j.pain.2010.12.020 . 140204185 .
12. Gale JD, Grossman CJ, Whitehead JW, Oxford AW, Bunce KT, Humphrey PP . GR113808: a novel, selective antagonist with high affinity at the 5-HT4 receptor . British Journal of Pharmacology . 111 . 1 . 332–8 . January 1994 . 8012715 . 1910004 . 10.1111/j.1476-5381.1994.tb14064.x .
13. Xu R, Hong J, Morse CL, Pike VW . Synthesis, structure-affinity relationships, and radiolabeling of selective high-affinity 5-HT4 receptor ligands as prospective imaging probes for positron emission tomography . Journal of Medicinal Chemistry . 53 . 19 . 7035–47 . October 2010 . 20812727 . 2951497 . 10.1021/jm100668r .
14. Simmen U, Kelber O, Okpanyi SN, Jaeggi R, Bueter B, Weiser D . 2006. Binding of STW 5 (Iberogast) and its components to intestinal 5-HT, muscarinic M3, and opioid receptors . Phytomedicine. 13. Suppl 5. 51–5. 16973340 . 10.1016/j.phymed.2006.03.012.