5-Hydroxytryptamine receptor 4 is a
protein that in humans is encoded by the HTR4gene.[5][6]
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]
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.
^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.
PMID12888181.
S2CID27945284.
^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.
PMID19922792.
^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.
PMID21239110.
S2CID140204185.
^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.
PMID16973340.
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.
doi:
10.3109/09687689809027521.
PMID9724925.
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.
PMID10220570.
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.
doi:
10.1046/j.1471-4159.2000.740478.x.
PMID10646498.
S2CID33817190.
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.
doi:
10.1007/s002100000299.
PMID11218067.
S2CID27504006.
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.
doi:
10.1016/S0169-328X(01)00095-X.
PMID11406291.
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.
doi:
10.1006/bbrc.2001.5979.
PMID11716477.
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.
doi:
10.1016/S0028-3908(01)00154-X.
hdl:10261/112650.
PMID11750916.
S2CID23722311.
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.
Bibcode:
2001JCAMD..15.1025L.
doi:
10.1023/A:1014895611874.
PMID11989623.
S2CID23478175.
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.
doi:
10.1038/sj.mp.4001133.
PMID12399948.
S2CID21064320.
5-Hydroxytryptamine receptor 4 is a
protein that in humans is encoded by the HTR4gene.[5][6]
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]
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.
^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.
PMID12888181.
S2CID27945284.
^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.
PMID19922792.
^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.
PMID21239110.
S2CID140204185.
^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.
PMID16973340.
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.
doi:
10.3109/09687689809027521.
PMID9724925.
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.
PMID10220570.
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.
doi:
10.1046/j.1471-4159.2000.740478.x.
PMID10646498.
S2CID33817190.
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.
doi:
10.1007/s002100000299.
PMID11218067.
S2CID27504006.
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.
doi:
10.1016/S0169-328X(01)00095-X.
PMID11406291.
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.
doi:
10.1006/bbrc.2001.5979.
PMID11716477.
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.
doi:
10.1016/S0028-3908(01)00154-X.
hdl:10261/112650.
PMID11750916.
S2CID23722311.
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.
Bibcode:
2001JCAMD..15.1025L.
doi:
10.1023/A:1014895611874.
PMID11989623.
S2CID23478175.
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.
doi:
10.1038/sj.mp.4001133.
PMID12399948.
S2CID21064320.