5-HT4 receptor Information & 5-HT4 receptor Links at HealthHaven.com

5-hydroxytryptamine (serotonin) receptor 4
Identifiers
Symbols	HTR4; 5-HT4; 5-HT4R
External IDs	OMIM: 602164 MGI: 109246 HomoloGene: 20243 IUPHAR: 5-HT4 GeneCards: HTR4 Gene
Gene ontology
Molecular function	• rhodopsin-like receptor activity; • receptor activity; • adrenoceptor activity; • serotonin receptor activity;
Cellular component	• membrane fraction; • integral to plasma membrane; • membrane; • integral to membrane;
Biological process	• signal transduction; • G-protein coupled receptor protein signaling pathway; • G-protein signaling, coupled to cyclic nucleotide second messenger;
RNA expression pattern
	More reference expression data
Orthologs

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

This gene is a member of the family of 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]

[edit] 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 and pontine nuclei and some areas of the thalamus. It has not been found in the cerebellum.^[5]

[edit] Ligands

Several drugs which act as 5-HT₄ selective agonists have recently been introduced into use in both scientific research and clinical medicine. Some drugs which 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.^[6]

SB-207,145 radiolabeled with carbon-11 is used as a radioligand for 5-HT₄ in positron emission tomography pig^[7] and human^[8] studies.

[edit] Agonists

BIMU-8
Cisapride
CJ-033,466
Mosapride
Prucalopride
Renzapride
RS-67506
RS-67333 - partial agonist
Tegaserod
Zacopride

[edit] Antagonists

Piboserod
GR-113,808 (1-methyl-1H-indole-3-carboxylic acid, [1-[2-[(methylsulfonyl)amino]ethyl]-4-piperidinyl]methyl ester)^[9]
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

[edit] See also

5-HT receptor

[edit] References

^ Claeysen S, Faye P, Sebben M, Lemaire S, Bockaert J, Dumuis A, Taviaux S (December 1997). "Assignment of 5-hydroxytryptamine receptor (HTR4) to human chromosome 5 bands q31→q33 by in situ hybridization.". Cytogenet Cell Genet 78 (2): 133–4. PMID 9371406.
^ , Blondel O, Vandecasteele G, Gastineau M, Leclerc S, Dahmoune Y, Langlois M, Fischmeister R (September 1997). "Molecular and functional characterization of a 5-HT4 receptor cloned from human atrium.". FEBS Lett 412 (3): 465–74. PMID 9276448.
^ "Entrez Gene: HTR4 5-hydroxytryptamine (serotonin) receptor 4". http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=3360.
^ S. S. Hegde; R. M. Eglen (1 October 1996). "Peripheral 5-HT4 receptors". The FASEB journal 10 (12): 1398–1407. PMID 8903510. http://www.fasebj.org/cgi/content/abstract/10/12/1398.
^ Katarina Varnäs; Christer Halldin; Victor W. Pike; Håkan Hall (2003). "Distribution of 5-HT₄ receptors in the postmortem human brain—an autoradiographic study using [¹²⁵]SB 207710". European Neuropsychopharmacology 13: 228–234. doi:10.1016/S0924-977X(03)00009-9.
^ Pellissier LP, Sallander J, Campillo M, Gaven F, Queffeulou E, Pillot M, Dumuis A, Claeysen S, Bockaert J, Pardo L (April 2009). "Conformational toggle switches implicated in basal constitutive and agonist-induced activated states of 5-hydroxytryptamine-4 receptors". Molecular Pharmacology 75 (4): 982–90. doi:10.1124/mol.108.053686. PMID 19168624.
^ B. R. Kornum, N. M. Lind, N. Gillings, Lisbeth Marner, F. Andersen, Gitte Moos Knudsen (September 2008). "Evaluation of the novel 5-HT(4) receptor PET ligand [(11)C]SB207145 in the Gottingen minipig". Journal of Cerebral Blood Flow and Metabolism 29: 186. doi:10.1038/jcbfm.2008.110. PMID 18797470.
^ Lisbeth Marner, Nic Gillings, Roger Gunn, Robert Comley, William Baaré, Steen Hasselbalch and Gitte Knudsen (05/01/2007). "Quantification of 11C-SB207145-PET for 5-HT4 receptors in the human brain: Preliminary results". Journal of Nuclear Medicine 48 (Supplement 2) (Supplement 2): 159P. http://jnumedmtg.snmjournals.org/cgi/content/meeting_abstract/48/MeetingAbstracts_2/159P.
^ 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. 1994 Jan;111(1):332-8. PMID 8012715

[edit] External links

"5-HT₄". IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology. http://www.iuphar-db.org/GPCR/ReceptorDisplayForward?receptorID=2329.

[edit] Further reading

Cecilie Löe Licht, Changes in the 5-HT₄ receptor in animal models of depression and antidepressant treatment, PhD thesis, Faculty of Health Sciences, University of Copenhagen. Submitted 2008 October.
Ullmer C, Schmuck K, Kalkman HO, Lübbert H (1995). "Expression of serotonin receptor mRNAs in blood vessels.". FEBS Lett. 370 (3): 215–21. doi:10.1016/0014-5793(95)00828-W. PMID 7656980.
Blondel O, Vandecasteele G, Gastineau M, et al. (1997). "Molecular and functional characterization of a 5-HT4 receptor cloned from human atrium.". FEBS Lett. 412 (3): 465–74. doi:10.1016/S0014-5793(97)00820-X. PMID 9276448.
Van den Wyngaert I, Gommeren W, Verhasselt P, et al. (1997). "Cloning and expression of a human serotonin 5-HT4 receptor cDNA.". J. Neurochem. 69 (5): 1810–9. PMID 9349523.
Claeysen S, Faye P, Sebben M, et al. (1997). "Cloning and expression of human 5-HT4S receptors. Effect of receptor density on their coupling to adenylyl cyclase.". Neuroreport 8 (15): 3189–96. doi:10.1097/00001756-199710200-00002. PMID 9351641.
Blondel O, Gastineau M, Dahmoune Y, et al. (1998). "Cloning, expression, and pharmacology of four human 5-hydroxytryptamine 4 receptor isoforms produced by alternative splicing in the carboxyl terminus.". J. Neurochem. 70 (6): 2252–61. PMID 9603189.
Cichon S, Kesper K, Propping P, Nöthen MM (1998). "Assignment of the human serotonin 4 receptor gene (HTR4) to the long arm of chromosome 5 (5q31-q33).". Mol. Membr. Biol. 15 (2): 75–8. doi:10.3109/09687689809027521. PMID 9724925.
Claeysen S, Sebben M, Becamel C, et al. (1999). "Novel brain-specific 5-HT4 receptor splice variants show marked constitutive activity: role of the C-terminal intracellular domain.". Mol. Pharmacol. 55 (5): 910–20. PMID 10220570.
Bender E, Pindon A, van Oers I, et al. (2000). "Structure of the human serotonin 5-HT4 receptor gene and cloning of a novel 5-HT4 splice variant.". J. Neurochem. 74 (2): 478–89. doi:10.1046/j.1471-4159.2000.740478.x. PMID 10646498.
Mialet J, Berque-Bestel I, Eftekhari P, et al. (2000). "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.". Br. J. Pharmacol. 129 (4): 771–81. doi:10.1038/sj.bjp.0703101. PMID 10683202.
Bach T, Syversveen T, Kvingedal AM, et al. (2001). "5HT4(a) and 5-HT4(b) receptors have nearly identical pharmacology and are both expressed in human atrium and ventricle.". Naunyn Schmiedebergs Arch. Pharmacol. 363 (2): 146–60. doi:10.1007/s002100000299. PMID 11218067.
Medhurst AD, Lezoualc'h F, Fischmeister R, et al. (2001). "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 Res. Mol. Brain Res. 90 (2): 125–34. doi:10.1016/S0169-328X(01)00095-X. PMID 11406291.
Hiroi T, Hayashi-Kobayashi N, Nagumo S, et al. (2002). "Identification and characterization of the human serotonin-4 receptor gene promoter.". Biochem. Biophys. Res. Commun. 289 (2): 337–44. doi:10.1006/bbrc.2001.5979. PMID 11716477.
Vilaró MT, Doménech T, Palacios JM, Mengod G (2002). "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. doi:10.1016/S0028-3908(01)00154-X. PMID 11750916.
López-Rodríguez ML, Murcia M, Benhamú B, et al. (2002). "Computational model of the complex between GR113808 and the 5-HT4 receptor guided by site-directed mutagenesis and the crystal structure of rhodopsin.". J. Comput. Aided Mol. Des. 15 (11): 1025–33. doi:10.1023/A:1014895611874. PMID 11989623.
Ohtsuki T, Ishiguro H, Detera-Wadleigh SD, et al. (2003). "Association between serotonin 4 receptor gene polymorphisms and bipolar disorder in Japanese case-control samples and the NIMH Genetics Initiative Bipolar Pedigrees.". Mol. Psychiatry 7 (9): 954–61. doi:10.1038/sj.mp.4001133. PMID 12399948.
Norum JH, Hart K, Levy FO (2003). "Ras-dependent ERK activation by the human G(s)-coupled serotonin receptors 5-HT4(b) and 5-HT7(a).". J. Biol. Chem. 278 (5): 3098–104. doi:10.1074/jbc.M206237200. PMID 12446729.
Strausberg RL, Feingold EA, Grouse LH, et al. (2003). "Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences.". Proc. Natl. Acad. Sci. U.S.A. 99 (26): 16899–903. doi:10.1073/pnas.242603899. PMID 12477932.
Cartier D, Lihrmann I, Parmentier F, et al. (2003). "Overexpression of serotonin4 receptors in cisapride-responsive adrenocorticotropin-independent bilateral macronodular adrenal hyperplasia causing Cushing's syndrome.". J. Clin. Endocrinol. Metab. 88 (1): 248–54. doi:10.1210/jc.2002-021107. PMID 12519861.
Manzke T, Guenther U, Ponimaskin EG, et al. (2003). "5-HT4(a) receptors avert opioid-induced breathing depression without loss of analgesia.". Science 301 (5630): 226–9. doi:10.1126/science.1084674. PMID 12855812.

This article incorporates text from the United States National Library of Medicine, which is in the public domain.

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[pmid9371406-0] Claeysen S, Faye P, Sebben M, Lemaire S, Bockaert J, Dumuis A, Taviaux S (December 1997). "Assignment of 5-hydroxytryptamine receptor (HTR4) to human chromosome 5 bands q31→q33 by in situ hybridization.". Cytogenet Cell Genet 78 (2): 133–4. PMID 9371406.

[pmid9276448-1] , Blondel O, Vandecasteele G, Gastineau M, Leclerc S, Dahmoune Y, Langlois M, Fischmeister R (September 1997). "Molecular and functional characterization of a 5-HT4 receptor cloned from human atrium.". FEBS Lett 412 (3): 465–74. PMID 9276448.

[entrez-2] "Entrez Gene: HTR4 5-hydroxytryptamine (serotonin) receptor 4". http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=3360.

[3] S. S. Hegde; R. M. Eglen (1 October 1996). "Peripheral 5-HT4 receptors". The FASEB journal 10 (12): 1398–1407. PMID 8903510. http://www.fasebj.org/cgi/content/abstract/10/12/1398.

[4] Katarina Varnäs; Christer Halldin; Victor W. Pike; Håkan Hall (2003). "Distribution of 5-HT₄ receptors in the postmortem human brain—an autoradiographic study using [¹²⁵]SB 207710". European Neuropsychopharmacology 13: 228–234. doi:10.1016/S0924-977X(03)00009-9.

[pmid19168624-5] Pellissier LP, Sallander J, Campillo M, Gaven F, Queffeulou E, Pillot M, Dumuis A, Claeysen S, Bockaert J, Pardo L (April 2009). "Conformational toggle switches implicated in basal constitutive and agonist-induced activated states of 5-hydroxytryptamine-4 receptors". Molecular Pharmacology 75 (4): 982–90. doi:10.1124/mol.108.053686. PMID 19168624.

[6] B. R. Kornum, N. M. Lind, N. Gillings, Lisbeth Marner, F. Andersen, Gitte Moos Knudsen (September 2008). "Evaluation of the novel 5-HT(4) receptor PET ligand [(11)C]SB207145 in the Gottingen minipig". Journal of Cerebral Blood Flow and Metabolism 29: 186. doi:10.1038/jcbfm.2008.110. PMID 18797470.

[7] Lisbeth Marner, Nic Gillings, Roger Gunn, Robert Comley, William Baaré, Steen Hasselbalch and Gitte Knudsen (05/01/2007). "Quantification of 11C-SB207145-PET for 5-HT4 receptors in the human brain: Preliminary results". Journal of Nuclear Medicine 48 (Supplement 2) (Supplement 2): 159P. http://jnumedmtg.snmjournals.org/cgi/content/meeting_abstract/48/MeetingAbstracts_2/159P.

[8] 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. 1994 Jan;111(1):332-8. PMID 8012715

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