5-HT4 receptor

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5-hydroxytryptamine (serotonin) receptor 4
Identifiers
SymbolsHTR4; 5-HT4; 5-HT4R
External IDsOMIM: 602164 MGI: 109246 HomoloGene: 20243 IUPHAR: 5-HT4 GeneCards: HTR4 Gene
RNA expression pattern
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More reference expression data
Orthologs
SpeciesHumanMouse
Entrez336015562
EnsemblENSG00000164270ENSMUSG00000026322
UniProtQ13639Q3URB5
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]

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]

Isoforms

Internalization is isoform-specific.[6]

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.[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.

Agonists

Antagonists

  • 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

References

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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 1571890 Freely 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 139241 Freely 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.


Class A: Rhodopsin like
α1 (A, B, D) · α2 (A, B, C) · β1 · β2 · β3
Adenosine (A1, A2A, A2B, A3) · P2Y (1, 2, 4, 5, 6, 8, 9, 10, 11, 12, 13, 14)
(all but 5-HT3) 5-HT1 (A, B, D, E, F) · 5-HT2 (A, B, C) · 5-HT (4, 5A, 6, 7)
Other
Acetylcholine (M1, M2, M3, M4, M5) · Dopamine (D1, D2, D3, D4, D5) · Histamine (H1, H2, H3, H4) · Melatonin (1A, 1B, 1C) · TAAR (1, 2, 3, 5, 6, 8, 9)
Metabolites and
signaling molecules
CysLT (1, 2) · LTB4 (1, 2) · FPRL1 · OXE · Prostaglandin (DP (1, 2), EP (1, 2, 3, 4), FP) · Prostacyclin · Thromboxane
Other
Bile acid · Cannabinoid (CB1, CB2, GPR (18, 55, 119)) · EBI2 · Estrogen · Free fatty acid (1, 2, 3, 4) · Lactate  · Lysophosphatidic acid (1, 2, 3, 4, 5, 6)  · Lysophospholipid (1, 2, 3, 4, 5, 6, 7, 8) · Niacin (1, 2) · Oxoglutarate · PAF · Sphingosine-1-phosphate (1, 2, 3, 4, 5) · Succinate
Peptide
B/W (1, 2) · FF (1, 2) · S · Y (1, 2, 4, 5) · Neuromedin (B, U (1, 2)) · Neurotensin (1, 2)
Other
Miscellaneous
GPR (1, 3, 4, 6, 12, 15, 17, 18, 19, 20, 21, 22, 23, 25, 26, 27, 31, 32, 33, 34, 35, 37, 39, 42, 44, 45, 50, 52, 55, 61, 62, 63, 65, 68, 75, 77, 78, 81, 82, 83, 84, 85, 87, 88, 92, 101, 103, 109A, 109B, 119, 120, 132, 135, 137B, 139, 141, 142, 146, 148, 149, 150, 151, 152, 153, 160, 161, 162, 171, 173, 174, 176, 177, 182, 183)
Other
Class B: Secretin like
GPR (56, 64, 97, 98, 110, 111, 112, 113, 114, 115, 116, 123, 124, 125, 126, 128, 133, 143, 144, 155, 157)
Other
Class C: Metabotropic
glutamate / pheromone
TAS1R (1, 2, 3) · TAS2R (1, 3, 4, 5, 8, 9, 10, 12, 13, 14, 16, 19, 20, 30, 31, 38, 39, 40, 41, 42, 43, 45, 46, 50)
Other
Class F:
Frizzled / Smoothened
Frizzled
Frizzled (1, 2, 3, 4, 5, 6, 7, 8, 9, 10)
Smoothened


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pt:Receptor 5-HT4
  1. ↑ Lua error in package.lua at line 80: module 'Module:Citation/CS1/Suggestions' not found.
  2. ↑ Lua error in package.lua at line 80: module 'Module:Citation/CS1/Suggestions' not found.
  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
  7. ↑ Lua error in package.lua at line 80: module 'Module:Citation/CS1/Suggestions' not found.
  8. ↑ Lua error in package.lua at line 80: module 'Module:Citation/CS1/Suggestions' not found.
  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
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