5-HT4 receptor

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.

Location

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

Isoforms

Internalization is isoform-specific.

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. 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 and human studies.

Agonists

• Tropisetron partial agonist
• BIMU-8
• Cisapride
• CJ-033,466 partial agonist
• Felcisetrag
• ML-10302
• Mosapride
• Prucalopride
• Renzapride
• RS-67506
• RS-67333 partial agonist
• SL65.0155 partial agonist
• Tegaserod
• Zacopride
• Metoclopramide
• Sulpiride
• Naronapride
• Usmarapride (SUVN-D4010) – partial agonist

Antagonists

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

References

References

1. (December 1997). "Assignment of 5-hydroxytryptamine receptor (HTR4) to human chromosome 5 bands q31→q33 by in situ hybridization". Cytogenetics and Cell Genetics.
2. (August 1997). "Molecular and functional characterization of a 5-HT4 receptor cloned from human atrium". FEBS Letters.
3. "Entrez Gene: HTR4 5-hydroxytryptamine (serotonin) receptor 4".
4. (October 1996). "Peripheral 5-HT4 receptors". FASEB Journal.
5. (August 2003). "Distribution of 5-HT4 receptors in the postmortem human brain--an autoradiographic study using [125I]SB 207710". European Neuropsychopharmacology.
6. (March 2010). "Serotonin 4 receptor (5-HT4R) internalization is isoform-specific: effects of 5-HT and RS67333 on isoforms A and B". Cellular Signalling.
7. (April 2009). "Conformational toggle switches implicated in basal constitutive and agonist-induced activated states of 5-hydroxytryptamine-4 receptors". Molecular Pharmacology.
8. (January 2009). "Evaluation of the novel 5-HT4 receptor PET ligand [11C]SB207145 in the Göttingen minipig". Journal of Cerebral Blood Flow and Metabolism.
9. (June 2009). "Kinetic modeling of 11C-SB207145 binding to 5-HT4 receptors in the human brain in vivo". Journal of Nuclear Medicine.
10. (November 1993). "The pharmacology of the 5-HT4 receptor". International Clinical Psychopharmacology.
11. (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.
12. (January 1994). "GR113808: a novel, selective antagonist with high affinity at the 5-HT4 receptor". British Journal of Pharmacology.
13. (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.
14. (2006). "Binding of STW 5 (Iberogast) and its components to intestinal 5-HT, muscarinic M3, and opioid receptors". Phytomedicine.