HTR4 (5-hydroxytryptamine receptor 4)

2019-08-01 Rafig Gurbanov , Hazel Karadag Affiliation

Identity

HGNC

HTR4

LOCATION

5q32

LOCUSID

3360

ALIAS

5-HT4,5-HT4R

Abstract

Being a member of the serotonin receptor family, 5-HT4 receptor ties up the neurotransmitter-serotonin (5-hydroxytryptamine\/ 5-HT) in the central nervous system (CNS) of mammals. Commonly 5-HT4 receptors (5-HTR4) are G-protein-coupled receptors (GPCRs), in which the G proteins cause the induction of adenylate cyclase, subsequently leading to cyclic adenosine monophosphate (cAMP) and protein kinase A (PKA) activations. These receptors are commonly expressed in gastrointestinal, cardiovascular, nervous, and urinary systems, as well as the adrenal cortex (Tack et al., 2012). In this review article, the genetic, cellular, and biochemical knowledge of 5-HT4 receptors is deliberated. Besides the emphasis on receptor-ligand interaction with therapeutics, the implication of these receptors in several health disturbances\/diseases is considered on the basis of available literature.

DNA/RNA

Note

The 5-HTR4 gene is 172,607 bp long (according to UCSC, GRCh38/hg38), located on the minus (-) strand and spans 12 exons (NCBI Homo sapiens Annotation Release 109).

Transcription

The gene has 13 transcripts (Table 1)
Table 1. Transcripts of the human 5-HTR4 gene (Ensemble, GRCh38.p12).

Name	Transcript ID	bp	Protein (aa)	Biotype
HTR4-201	ENST00000360693.7	3082	428	Protein coding
HTR4-202	ENST00000362016.6	2979	428	Protein coding
HTR4-203	ENST00000377888.7	2962	388	Protein coding
HTR4-209	ENST00000521530.5	1323	387	Protein coding
HTR4-210	ENST00000521735.5	1242	378	Protein coding
HTR4-207	ENST00000520514.5	1236	411	Protein coding
HTR4-213	ENST00000631296.1	1224	388	Protein coding
HTR4-204	ENST00000517929.5	1201	360	Protein coding
HTR4-206	ENST00000520086.1	2272	87	Protein coding
HTR4-211	ENST00000522588.5	1326	378	Nonsense mediated decay
HTR4-212	ENST00000524063.3	2274	371	Nonsense mediated decay
HTR4-205	ENST00000519495.1	869	No protein	Processed transcript
HTR4-208	ENST00000521124.5	1221	No protein	Retained intron

Proteins

Note

The product of HTR4 gene (5q32) is 5-HT4 receptor (Ohtsuki et al., 2002), weight as 43.761 Dalton with a length of 388 amino acids (Blondel et al., 1997; Claeysen et al., 1997; Van den Wyngaert et al., 1997). The protein has 9 known isoforms produced by alternative splicing, but the potential isoforms seem to exist (https://www.uniprot.org/uniprot/Q13639). Isoform 5-HT4(B) (Q13639-1) was considered as canonical sequence and provided in Figure 1. The translated glycoprotein is a member of the serotonin receptor family which are induced in response to the presence of serotonin via G-protein coupling process. In general, the 5-HT4 receptor is a glycosylated transmembrane protein expressed in both CNS and peripheric nervous system (PNS) that acts as a modulator in the release of various neurotransmitters (NCBI). It expressed in various tissues/cells such as the brain, esophagus, ileum, colon, bladder, heart, and adrenocortical cells. In the brain, they are particularly expressed in the hypothalamus, nucleus accumbens, amygdala, Calleja islands, olfactory tubercle, fundus striatum, ventral pallidum, septum, hippocampus, and basal ganglia including substantia nigra (Bockaert et al., 2008).

Figure 1. A canonical protein sequence (388 amino acids) of the human 5-HT4 receptor (PDB ID 5EM9.B ) (Data was taken from the https://www.rcsb.org/pdb/protein/Q13639)

Expression

5-HTR4 is expressed in different human tissues/organs but mostly in gastrointestinal tract, brain, and muscles in descending order. Please see The Human Protein Atlas (http://www.proteinatlas.org)

Function

5-hydroxytryptamine (5-HT or serotonin) is a crucial neurotransmitter of CNS with highly conserved monoamine structure (Hodge et al., 2013). It plays a role in different physiological events of CNS and PNS by interacting with more than one receptor subtype (Cichon et al., 1998). These countless functions are actualized by seven 5-HT subtype receptors (Kroeze et al., 2002; Hodge et al., 2013). The 5-HTR4 is a G-protein-coupled receptor that arouses adenylate cyclase as a primary mode of signal transduction. By the arousal of adenylate cyclase, the concentration of cAMP elevates (Lalut vd., 2017). However, 5-HTR4 refers to both G protein-dependent and G protein-independent pathways (Figure 2a-b). The main G protein introduced by 5-HTR4 signaling is the Gs (shown in Figure 2a) that leads to the activation of the cAMP/ PKA pathway (Barthet et al., 2005). The G-protein independent non-canonical pathway activates Src (shown in Figure 2b) and subsequently ERK kinases, causing pERK1/ 2 phosphorylation (Barthet et al., 2007).
This receptor was first described in primary cultures of mouse embryonic colliculus neurons based on 5-HT-induced cAMP production (Dumuis et al., 1988). It plays potential roles in the physiology of cardiovascular, urinary, and endocrine systems. It is also implicated in the pathophysiology of diseases occurring in adrenal glands as well as urinary and gastrointestinal systems (Ford and Clarke., 1994). 5-HTR4s are responsive in the events occurring in adrenal glands, colon, cortex (Monferini et al.,1993), and atrial appendages (Kaumann et al., 1990, 1991; Turconi et al., 1991; Quadid et al., 1992) of human tissues by encouraging cAMPs. In turn, cAMP inductions lead to steroid secretion in adrenal glands (Lefebvre et al., 1992) and circular muscle contraction in the colon (Tam et al.,1992).
Therapeutic agents interacting with 5-HTR4
Advances in research on 5-HT set forward the development of therapeutics selectively interacting with 5-HT receptors. In the present day, these ligands mainly divided into 5 categories/classes. They are indoles including 5-HT analogs, indole carboxylates, and indole carboxamides, benzamides, benzoates, aryl ketones, and benzimidazoles (Bockaert et al., 2004).
First-class 5-HTR4 agonists include substituted tryptamines or 5-HT agonists next to the substituted triple-carbazimidamides. 5-MeOtryptamine is an interesting vehicle due to the lack of its affinity to 5-HTR3 (Craig et al., 1990). The indole carbazimidamide derivative, HTF 919 (Tegaserod), has been found to be a potent partial agonist with high affinity to 5-HTR4. In vivo studies show that Tegaserod enhances gastrointestinal motor activity and adjusts impaired motility throughout the gastrointestinal tract. (Bockaert et al., 2004). Tegaserod is a benzamide derivative which was approved by the FDA and other regulatory agencies for the treatment of women with inflammatory bowel disease (IBD) in which the constipation is predominant or functional constipation (Tonini and Pace 2006; Shin et al., 2015). However, it was later withdrawn from the market due to possible cardiovascular side-effects (Chey et al., 2008; Thompson 2007). Three novel 5-HTR4 agonists (Prucaloprid, Naronapride, and Velusetrag) have therapeutic potential for patients with IBD. These alternative drugs have a higher affinity for 5-HTR4 compared to Tegaserod (Halland and Talley, 2013). YKP10811 is a mucosal partial agonist for the 5-HTR4, induces serotonin release, initiates peristaltic reflex, and has a low cardiovascular adverse effect. Unlike traditional prokinetic drugs such as Tegaserod, YKP10811 exhibits an antinociceptive effect on inflammation as well as acute stress-associated colonic hypersensitivity, and also considered as a candidate drug for IBD (Gilet et al., 2014).
The second class of 5-HTR4 agonists includes first-generation benzamides carrying 2-methoxy-4-amino-5-chloro substitution (Dumuis et al., 1989). These benzamides (zacopride, renzapride, and metoclopramide) were found to be non-selective and always cause antagonistic activity at the 5-HTR3 (Bockaert et al., 2004).
The third class of agonists, so-called benzoate derivatives were deliberated with the replacement of benzamides amide bond with an ester one, resulting in increased affinity for 5-HTR4. The first partial and selective drug of this series is ML 10302, which has a high affinity for 5-HTR4 and poor affinity for other 5-HT receptor subtypes including 5-HTR3 (Langlois et al., 1994; Bockaert et al., 2004). Moser and colleagues (2002) synthesized SL65.0155, a novel compound with high affinity for 5-HTR4. Being a benzodioxane derivative, it is particularly effective for learning and memory (Moser et al., 2002).
The fourth class is consist of benzimidazoles (BIMU 8 and BIMU 1), which are potent and effective 5-HTR4 agonists entering CNS (Dumuis et al., 1991; Rizzi et al., 1992). To overcome their metabolic variability, aryl ketones were prepared with 5-HTR4 ester ligands; instead of the ester linkage of the antagonist RS 23597, a partial agonist RS 17017 was synthesized, which has a similar affinity for 5-HTR4 (Clark et al., 1994). Increasing the size of the alkyl group led to an increase in the activity of the agonists RS 67333 and RS 67506 (Eglen et al., 1995). RS 67333, a selective 5-HTR4 partial agonist, is known to easily cross the blood-brain barrier. Systemic administration of selective 5-HT4 receptor partial agonists, like RS 67333 and RS 17017, enhances rodent performance in olfactory relational learning (Marchetti et al., 2004), social-spatial memory tests (Letty et al., 1997), and also improves delayed sample matching in young/ old macaques (Terry et al., 1998). RS 67333 has been shown to inhibit β-amyloid peptide formation in primary cortical neurons (Cho and Hu, 2007). Interestingly, RS 67333 produces a rapid antidepressant effect after only three days of administration to rodents (Lucas et al., 2007). A more recent study comparing RS67333 with antidepressant drug Fluoxetine (FLX) confirmed that RS67333 causes anxiolytic-like effects after only 7 days in several behavioral tests and that 5-HTR4 agonists produce faster effects than currently used antidepressants (Mendez-David et al., 2014). Another interesting agonist is a pyridine carboxamide, a cognitive drug (VRX-03011) for Alzheimers disease (Bockaert et al., 2008).
Fifth class includes indoles such as GR 113808 with high affinity for 5-HTR4, and low affinity for 5-HTR3 (Gale et al., 1994). Further, [3H] GR 113808 is the first commercially available radioligand for 5-HTR4 affinity studies (Grossman et al., 1993). SB 203186 is an indole ester with potent and selective 5-HTR4 antagonistic properties in various physiological assays, but the short half-life limits its in vivo application (Parker et al., 1993). In contrast, SB 207266 is a highly potent and selective antagonist with a long duration of action after oral administration (Gaster et al., 1995). SB 207266 is a very useful vehicle in CNS studies (Wardle et al., 1996; Gaster and King 1997).
Three selective and high-affinity 5-HTR4 antagonists (GR 125487, SB 207266, and ML 10375) have been reported to exhibit reverse agonistic activity (Claeysen et al., 2000; Blondel et al., 1998). Roche Bioscience generated three potent 5-HTR4 reverse agonists, RO 116-2617, RO 116-0086, and RO 116-1148 (Joubert et al., 2002). 5-HTR4 ligands that may be of interest in CNS studies are listed in Table 2.
Table 2. 5-HTR4 ligands used in CNS studies (Adopted from Bockaert et al., 2004).

Agonists	Antagonists	Reverse Antagonists
5-HT	GR 113308	RO 116-2617
5-MeOT	GF 125487	RO 116-0086
HTF919	SB 203186	RO 116-1148
Cisapride	LY 353433
SC 53 116	SB 207 266
SB 205 149	SB 204070
Prucalopride	RS 23597
Mosapride	ML 10375
Y-34959	ATBI 221
ML10302	RS 39606
LS-65 0155	RS 67532
RS 67333	RS 100235
RS 67506	RS 100302
BUMI 1
BUMI 8

Figure 2. A simplified pathway of G-protein dependent (a) and G-protein independent (b) signaling of 5-HTR4s (Modified from Bockaert et al., 2008)

Figure 3. A simplified pathway showing release of 5-HT and its interaction with 5-HTR4 in neuronal cells. Data were adopted and modified from KEGG: Kyoto Encyclopedia of Genes and Genomes (https://www.genome.jp/kegg/) in August 2019.

Homology

Table 3. Pairwise alignment of 5-HTR4 gene protein sequences (in distance from human) (HomoloGene, NCBI).

Pairwise Aligment Scores
Gene		Identity (%)
Species	Symbol	Protein	DNA
H.sapiens	HTR4
vs. P.trogladytes	HTR4	99,8	99,6
vs. M.mulatta	HTR4	98,6	98,1
vs. C.lupus	HTR4	96,6	93,6
vs. B.taurus	HTR4	94,8	93,7
vs. M.musculus	Htr4	93,3	90,9
vs. R. norvegicus	Htr4	92,7	90,6
vs. G. gallus	HTR4	88,5	82,6
vs. X. tropicalis	LOC100493952	83,4	74,5
vs. D. rerio	LOC556843	75,3	71,9
vs. D. melanogaster	Oa2	47,5	54,3

Mutations

Somatic

A list of 5-HTR4 mutations in cancer can be found in COSMIC, the Catalogue Of Somatic Mutations In Cancer, https://cancer.sanger.ac.uk/cosmic/gene/analysis?ln=HTR4. According to the Human Protein Atlas, HTR4 has been found strongly expressed in prostate and endometrial cancers.

Implicated in

Top note

Animal Experiments 5-HTR4 was initially identified in cultured mouse colliculus cells and guinea pig brain using a functional cAMP stimulation assay (Dumuis et al., 1988). One of the oldest functions attributed to 5-HTR4 in rodents is related to its role in increasing the release of acetylcholine in the frontal cortex (Siniscalchi et al., 1999) and a stimulating effect on the hippocampus to enhance memory and cognition (Bijak et al., 1997; Mohler et al., 2007). The absence of this receptor has been found to impair stress-induced hypophagia and novelty-induced discovery efficiency in mice (Compan et al., 2004a). The 5-HTR4 expression is also associated with the development of certain behavioral characteristics of depression, like deletion or pharmacological blockade of 5-HTR4s results in increased depressive and anxiety-like behaviors in rodents (Carr and Lucki, 2011; Compan et al., 2004a; Conductier et al., 2006). Serotonin affects cardiac contraction by interacting with 5-HTR4 expressed in the human and porcine atrium and ventricle, interestingly, expressed only in the atrium in the rat. 5-HTR4 activation causes cardiac spasm as well as tachycardia and arrhythmia (Qvigstad et al., 2005). This cardiac effect of 5-HTR4 is limited to human and porcine atria and are not declared in other laboratory animals such as rats, guinea pigs, rabbits, and frogs. Moreover, 5-HTR4 activation triggers the release of acetylcholine in the ileum of guinea pig and causes esophageal and colonic strictures (Hoyer et al., 2002).

Entity name

Inflammatory bowel disease (IBD)

Note

5-HTR4s which are widely expressed in the human intestine can also be expressed in inhibitory nitrergic neurons to induce smooth muscle relaxation and cholinergic neurons to control muscle contraction (Bockaert et al., 2011; Hoffman et al., 2012). In addition to their neuronal localization, they are found in enterocytes and enteroendocrine cells of the intestinal mucosa that regulate fluid, mucus and 5-HT secretion (Hoffman et al., 2012; Tonini, 2005). Accordingly, 5-HTR4s are attractive targets for the treatment of IBD. The receptor agonists increase motility and accelerate transit from the gut, thereby help in the alleviation of IBD and functional constipation (Halland and Talley, 2013). More selective 5-HTR4 agonists, including Naronapride (ATI-7505), Prucaloprid and Velusetrag (TD-5108), effectively target this receptor to support the intestinal motility. However, the full mechanism of action of these compounds is not clearly resolved. One possibility is that 5-HTR4 agonists increase mobility by stimulating receptors on the enteric nerve terminals and increasing neurotransmitter release (Hoffman et al., 2012). A single nucleotide polymorphism (SNP) (rs201253747) c.* 61T>C in HTR4 were identified in diarrhea-IBD patients (Wohlfarth et al., 2017). miRNAs can adjust HTR4 expression, and this regulation can be influenced either by the SNP c.*61 T>C or by lessened amounts of miR-16 and miR-103 proposing the role HTR4 in the pathogenesis of IBD (Wohlfarth et al., 2017). Colonic biopsy specimens from patients with Crohns disease also showed greatly increased mucosal 5-HTR4 expression (Shajib et al., 2018).

Entity name

Cardiac Disorders

Note

5-HTR4 is expressed in the atria and ventricles in humans; just like other serotonergic receptors, its expression level is quite low under physiological state but may increase significantly in the case of ventricular dysfunction. 5-HTR4 activation is known to cause heart spasms, as well as tachycardia and arrhythmia (Qvigstad et al., 2005). Even at low expression levels, 5-HTR4 increases contraction strength (inotropic effect), accelerates early stage of muscle relaxation (lusitropic effect) or enhances pulse rate (chronotropic effect) (De Maeyer et al., 2008). Since 5-HT is a neurotransmitter responsible for blood pressure regulation, peristaltic movements, heart rate, and coagulation system, it acts on 5-HTR4 in the human heart, producing a positive inotropic effect on the stimulation of the atrium (Dorszewska et al., 2017).

Entity name

Cushings Syndrome

Note

5-HTR4 has been shown to be overexpressed in the cortex of the adrenal gland in Cushings syndrome, a disease that is caused by cortisone overproduction (Cartier et al., 2003). In one study, cortisol secretion was encouraged with chorionic gonadotropin, luteinizing hormone, and 5-HTR4 stimulating drugs in patients with Cushings syndrome (Lacroix et al., 1999). Long-term suppression of luteinizing hormone secretion by administering leuprolide acetate every four weeks led to a complete reversal of Cushings syndrome (Lacroix et al., 1999). The administration of 5-HTR4 agonists such as metoclopramide, cisapride, and tegaserod stimulated aldosterone levels (Zwermann et al., 2009; Lefebvre et al., 2002; Cartier et al., 2005). Specific 5-HTR4 antagonists such as GR 113808 are potent inhibitors of basal and/or cisapride-induced aldosterone secretion (Lefebvre et al., 2002).

Entity name

Asthma

Note

The 5-HTR4 gene is located in an area previously associated with an increased risk of Asthma and Atopy (allergic diseases). Previously, 32 genetic variants in HTR4 consisting of 22 intronic SNPs, 2 SNPs in the 3-untranslated region (exon 7) and 8 SNPs in the 3-downstream region were examined (Kim et al., 2011). Logistic regression analysis demonstrated the relationship between the 2 intronic polymorphisms with the risk of Asthma. Two minor HTR4 alleles, +142828G>A and +122769G>A, appeared at higher frequencies in the Asthma patients compared to healthy individuals. Therefore, SNP and haplotypes of the HTR4 gene have been reported to be associated with the Asthma phenotype (Kim et al., 2011).

Entity name

Obesity

Note

Obesity has been associated with chronic elevation of brain serotonin levels in humans (Lambert et al., 1999). Animal studies showed that 5-HTR4 is involved in food intake. The genetic or pharmacological modifications of the receptor in pleasure-associated brain segments modulate food intake as well (Haahr et al., 2012). It has been also reported that there is a strong positive correlation between body mass index (BMI) and 5-HTR4 concentrations in pleasure circuits (nucleus accumbens and ventral pallidum) controlling food intake, as well as in the left hippocampal region and orbitofrontal cortex. Therefore, stimulation of brain 5-HTR4s may be considered in the reduction of human hedonic overeating (Haahr et al., 2012). The direct stimulation of 5-HTR4s in the nucleus accumbens reduces the physiological drive to eat and increases cocaine- and amphetamine-regulated transcript (CART) mRNA levels in fed and food-deprived mice (Jean et al., 2007). The 5-HTR4 was shown to regulate CART mRNA expression through cAMP/PKA signaling pathway. This receptor-mediated upregulation of CART in the nucleus accumbens triggers the appetite-suppressant effects of ecstasy (Jean et al., 2007). The mechanisms underlying feeding disorders in 5-HT4 receptor knockout mice are related to a lesser efficacy of 5-HT (hypothalamus, nucleus accumbens), leptin and the cocaine-amphetamine related transcript to reduce food intake following stress (Compan et al., 2004b). These results show that 5-HTR4 plays an important role in nutritional behavior.

Entity name

Huntingtons Disease

Note

Post-mortem brain samples of Huntingtons disease patients revealed a 50% loss of 5-HTR4 in putamens (Reynolds et al., 1995).

Entity name

Alzheimers Disease

Note

Studies focused on neurodegenerative disorders such as Alzheimers disease associated with decreased expression of 5-HTR4 in the hippocampus and prefrontal cortex (Reynolds et al., 1995). Activation of 5-HTR4s stimulates acetylcholine release in the prefrontal cortex and hippocampus and improves learning and memory in various acquisition and memory paradigms (Cachard-Chastel et al., 2008; Bockaert et al., 2011). These findings suggest that 5-HTR4 agonists can be used to improve cholinergic function and cognition in Alzheimers disease. The impact of 5-HTR4s on the non-amyloidogenic metabolic pathway of the amyloid precursor protein by stimulation of α-secretase has been described (Lezoualch and Robert, 2003; Cachard-Chastel et al., 2007). Stimulation of 5-HTR4 triggers soluble amyloid precursor protein α (sAPPα) release and reduces amyloid-beta (aβ) peptide formation in neuronal cell cultures (Maillet et al., 2003; Cho and Yu, 2007). A significant loss of 5-HTR4 was observed in the hippocampus and frontal cortex of patients suffering from Alzheimers disease. This reduction in certain cerebral concentrations of 5-HTR4 has demonstrated its effects on cognitive learning and memory processes and has been recently described as a valuable target against Alzheimers. (Lalut et al., 2017). 5-HTR4 receptor agonists are known to improve memory deficits by increasing acetylcholine neurotransmission (Consolo et al., 1994; Bockaert et al., 2011; Johnson et al., 2012). In a transgenic Alzheimers mouse model, stimulation of 5-HTR4 by agonists led to cognitive effects resulting in increased learning at elevated levels of acetylcholine (Consolo et al., 1994; Baranger et al., 2017; Bockaert et al., 2011; Brodney et al., 2012). In other words, 5-HTR4 stimulation improves performance in memory tasks in rodents, while receptor antagonists cause performance deterioration in these tasks. In view of all this, 5-HTR4 activation may have beneficial effects on Alzheimers disease, both by preventing disease formation and by improving memory performance (Rebholz et al., 2018).

Entity name

Schizophrenia

Note

Limited evidence suggests that 5-HTR4 polymorphisms may be associated with susceptibility to Schizophrenia (Suzuki et al., 2003), attention deficit, and hyperactivity disorder (Li et al., 2006). 5-HTR4 plays a role in cognitive function; that is assumed to be one of the main disorders of Schizophrenia. HTR4 coding regions were examined in 96 Japanese Schizophrenia patients. Within the coding region, a silent SNP and six intronic SNPs were detected and a significant relationship was reported between Schizophrenia and haplotype A-T (Suzuki et al., 2003).

Entity name

Suicidal behavior

Note

In a study evaluating the role of HTR4 on suicidal behavior, significantly high levels of 5-HTR4 and cAMP were found in the frontal cortex and caudate nucleus of the depressed suicide victims (Rosel et al., 2004). Another secondary messenger 5-HTR4, 1,4,5-inositol triphosphate (IP3) were elevated in the caudate nucleus and hippocampus, whereas no changes were observed in these parameters in the amygdala region. The caudate nucleus appears as the most affected brain site on account of the significant changes in the serotonergic system and thereby is important in terms of diagnostic sensitivity (Rosel et al., 2004).

Article Bibliography

Pubmed ID	Last Year	Title	Authors
28844596	2017	Chronic treatments with a 5-HT(4) receptor agonist decrease amyloid pathology in the entorhinal cortex and learning and memory deficits in the 5xFAD mouse model of Alzheimer's disease.	Baranger K et al
17377064	2007	5-hydroxytryptamine 4 receptor activation of the extracellular signal-regulated kinase pathway depends on Src activation but not on G protein or beta-arrestin signaling.	Barthet G et al
15919661	2005	Uncoupling and endocytosis of 5-hydroxytryptamine 4 receptors. Distinct molecular events with different GRK2 requirements.	Barthet G et al
9174070	1997	Effects of serotonin through serotonin1A and serotonin4 receptors on inhibition in the guinea-pig dentate gyrus in vitro.	Bijak M et al
9831890	1998	The 5-HT4 receptor antagonist ML10375 inhibits the constitutive activity of human 5-HT4(c) receptor.	Blondel O et al
9276448	1997	Molecular and functional characterization of a 5-HT4 receptor cloned from human atrium.	Blondel O et al
21342787	2011	5-HT(4) receptors, a place in the sun: act two.	Bockaert J et al
22974325	2012	Identification of multiple 5-HT₄ partial agonist clinical candidates for the treatment of Alzheimer's disease.	Brodney MA et al
18061284	2008	Prucalopride and donepezil act synergistically to reverse scopolamine-induced memory deficit in C57Bl/6j mice.	Cachard-Chastel M et al
21107537	2011	The role of serotonin receptor subtypes in treating depression: a review of animal studies.	Carr GV et al
16322401	2005	Expression profile of serotonin4 (5-HT4) receptors in adrenocortical aldosterone-producing adenomas.	Cartier D et al
12519861	2003	Overexpression of serotonin4 receptors in cisapride-responsive adrenocorticotropin-independent bilateral macronodular adrenal hyperplasia causing Cushing's syndrome.	Cartier D et al
18477346	2008	Tegaserod for female patients suffering from IBS with mixed bowel habits or constipation: a randomized controlled trial.	Chey WD et al
16978609	2007	Activation of 5-HT4 receptors inhibits secretion of beta-amyloid peptides and increases neuronal survival.	Cho S et al
9724925	1998	Assignment of the human serotonin 4 receptor gene (HTR4) to the long arm of chromosome 5 (5q31-q33).	Cichon S et al
10860935	2000	Pharmacological properties of 5-Hydroxytryptamine(4) receptor antagonists on constitutively active wild-type and mutated receptors.	Claeysen S et al
15146954	2004	[Feeding disorders in 5-HT4 receptor knockout mice].	Compan V et al
14724239	2004	Attenuated response to stress and novelty and hypersensitivity to seizures in 5-HT4 receptor knock-out mice.	Compan V et al
16930432	2006	Adaptive changes in serotonin neurons of the raphe nuclei in 5-HT(4) receptor knock-out mouse.	Conductier G et al
7919171	1994	5-HT4 receptor stimulation facilitates acetylcholine release in rat frontal cortex.	Consolo S et al
2402303	1990	5-Methoxytryptamine and 2-methyl-5-hydroxytryptamine-induced desensitization as a discriminative tool for the 5-HT3 and putative 5-HT4 receptors in guinea pig ileum.	Craig DA et al
18199093	2008	5-HT4 receptor agonists: similar but not the same.	De Maeyer JH et al
2849052	1988	A nonclassical 5-hydroxytryptamine receptor positively coupled with adenylate cyclase in the central nervous system.	Dumuis A et al
1650917	1991	Azabicycloalkyl benzimidazolone derivatives as a novel class of potent agonists at the 5-HT4 receptor positively coupled to adenylate cyclase in brain.	Dumuis A et al
8564196	1995	Pharmacological characterization of two novel and potent 5-HT4 receptor agonists, RS 67333 and RS 67506, in vitro and in vivo.	Eglen RM et al
8012715	1994	GR113808: a novel, selective antagonist with high affinity at the 5-HT4 receptor.	Gale JD et al
7490724	1995	N-[(1-butyl-4-piperidinyl)methyl]-3,4dihydro-2H-[1,3]oxazino[3,2- a]indole10-carboxamide hydrochloride: the first potent and selective 5-HT4 receptor antagonist amide with oral activity.	Gaster LM et al
9057164	1997	Serotonin 5-HT3 and 5-HT4 receptor antagonists.	Gaster LM et al
25316608	2014	Influence of a new 5-HT4 receptor partial agonist, YKP10811, on visceral hypersensitivity in rats triggered by stress and inflammation.	Gilet M et al
8358562	1993	Development of a radioligand binding assay for 5-HT4 receptors in guinea-pig and rat brain.	Grossman CJ et al
22709820	2012	Obesity is associated with high serotonin 4 receptor availability in the brain reward circuitry.	Haahr ME et al
23147658	2013	New treatments for IBS.	Halland M et al
23890215	2013	HTR4 gene structure and altered expression in the developing lung.	Hodge E et al
22226658	2012	Activation of colonic mucosal 5-HT(4) receptors accelerates propulsive motility and inhibits visceral hypersensitivity.	Hoffman JM et al
11888546	2002	Molecular, pharmacological and functional diversity of 5-HT receptors.	Hoyer D et al
22408061	2012	The 5-hydroxytryptamine4 receptor agonists prucalopride and PRX-03140 increase acetylcholine and histamine levels in the rat prefrontal cortex and the power of stimulated hippocampal θ oscillations.	Johnson DE et al
11976337	2002	A 5-HT4 receptor transmembrane network implicated in the activity of inverse agonists but not agonists.	Joubert L et al
1658664	1991	A 5-HT4-like receptor in human right atrium.	Kaumann AJ et al
21382128	2011	Association of 5-hydroxytryptamine (serotonin) receptor 4 (5-HTR4) gene polymorphisms with asthma.	Kim TH et al
12052191	2002	Molecular biology of serotonin receptors structure and function at the molecular level.	Kroeze WK et al
10564687	1999	Leuprolide acetate therapy in luteinizing hormone--dependent Cushing's syndrome.	Lacroix A et al
28504917	2017	Modulating 5-HT(4) and 5-HT(6) receptors in Alzheimer's disease treatment.	Lalut J et al
9918900	1999	Human obesity is associated with a chronic elevation in brain 5-hydroxytryptamine turnover.	Lambert GW et al
11889190	2002	Characterization of serotonin(4) receptors in adrenocortical aldosterone-producing adenomas: in vivo and in vitro studies.	Lefebvre H et al
9225294	1997	5-HT4 receptors improve social olfactory memory in the rat.	Letty S et al
12543273	2003	The serotonin 5-HT4 receptor and the amyloid precursor protein processing.	Lezoualc'h F et al
16563621	2006	Association of attention-deficit/hyperactivity disorder with serotonin 4 receptor gene polymorphisms in Han Chinese subjects.	Li J et al
17785179	2007	Serotonin(4) (5-HT(4)) receptor agonists are putative antidepressants with a rapid onset of action.	Lucas G et al
12819788	2003	Crosstalk between Rap1 and Rac regulates secretion of sAPPalpha.	Maillet M et al
15555636	2004	Modulation of memory processes and cellular excitability in the dentate gyrus of freely moving rats by a 5-HT4 receptors partial agonist, and an antagonist.	Marchetti E et al
24287720	2014	Rapid anxiolytic effects of a 5-HT₄ receptor agonist are mediated by a neurogenesis-independent mechanism.	Mendez-David I et al
17692343	2007	VRX-03011, a novel 5-HT4 agonist, enhances memory and hippocampal acetylcholine efflux.	Mohler EG et al
8437506	1993	Pharmacological characterization of the 5-hydroxytryptamine receptor coupled to adenylyl cyclase stimulation in human brain.	Monferini E et al
12130738	2002	SL65.0155, a novel 5-hydroxytryptamine(4) receptor partial agonist with potent cognition-enhancing properties.	Moser PC et al
12399948	2002	Association between serotonin 4 receptor gene polymorphisms and bipolar disorder in Japanese case-control samples and the NIMH Genetics Initiative Bipolar Pedigrees.	Ohtsuki T et al
1311410	1992	Serotonin increases calcium current in human atrial myocytes via the newly described 5-hydroxytryptamine4 receptors.	Ouadid H et al
15721867	2005	Appearance of a ventricular 5-HT4 receptor-mediated inotropic response to serotonin in heart failure.	Qvigstad E et al
30428567	2018	Alterations of Expression of the Serotonin 5-HT4 Receptor in Brain Disorders.	Rebholz H et al
7780656	1995	5-Hydroxytryptamine (5-HT)4 receptors in post mortem human brain tissue: distribution, pharmacology and effects of neurodegenerative diseases.	Reynolds GP et al
1578356	1992	Benzimidazolone derivatives: a new class of 5-hydroxytryptamine4 receptor agonists with prokinetic and acetylcholine releasing properties in the guinea pig ileum.	Rizzi CA et al
25148765	2015	A randomized trial of 5-hydroxytryptamine4-receptor agonist, YKP10811, on colonic transit and bowel function in functional constipation.	Shin A et al
10208587	1999	5-HT4 receptor modulation of acetylcholine outflow in guinea pig brain slices.	Siniscalchi A et al
12898568	2003	Association of a haplotype in the serotonin 5-HT4 receptor gene (HTR4) with Japanese schizophrenia.	Suzuki T et al
22356640	2012	Systematic review: cardiovascular safety profile of 5-HT(4) agonists developed for gastrointestinal disorders.	Tack J et al
7812604	1994	Characterization of the 5-hydroxytryptamine receptor type involved in inhibition of spontaneous activity of human isolated colonic circular muscle.	Tam FS et al
9539266	1998	Enhanced delayed matching performance in younger and older macaques administered the 5-HT4 receptor agonist, RS 17017.	Terry AV Jr et al
17494895	2007	Novartis suspends tegaserod sales at FDA's request.	Thompson CA et al
16185301	2005	5-Hydroxytryptamine effects in the gut: the 3, 4, and 7 receptors.	Tonini M et al
16699264	2006	Drugs acting on serotonin receptors for the treatment of functional GI disorders.	Tonini M et al
9349523	1997	Cloning and expression of a human serotonin 5-HT4 receptor cDNA.	Van den Wyngaert I et al
8762092	1996	Selective and functional 5-hydroxytryptamine4 receptor antagonism by SB 207266.	Wardle KA et al
29089619	2017	miR-16 and miR-103 impact 5-HT(4) receptor signalling and correlate with symptom profile in irritable bowel syndrome.	Wohlfarth C et al
19131502	2009	Screening for membrane hormone receptor expression in primary aldosteronism.	Zwermann O et al

Other Information

Locus ID:

NCBI: 3360
MIM: 602164
HGNC: 5299
Ensembl: ENSG00000164270

Variants:

dbSNP: 3360
ClinVar: 3360
TCGA: ENSG00000164270
COSMIC: HTR4

RNA/Proteins

Gene ID	Transcript ID	Uniprot
ENSG00000164270	ENST00000360693	Q13639
ENSG00000164270	ENST00000362016	Q13639
ENSG00000164270	ENST00000377888	Q13639
ENSG00000164270	ENST00000377888	A0A2D3FAF9
ENSG00000164270	ENST00000517929	Q13639
ENSG00000164270	ENST00000520086	E5RHV8
ENSG00000164270	ENST00000520514	Q13639
ENSG00000164270	ENST00000521530	Q13639
ENSG00000164270	ENST00000521735	Q13639
ENSG00000164270	ENST00000522588	Q13639
ENSG00000164270	ENST00000524063	E5RK45
ENSG00000164270	ENST00000631296	Q13639
ENSG00000164270	ENST00000631296	A0A2D3FAF9

Expression (GTEx)

Adipose - Subcutaneous

Adipose - Visceral

Adrenal Gland

Artery - Aorta

Artery - Tibial

Bladder

Brain - Amygdala

Brain - Anterior cingulate cortex

Brain - Caudate

Brain - Cerebellar Hemisphere

Brain - Cerebellum

Brain - Cortex

Brain - Frontal Cortex

Brain - Hippocampus

Brain - Hypothalamus

Brain - Nucleus accumbens

Brain - Putamen

Brain - Spinal cord

Brain - Substantia nigra

Breast - Mammary Tissue

Cells - Cultured fibroblasts

Cells - EBV - transformed lymphocytes

Cervix - Ectocervix

Cervix - Endocervix

Colon - Sigmoid

Colon - Transverse

Esophagus - Gastroesophageal Junction

Esophagus - Mucosa

Esophagus - Muscularis

Fallopian Tube

Heart - Atrial Appendage

Heart - Left Ventricle

Kidney - Cortex

Kidney - Medulla

Liver

Lung

Minor Salivary Gland

Muscle - Skeletal

Nerve - Tibial

Ovary

Pancreas

Pituitary

Prostate

Skin - Not Sun Exposed

Skin - Sun Exposed

Small Intestine - Terminal Ileum

Spleen

Stomach

Testis

Thyroid

Uterus

Vagina

Whole Blood

Pathways

Pathway	Source	External ID
Calcium signaling pathway	KEGG	ko04020
Neuroactive ligand-receptor interaction	KEGG	ko04080
Calcium signaling pathway	KEGG	hsa04020
Neuroactive ligand-receptor interaction	KEGG	hsa04080
Serotonergic synapse	KEGG	hsa04726
cAMP signaling pathway	KEGG	hsa04024
cAMP signaling pathway	KEGG	ko04024
Signal Transduction	REACTOME	R-HSA-162582
Signaling by GPCR	REACTOME	R-HSA-372790
GPCR ligand binding	REACTOME	R-HSA-500792
Class A/1 (Rhodopsin-like receptors)	REACTOME	R-HSA-373076
Amine ligand-binding receptors	REACTOME	R-HSA-375280
Serotonin receptors	REACTOME	R-HSA-390666
GPCR downstream signaling	REACTOME	R-HSA-388396
G alpha (s) signalling events	REACTOME	R-HSA-418555

Protein levels (Protein atlas)

Not detected

Low

Medium

High

PharmGKB

Entity ID	Name	Type	Evidence	Association	PK	PD	PMIDs
PA175	GNAS	Gene	Pathway	associated			19741567

References

Pubmed ID	Year	Title	Citations
34906639	2022	The GG genotype of the serotonin 4 receptor genetic polymorphism, rs1345697, is associated with lower remission rates after antidepressant treatment: Findings from the METADAP cohort.	1
35821015	2022	Concurrent anxiety in patients with major depression and cerebral serotonin 4 receptor binding. A NeuroPharm-1 study.	4
34906639	2022	The GG genotype of the serotonin 4 receptor genetic polymorphism, rs1345697, is associated with lower remission rates after antidepressant treatment: Findings from the METADAP cohort.	1
35821015	2022	Concurrent anxiety in patients with major depression and cerebral serotonin 4 receptor binding. A NeuroPharm-1 study.	4
31977880	2020	Association of human serotonin receptor 4 promoter methylation with autism spectrum disorder.	7
31977880	2020	Association of human serotonin receptor 4 promoter methylation with autism spectrum disorder.	7
31502579	2019	Down-regulation effects of IFN-α on p11, 5-htr1b and 5-HTR4 protein levels were affected by NH(4)CL or MG132 treatment in SH-sy5y cells.	2
31502579	2019	Down-regulation effects of IFN-α on p11, 5-htr1b and 5-HTR4 protein levels were affected by NH(4)CL or MG132 treatment in SH-sy5y cells.	2
28799255	2018	Synergy between 5-HT(4) receptor stimulation and phosphodiesterase 4 inhibition in facilitating acetylcholine release in human large intestinal circular muscle.	2
28799255	2018	Synergy between 5-HT(4) receptor stimulation and phosphodiesterase 4 inhibition in facilitating acetylcholine release in human large intestinal circular muscle.	2
28103616	2017	l-Lysine Acts as a Serotonin Type 4 Receptor Antagonist to Counteract In Vitro and In Vivo the Stimulatory Effect of Serotonergic Agents on Aldosterone Secretion in Man.	4
28195088	2017	Serotonin receptor 4 (5-hydroxytryptamine receptor Type 4) regulates expression of estrogen receptor beta and cell migration in hormone-naive prostate cancer.	4
28413715	2017	Brain serotonin 4 receptor binding is inversely associated with verbal memory recall.	9
28426945	2017	Testosterone levels in healthy men correlate negatively with serotonin 4 receptor binding.	17
29089619	2017	miR-16 and miR-103 impact 5-HT(4) receptor signalling and correlate with symptom profile in irritable bowel syndrome.	24

Citation

Rafig Gurbanov ; Hazel Karadag

HTR4 (5-hydroxytryptamine receptor 4)

Atlas Genet Cytogenet Oncol Haematol. 2019-08-01

Online version: http://atlasgeneticsoncology.org/gene/52727/htr4