5-HT4 receptor

HTR4
Identifiers
AliasesHTR4, 5-HT4, 5-HT4R, 5-HT4 receptor, 5-hydroxytryptamine receptor 4
External IDsMGI: 109246 HomoloGene: 20243 GeneCards: HTR4
RNA expression pattern




More reference expression data
Orthologs
SpeciesHumanMouse
Entrez

3360

15562

Ensembl

ENSG00000164270

ENSMUSG00000026322

UniProt

Q13639

P97288

RefSeq (mRNA)

NM_008313

RefSeq (protein)

NP_032339

Location (UCSC)Chr 5: 148.45 – 148.68 MbChr 18: 62.32 – 62.47 Mb
PubMed search[1][2]
Wikidata
View/Edit HumanView/Edit Mouse

5-Hydroxytryptamine receptor 4 is a protein that in humans is encoded by the HTR4 gene.[3][4]

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.[5]

Location

The receptor is located in the alimentary tract, urinary bladder, heart and adrenal gland as well as the central nervous system (CNS).[6] 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.[7]

Isoforms

Internalization is isoform-specific.[8]

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.[9]

SB-207,145 radiolabeled with carbon-11 is used as a radioligand for 5-HT4 in positron emission tomography pig[10] and human[11] studies.

Agonists

Antagonists

See also

References

  1. ↑ "Human PubMed Reference:".
  2. ↑ "Mouse PubMed Reference:".
  3. ↑ 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". Cytogenetics and Cell Genetics. 78 (2): 133–4. PMID 9371406. doi:10.1159/000134646.
  4. ↑ Blondel O, Vandecasteele G, Gastineau M, Leclerc S, Dahmoune Y, Langlois M, Fischmeister R (August 1997). "Molecular and functional characterization of a 5-HT4 receptor cloned from human atrium". FEBS Letters. 412 (3): 465–74. PMID 9276448. doi:10.1016/S0014-5793(97)00820-X.
  5. ↑ "Entrez Gene: HTR4 5-hydroxytryptamine (serotonin) receptor 4".
  6. ↑ Hegde SS, Eglen RM (October 1996). "Peripheral 5-HT4 receptors". FASEB Journal. 10 (12): 1398–407. PMID 8903510.
  7. ↑ Varnäs K, Halldin C, Pike VW, Hall H (August 2003). "Distribution of 5-HT4 receptors in the postmortem human brain--an autoradiographic study using [125I]SB 207710". European Neuropsychopharmacology. 13 (4): 228–34. PMID 12888181. doi:10.1016/S0924-977X(03)00009-9.
  8. ↑ Mnie-Filali O, Amraei MG, Benmbarek S, Archer-Lahlou E, Peñas-Cazorla R, Vilaró MT, Boye SM, Piñeyro G (March 2010). "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. PMID 19922792. doi:10.1016/j.cellsig.2009.11.004.
  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. PMID 19168624. doi:10.1124/mol.108.053686.
  10. ↑ Kornum BR, Lind NM, Gillings N, Marner L, Andersen F, Knudsen GM (January 2009). "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. PMID 18797470. doi:10.1038/jcbfm.2008.110.
  11. ↑ Marner L, Gillings N, Comley RA, Baaré WF, Rabiner EA, Wilson AA, Houle S, Hasselbalch SG, Svarer C, Gunn RN, Laruelle M, Knudsen GM (June 2009). "Kinetic modeling of 11C-SB207145 binding to 5-HT4 receptors in the human brain in vivo". Journal of Nuclear Medicine. 50 (6): 900–8. PMID 19470850. doi:10.2967/jnumed.108.058552.
  12. ↑ Godínez-Chaparro B, Barragán-Iglesias P, Castañeda-Corral G, Rocha-González HI, Granados-Soto V (March 2011). "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. PMID 21239110. doi:10.1016/j.pain.2010.12.020.
  13. ↑ Gale JD, Grossman CJ, Whitehead JW, Oxford AW, Bunce KT, Humphrey PP (January 1994). "GR113808: a novel, selective antagonist with high affinity at the 5-HT4 receptor". British Journal of Pharmacology. 111 (1): 332–8. PMC 1910004 Freely accessible. PMID 8012715. doi:10.1111/j.1476-5381.1994.tb14064.x.
  14. ↑ Xu R, Hong J, Morse CL, Pike VW (October 2010). "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. PMC 2951497 Freely accessible. PMID 20812727. doi:10.1021/jm100668r.
  15. ↑ Simmen U, Kelber O, Okpanyi SN, Jaeggi R, Bueter B, Weiser D. "Binding of STW 5 (Iberogast) and its components to intestinal 5-HT, muscarinic M3, and opioid receptors". Phytomedicine. 13 Suppl 5: 51–5. PMID 16973340. doi:10.1016/j.phymed.2006.03.012.

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 (August 1995). "Expression of serotonin receptor mRNAs in blood vessels". FEBS Letters. 370 (3): 215–21. PMID 7656980. doi:10.1016/0014-5793(95)00828-W. 
  • Blondel O, Vandecasteele G, Gastineau M, Leclerc S, Dahmoune Y, Langlois M, Fischmeister R (August 1997). "Molecular and functional characterization of a 5-HT4 receptor cloned from human atrium". FEBS Letters. 412 (3): 465–74. PMID 9276448. doi:10.1016/S0014-5793(97)00820-X. 
  • Van den Wyngaert I, Gommeren W, Verhasselt P, Jurzak M, Leysen J, Luyten W, Bender E (November 1997). "Cloning and expression of a human serotonin 5-HT4 receptor cDNA". Journal of Neurochemistry. 69 (5): 1810–9. PMID 9349523. doi:10.1046/j.1471-4159.1997.69051810.x. 
  • Claeysen S, Faye P, Sebben M, Lemaire S, Bockaert J, Dumuis A (October 1997). "Cloning and expression of human 5-HT4S receptors. Effect of receptor density on their coupling to adenylyl cyclase". NeuroReport. 8 (15): 3189–96. PMID 9351641. doi:10.1097/00001756-199710200-00002. 
  • Blondel O, Gastineau M, Dahmoune Y, Langlois M, Fischmeister R (June 1998). "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. PMID 9603189. doi:10.1046/j.1471-4159.1998.70062252.x. 
  • 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)". Molecular Membrane Biology. 15 (2): 75–8. PMID 9724925. doi:10.3109/09687689809027521. 
  • Claeysen S, Sebben M, Becamel C, Bockaert J, Dumuis A (May 1999). "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. PMID 10220570. 
  • Bender E, Pindon A, van Oers I, Zhang YB, Gommeren W, Verhasselt P, Jurzak M, Leysen J, Luyten W (February 2000). "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. PMID 10646498. doi:10.1046/j.1471-4159.2000.740478.x. 
  • 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 (February 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". British Journal of Pharmacology. 129 (4): 771–81. PMC 1571890 Freely accessible. PMID 10683202. doi:10.1038/sj.bjp.0703101. 
  • Bach T, Syversveen T, Kvingedal AM, Krobert KA, Brattelid T, Kaumann AJ, Levy FO (February 2001). "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. PMID 11218067. doi:10.1007/s002100000299. 
  • Medhurst AD, Lezoualc'h F, Fischmeister R, Middlemiss DN, Sanger GJ (June 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 Research. Molecular Brain Research. 90 (2): 125–34. PMID 11406291. doi:10.1016/S0169-328X(01)00095-X. 
  • Hiroi T, Hayashi-Kobayashi N, Nagumo S, Ino M, Okawa Y, Aoba A, Matsui H (November 2001). "Identification and characterization of the human serotonin-4 receptor gene promoter". Biochemical and Biophysical Research Communications. 289 (2): 337–44. PMID 11716477. doi:10.1006/bbrc.2001.5979. 
  • Vilaró MT, Doménech T, Palacios JM, Mengod G (January 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. PMID 11750916. doi:10.1016/S0028-3908(01)00154-X. 
  • López-Rodríguez ML, Murcia M, Benhamú B, Olivella M, Campillo M, Pardo L (November 2001). "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. PMID 11989623. doi:10.1023/A:1014895611874. 
  • Ohtsuki T, Ishiguro H, Detera-Wadleigh SD, Toyota T, Shimizu H, Yamada K, Yoshitsugu K, Hattori E, Yoshikawa T, Arinami T (2003). "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. PMID 12399948. doi:10.1038/sj.mp.4001133. 
  • Norum JH, Hart K, Levy FO (January 2003). "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. PMID 12446729. doi:10.1074/jbc.M206237200. 
  • Cartier D, Lihrmann I, Parmentier F, Bastard C, Bertherat J, Caron P, Kuhn JM, Lacroix A, Tabarin A, Young J, Vaudry H, Lefebvre H (January 2003). "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. PMID 12519861. doi:10.1210/jc.2002-021107. 
  • Manzke T, Guenther U, Ponimaskin EG, Haller M, Dutschmann M, Schwarzacher S, Richter DW (July 2003). "5-HT4(a) receptors avert opioid-induced breathing depression without loss of analgesia". Science. 301 (5630): 226–9. PMID 12855812. doi:10.1126/science.1084674. 

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