5-HT4 receptor

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5-hydroxytryptamine (serotonin) receptor 4
SymbolsHTR4; 5-HT4; 5-HT4R
External IDsOMIM602164 MGI109246 HomoloGene20243 IUPHAR: 5-HT4 GeneCards: HTR4 Gene
RNA expression pattern
More reference expression data
RefSeq (mRNA)NM_000870NM_008313
RefSeq (protein)NP_000861NP_032339
Location (UCSC)Chr 5:
147.81 - 148.01 Mb
Chr 18:
62.45 - 62.59 Mb
PubMed search[1][2]

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]


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]


Internalization is isoform-specific.[6]


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.[7]

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.



  • Piboserod
  • GR-113,808 (1-methyl-1H-indole-3-carboxylic acid, [1-[2-[(methylsulfonyl)amino]ethyl]-4-piperidinyl]methyl ester)[10]
  • 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

See also


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External links

  • "5-HT4". IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology. 

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. 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 1571890Freely accessible. 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. PMC 139241Freely accessible. 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.

pt:Receptor 5-HT4
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  3. "Entrez Gene: HTR4 5-hydroxytryptamine (serotonin) receptor 4". 
  4. Hegde, SS; Eglen, RM; R. M. Eglen (1 October 1996). "Peripheral 5-HT4 receptors". The FASEB journal. 10 (12): 1398–1407. PMID 8903510.  More than one of |author1= and |author= specified (help)
  5. Varnas, K; 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.  More than one of |author1= and |author= specified (help)
  6. PMID 19922792
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  9. Lisbeth Marner, Nic Gillings, Roger Gunn, Robert Comley, William Baaré, Steen Hasselbalch and Gitte Knudsen (1 May 2008). "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. 
  10. 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