Biology:5-HT4 receptor
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Short description: Protein-coding gene in the species Homo sapiens
 Generic protein structure example |
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
References
- ↑ "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. doi:10.1159/000134646. PMID 9371406. https://hal.archives-ouvertes.fr/hal-02491196/file/1997%20CytoCellGen%20Claeysen.pdf.
- ↑ "Molecular and functional characterization of a 5-HT4 receptor cloned from human atrium". FEBS Letters 412 (3): 465–74. August 1997. doi:10.1016/S0014-5793(97)00820-X. PMID 9276448.
- ↑ "Entrez Gene: HTR4 5-hydroxytryptamine (serotonin) receptor 4". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=3360.
- ↑ "Peripheral 5-HT4 receptors". FASEB Journal 10 (12): 1398–407. October 1996. doi:10.1096/fasebj.10.12.8903510. PMID 8903510.
- ↑ "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. doi:10.1016/S0924-977X(03)00009-9. PMID 12888181.
- ↑ "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. doi:10.1016/j.cellsig.2009.11.004. PMID 19922792.
- ↑ "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. doi:10.1124/mol.108.053686. PMID 19168624. https://hal.archives-ouvertes.fr/hal-02483472/file/2009%20MolPharm%20Pellissier.pdf.
- ↑ "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. doi:10.1038/jcbfm.2008.110. PMID 18797470.
- ↑ "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. doi:10.2967/jnumed.108.058552. PMID 19470850.
- ↑ Costall, B.; Naylor, R. J. (November 1993). "The pharmacology of the 5-HT4 receptor". International Clinical Psychopharmacology 8 (Suppl 2): 11–18. doi:10.1097/00004850-199311002-00002. ISSN 0268-1315. PMID 8201242. https://pubmed.ncbi.nlm.nih.gov/8201242/.
- ↑ "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. doi:10.1016/j.pain.2010.12.020. PMID 21239110.
- ↑ "GR113808: a novel, selective antagonist with high affinity at the 5-HT4 receptor". British Journal of Pharmacology 111 (1): 332–8. January 1994. doi:10.1111/j.1476-5381.1994.tb14064.x. PMID 8012715.
- ↑ "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. doi:10.1021/jm100668r. PMID 20812727.
- ↑ "Binding of STW 5 (Iberogast) and its components to intestinal 5-HT, muscarinic M3, and opioid receptors". Phytomedicine 13 (Suppl 5): 51–5. 2006. doi:10.1016/j.phymed.2006.03.012. PMID 16973340.
Further reading
- Licht CL, 2009, Changes in the 5-HT4 receptor in animal models of depression and antidepressant treatment, PhD thesis, University of Copenhagen.
- "Expression of serotonin receptor mRNAs in blood vessels". FEBS Letters 370 (3): 215–21. August 1995. doi:10.1016/0014-5793(95)00828-W. PMID 7656980.
- "Molecular and functional characterization of a 5-HT4 receptor cloned from human atrium". FEBS Letters 412 (3): 465–74. August 1997. doi:10.1016/S0014-5793(97)00820-X. PMID 9276448.
- "Cloning and expression of a human serotonin 5-HT4 receptor cDNA". Journal of Neurochemistry 69 (5): 1810–9. November 1997. doi:10.1046/j.1471-4159.1997.69051810.x. PMID 9349523.
- "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. doi:10.1097/00001756-199710200-00002. PMID 9351641. https://hal.archives-ouvertes.fr/hal-02491123/file/1997%20Neuroreport%20Claeysen.pdf.
- "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. doi:10.1046/j.1471-4159.1998.70062252.x. PMID 9603189. https://hal-universite-paris-saclay.archives-ouvertes.fr/hal-03617007/file/Version%20HAL.pdf.
- "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. doi:10.3109/09687689809027521. PMID 9724925.
- "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. PMID 10220570.
- "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. doi:10.1046/j.1471-4159.2000.740478.x. PMID 10646498.
- "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. doi:10.1038/sj.bjp.0703101. PMID 10683202.
- "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. doi:10.1007/s002100000299. PMID 11218067.
- "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. doi:10.1016/S0169-328X(01)00095-X. PMID 11406291.
- "Identification and characterization of the human serotonin-4 receptor gene promoter". Biochemical and Biophysical Research Communications 289 (2): 337–44. November 2001. doi:10.1006/bbrc.2001.5979. PMID 11716477.
- "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. doi:10.1016/S0028-3908(01)00154-X. PMID 11750916.
- "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. doi:10.1023/A:1014895611874. PMID 11989623. Bibcode: 2001JCAMD..15.1025L.
- "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. doi:10.1038/sj.mp.4001133. PMID 12399948.
- "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. doi:10.1074/jbc.M206237200. PMID 12446729.
- "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. doi:10.1210/jc.2002-021107. PMID 12519861.
- "5-HT4(a) receptors avert opioid-induced breathing depression without loss of analgesia". Science 301 (5630): 226–9. July 2003. doi:10.1126/science.1084674. PMID 12855812. Bibcode: 2003Sci...301..226M.
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.
- Human HTR4 genome location and HTR4 gene details page in the UCSC Genome Browser.
This article incorporates text from the United States National Library of Medicine, which is in the public domain.
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