5-HT4 receptor

5-hydroxytryptamine (serotonin) receptor 4
Identifiers
Symbols	HTR4; 5-HT4; 5-HT4R
External IDs	OMIM: 602164 MGI: 109246 HomoloGene: 20243 GeneCards: HTR4 Gene
Gene Ontology Molecular function • receptor activity • G-protein coupled receptor activity • serotonin receptor activity Cellular component • membrane fraction • cytoplasm • endosome • plasma membrane • plasma membrane • integral to plasma membrane Biological process • G-protein coupled receptor protein signaling pathway • G-protein signaling, coupled to cyclic nucleotide second messenger • positive regulation of cell proliferation Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	3360	15562
Ensembl	ENSG00000164270	ENSMUSG00000026322
UniProt	Q13639	Q3URB5
RefSeq (mRNA)	NM_000870.5	NM_008313.4
RefSeq (protein)	NP_000861.1	NP_032339.2
Location (UCSC)	Chr 5: 147.83 – 148.06 Mb	Chr 18: 62.48 – 62.63 Mb
PubMed search	[1]	[2]

5-hydroxytryptamine receptor 4 is a protein that in humans is encoded by the HTR4 gene.

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.

Location

The receptor is located in the alimentary tract, urinary bladder, heart and adrenal gland as well as the central nervous system (CNS). 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.

Isoforms

Internalization is isoform-specific.

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.

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

Agonists

• BIMU-8
• Cisapride
• CJ-033,466 - partial agonist
• ML-10302
• Mosapride
• Prucalopride
• Renzapride
• RS-67506
• RS-67333 - partial agonist
• SL65.0155 - partial agonist
• Tegaserod
• Zacopride

Antagonists

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

See also

• 5-HT receptor

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. 

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 (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. doi:10.1046/j.1471-4159.1997.69051810.x. 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. doi:10.1046/j.1471-4159.1998.70062252.x. 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. PMC 1571890. PMID 10683202. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1571890. 
• 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. PMC 139241. PMID 12477932. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=139241. 
• 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.