5-HT4 receptor

5-Hydroxytryptamine receptor 4 is a protein that in humans is encoded by the HTR4 gene.[5][6]

HTR4
Identifiers
AliasesHTR4, 5-HT4, 5-HT4R, 5-HT4 receptor, 5-hydroxytryptamine receptor 4
External IDsOMIM: 602164 MGI: 109246 HomoloGene: 20243 GeneCards: HTR4
Orthologs
SpeciesHumanMouse
Entrez

3360

15562

Ensembl

ENSG00000164270

ENSMUSG00000026322

UniProt

Q13639

P97288

RefSeq (mRNA)

NM_008313
NM_001364956
NM_001364957
NM_001364958
NM_001364959

RefSeq (protein)

NP_032339
NP_001351885
NP_001351886
NP_001351887
NP_001351888

Location (UCSC)Chr 5: 148.45 – 148.68 MbChr 18: 62.46 – 62.63 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

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.[7]

Location

The receptor is located in the alimentary tract, urinary bladder, heart and adrenal gland as well as the central nervous system (CNS).[8] 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.[9]

Isoforms

Internalization is isoform-specific.[10]

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.[11] 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[12] and human[13] studies.

Agonists

Antagonists
  • l-lysine
  • Piboserod
  • GR-113,808 (1-methyl-1H-indole-3-carboxylic acid, [1-[2-[(methylsulfonyl)amino]ethyl]-4-piperidinyl]methyl ester)[16]
  • 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[17]
  • Chamomile (ethanol extract)[18]

See also

References
  1. GRCh38: Ensembl release 89: ENSG00000164270 - Ensembl, May 2017
  2. GRCm38: Ensembl release 89: ENSMUSG00000026322 - Ensembl, May 2017
  3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. 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" (PDF). Cytogenetics and Cell Genetics. 78 (2): 133–4. doi:10.1159/000134646. PMID 9371406.
  6. 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. doi:10.1016/S0014-5793(97)00820-X. PMID 9276448. S2CID 23714426.
  7. "Entrez Gene: HTR4 5-hydroxytryptamine (serotonin) receptor 4".
  8. Hegde SS, Eglen RM (October 1996). "Peripheral 5-HT4 receptors". FASEB Journal. 10 (12): 1398–407. doi:10.1096/fasebj.10.12.8903510. PMID 8903510. S2CID 21596751.
  9. 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. doi:10.1016/S0924-977X(03)00009-9. PMID 12888181. S2CID 27945284.
  10. 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. doi:10.1016/j.cellsig.2009.11.004. PMID 19922792.
  11. 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" (PDF). Molecular Pharmacology. 75 (4): 982–90. doi:10.1124/mol.108.053686. PMID 19168624. S2CID 17957338.
  12. 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. doi:10.1038/jcbfm.2008.110. PMID 18797470.
  13. 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. doi:10.2967/jnumed.108.058552. PMID 19470850.
  14. 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. S2CID 36692776.
  15. 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. doi:10.1016/j.pain.2010.12.020. PMID 21239110. S2CID 140204185.
  16. 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. doi:10.1111/j.1476-5381.1994.tb14064.x. PMC 1910004. PMID 8012715.
  17. 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. doi:10.1021/jm100668r. PMC 2951497. PMID 20812727.
  18. Simmen U, Kelber O, Okpanyi SN, Jaeggi R, Bueter B, Weiser D (2006). "Binding of STW 5 (Iberogast) and its components to intestinal 5-HT, muscarinic M3, and opioid receptors". Phytomedicine. 13 (Suppl 5): 51–5. doi:10.1016/j.phymed.2006.03.012. PMID 16973340.

Further reading
  • "5-HT4". IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology.
  • Human HTR4 genome location and HTR4 gene details page in the UCSC Genome Browser.

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