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HTR4 (5-hydroxytryptamine receptor 4)

Written2019-08Rafig Gurbanov, Hazel Karadag
Bilecik Seyh Edebali University, Department of Molecular Biology and Genetics Bilecik Seyh Edebali University, Biotechnology Application and Research Center; rafig.gurbanov@bilecik.edu.tr (RG), Bilecik Seyh Edebali University, Department of Biotechnology, Bilecik Seyh Edebali University, Biotechnology Application and Research Center; hazelkaradag44@gmail.com (HK), Turkey.

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.

Keywords 5-hydroxytryptamine receptor 4, Serotonin (5-HT), Central Nervous System (CNS), Alzheimer's Disease, Inflammatory Bowel Disease (IBD), Obesity.

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Identity

Alias_names5-hydroxytryptamine (serotonin) receptor 4
5-hydroxytryptamine (serotonin) receptor 4, G protein-coupled
Alias_symbol (synonym)5-HT4
Other alias5-HT4R
HGNC (Hugo) HTR4
LocusID (NCBI) 3360
Atlas_Id 52727
Location 5q32  [Link to chromosome band 5q32]
Location_base_pair Starts at 148451032 and ends at 148637061 bp from pter ( according to hg19-Feb_2009)  [Mapping HTR4.png]
Local_order Shown in Chromosome 5 - NC_000005.10 Reference GRCh38.p13 Primary Assembly. Cytogenetic Location of 5-HTR: 5q32, which is the long (q) arm of chromosome 5 at a position 32 (UCSC Genome Browser on Human Dec. 2013 (GRCh38/hg38) Assembly)
Fusion genes
(updated 2017)
Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)

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).
NameTranscript IDbpProtein (aa)Biotype
HTR4-201ENST00000360693.73082 428Protein coding
HTR4-202ENST00000362016.62979 428Protein coding
HTR4-203ENST00000377888.72962 388Protein coding
HTR4-209ENST00000521530.51323 387Protein coding
HTR4-210ENST00000521735.51242 378Protein coding
HTR4-207ENST00000520514.51236 411Protein coding
HTR4-213ENST00000631296.11224 388Protein coding
HTR4-204ENST00000517929.51201 360Protein coding
HTR4-206ENST00000520086.12272 87Protein coding
HTR4-211ENST00000522588.51326 378Nonsense mediated decay
HTR4-212ENST00000524063.32274 371Nonsense mediated decay
HTR4-205ENST00000519495.1869 No proteinProcessed transcript
HTR4-208ENST00000521124.51221 No proteinRetained intron

Protein

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)
 
  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)
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)
 
  Figure 3. A simplified pathway showing release of 5-HT and it's 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.
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 benzamide's 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 Alzheimer's 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 it's 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).
AgonistsAntagonistsReverse Antagonists
5-HTGR 113308RO 116-2617
5-MeOTGF 125487RO 116-0086
HTF919SB 203186RO 116-1148
CisaprideLY 353433 
SC 53 116SB 207 266 
SB 205 149SB 204070 
PrucaloprideRS 23597 
MosaprideML 10375 
Y-34959ATBI 221 
ML10302RS 39606 
LS-65 0155RS 67532 
RS 67333RS 100235 
RS 67506RS 100302 
BUMI 1  
BUMI 8  
Homology Table 3. Pairwise alignment of 5-HTR4 gene protein sequences (in distance from human) (HomoloGene, NCBI).
Pairwise Aligment Scores
GeneIdentity (%)
SpeciesSymbolProteinDNA
H.sapiensHTR4  
vs. P.trogladytesHTR499,899,6
vs. M.mulattaHTR498,698,1
vs. C.lupusHTR496,693,6
vs. B.taurusHTR494,893,7
vs. M.musculusHtr493,390,9
vs. R. norvegicusHtr492,790,6
vs. G. gallusHTR488,582,6
vs. X. tropicalisLOC10049395283,474,5
vs. D. rerioLOC55684375,371,9
vs. D. melanogasterOa247,554,3

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

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 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 Crohn's disease also showed greatly increased mucosal 5-HTR4 expression (Shajib et al., 2018).
  
  
Entity 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 Cushing's Syndrome
Note 5-HTR4 has been shown to be overexpressed in the cortex of the adrenal gland in Cushing's 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 Cushing's 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 Cushing's 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 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 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 Huntington's Disease
Note Post-mortem brain samples of Huntington's disease patients revealed a 50% loss of 5-HTR4 in putamens (Reynolds et al., 1995).
  
  
Entity Alzheimer's Disease
Note Studies focused on neurodegenerative disorders such as Alzheimer's 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 Alzheimer's 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 (Lezoualc'h 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 Alzheimer's 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 Alzheimer's. (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 Alzheimer's 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 Alzheimer's disease, both by preventing disease formation and by improving memory performance (Rebholz et al., 2018).
  
  
Entity 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 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).
  

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PMID 16930432
 
5-HT4 receptor stimulation facilitates acetylcholine release in rat frontal cortex
Consolo S, Arnaboldi S, Giorgi S, Russi G, Ladinsky H
Neuroreport 1994 Jun 2;5(10):1230-2
PMID 7919171
 
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, Eglen RM, Walsh LK, Perkins LA, Whiting RL, Clarke DE
Naunyn Schmiedebergs Arch Pharmacol 1990 Jul;342(1):9-16
PMID 2402303
 
5-HT4 receptor agonists: similar but not the same
De Maeyer JH, Lefebvre RA, Schuurkes JA
Neurogastroenterol Motil 2008 Feb;20(2):99-112
PMID 18199093
 
Serotonin in Neurological Diseases.
Dorszewska J, Florczak-Wyspianska J, Kowalska M, Stanski M, Kowalewska A, Kozubski W.
Additional information is available at the end of the chapter, 2017
 
A nonclassical 5-hydroxytryptamine receptor positively coupled with adenylate cyclase in the central nervous system
Dumuis A, Bouhelal R, Sebben M, Cory R, Bockaert J
Mol Pharmacol 1988 Dec;34(6):880-7
PMID 2849052
 
Azabicycloalkyl benzimidazolone derivatives as a novel class of potent agonists at the 5-HT4 receptor positively coupled to adenylate cyclase in brain
Dumuis A, Sebben M, Monferini E, Nicola M, Turconi M, Ladinsky H, Bockaert J
Naunyn Schmiedebergs Arch Pharmacol 1991 Mar;343(3):245-51
PMID 1650917
 
Pharmacological characterization of two novel and potent 5-HT4 receptor agonists, RS 67333 and RS 67506, in vitro and in vivo
Eglen RM, Bonhaus DW, Johnson LG, Leung E, Clark RD
Br J Pharmacol 1995 Aug;115(8):1387-92
PMID 8564196
 
GR113808: a novel, selective antagonist with high affinity at the 5-HT4 receptor
Gale JD, Grossman CJ, Whitehead JW, Oxford AW, Bunce KT, Humphrey PP
Br J Pharmacol 1994 Jan;111(1):332-8
PMID 8012715
 
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, Joiner GF, King FD, Wyman PA, Sutton JM, Bingham S, Ellis ES, Sanger GJ, Wardle KA
J Med Chem 1995 Nov 24;38(24):4760-3
PMID 7490724
 
Serotonin 5-HT3 and 5-HT4 receptor antagonists
Gaster LM, King FD
Med Res Rev 1997 Mar;17(2):163-214
PMID 9057164
 
Influence of a new 5-HT4 receptor partial agonist, YKP10811, on visceral hypersensitivity in rats triggered by stress and inflammation
Gilet M, Eutamene H, Han H, Kim HW, Bueno L
Neurogastroenterol Motil 2014 Dec;26(12):1761-70
PMID 25316608
 
Development of a radioligand binding assay for 5-HT4 receptors in guinea-pig and rat brain
Grossman CJ, Kilpatrick GJ, Bunce KT
Br J Pharmacol 1993 Jul;109(3):618-24
PMID 8358562
 
Obesity is associated with high serotonin 4 receptor availability in the brain reward circuitry
Haahr ME, Rasmussen PM, Madsen K, Marner L, Ratner C, Gillings N, Baaré WF, Knudsen GM
Neuroimage 2012 Jul 16;61(4):884-8
PMID 22709820
 
New treatments for IBS
Halland M, Talley NJ
Nat Rev Gastroenterol Hepatol 2013 Jan;10(1):13-23
PMID 23147658
 
HTR4 gene structure and altered expression in the developing lung
Hodge E, Nelson CP, Miller S, Billington CK, Stewart CE, Swan C, Malarstig A, Henry AP, Gowland C, Melén E, Hall IP, Sayers I
Respir Res 2013 Jul 26;14:77
PMID 23890215
 
Activation of colonic mucosal 5-HT(4) receptors accelerates propulsive motility and inhibits visceral hypersensitivity
Hoffman JM, Tyler K, MacEachern SJ, Balemba OB, Johnson AC, Brooks EM, Zhao H, Swain GM, Moses PL, Galligan JJ, Sharkey KA, Greenwood-Van Meerveld B, Mawe GM
Gastroenterology 2012 Apr;142(4):844-854
PMID 22226658
 
Molecular, pharmacological and functional diversity of 5-HT receptors
Hoyer D, Hannon JP, Martin GR
Pharmacol Biochem Behav 2002 Apr;71(4):533-54
PMID 11888546
 
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 oscillations
Johnson DE, Drummond E, Grimwood S, Sawant-Basak A, Miller E, Tseng E, McDowell LL, Vanase-Frawley MA, Fisher KE, Rubitski DM, Stutzman-Engwall KJ, Nelson RT, Horner WE, Gorczyca RR, Hajos M, Siok CJ
J Pharmacol Exp Ther 2012 Jun;341(3):681-91
PMID 22408061
 
A 5-HT4 receptor transmembrane network implicated in the activity of inverse agonists but not agonists
Joubert L, Claeysen S, Sebben M, Bessis AS, Clark RD, Martin RS, Bockaert J, Dumuis A
J Biol Chem 2002 Jul 12;277(28):25502-11
PMID 11976337
 
A 5-HT4-like receptor in human right atrium
Kaumann AJ, Sanders L, Brown AM, Murray KJ, Brown MJ
Naunyn Schmiedebergs Arch Pharmacol 1991 Aug;344(2):150-9
PMID 1658664
 
Association of 5-hydroxytryptamine (serotonin) receptor 4 (5-HTR4) gene polymorphisms with asthma
Kim TH, An SH, Cha JY, Shin EK, Lee JY, Yoon SH, Lee YM, Uh ST, Park SW, Park JS, Kim YH, Choi JS, Lee SO, Park BL, Shin HD, Park CS
Respirology 2011 May;16(4):630-8
PMID 21382128
 
Molecular biology of serotonin receptors structure and function at the molecular level
Kroeze WK, Kristiansen K, Roth BL
Curr Top Med Chem 2002 Jun;2(6):507-28
PMID 12052191
 
Leuprolide acetate therapy in luteinizing hormone--dependent Cushing's syndrome
Lacroix A, Hamet P, Boutin JM
N Engl J Med 1999 Nov 18;341(21):1577-81
PMID 10564687
 
Modulating 5-HT(4) and 5-HT(6) receptors in Alzheimer's disease treatment
Lalut J, Karila D, Dallemagne P, Rochais C
Future Med Chem 2017 May;9(8):781-795
PMID 28504917
 
Human obesity is associated with a chronic elevation in brain 5-hydroxytryptamine turnover
Lambert GW, Vaz M, Cox HS, Turner AG, Kaye DM, Jennings GL, Esler MD
Clin Sci (Lond) 1999 Feb;96(2):191-7
PMID 9918900
 
Design of a potent 5-HT4 receptor agonist with nanomolar affinity.
Langlois M, Zhang L, Yang D, Bremont B, Shen S, Manara L, Croci T.
Bioorg. Med. Chem. Lett., 1994 ; 4, 1433
 
Characterization of serotonin(4) receptors in adrenocortical aldosterone-producing adenomas: in vivo and in vitro studies
Lefebvre H, Cartier D, Duparc C, Lihrmann I, Contesse V, Delarue C, Godin M, Fischmeister R, Vaudry H, Kuhn JM
J Clin Endocrinol Metab 2002 Mar;87(3):1211-6
PMID 11889190
 
5-HT4 receptors improve social olfactory memory in the rat
Letty S, Child R, Dumuis A, Pantaloni A, Bockaert J, Rondouin G
Neuropharmacology 1997 Apr-May;36(4-5):681-7
PMID 9225294
 
The serotonin 5-HT4 receptor and the amyloid precursor protein processing
Lezoualc'h F, Robert SJ
Exp Gerontol 2003 Jan-Feb;38(1-2):159-66
PMID 12543273
 
Association of attention-deficit/hyperactivity disorder with serotonin 4 receptor gene polymorphisms in Han Chinese subjects
Li J, Wang Y, Zhou R, Wang B, Zhang H, Yang L, Faraone SV
Neurosci Lett 2006 Jun 19;401(1-2):6-9
PMID 16563621
 
Serotonin(4) (5-HT(4)) receptor agonists are putative antidepressants with a rapid onset of action
Lucas G, Rymar VV, Du J, Mnie-Filali O, Bisgaard C, Manta S, Lambas-Senas L, Wiborg O, Haddjeri N, Piñeyro G, Sadikot AF, Debonnel G
Neuron 2007 Sep 6;55(5):712-25
PMID 17785179
 
Crosstalk between Rap1 and Rac regulates secretion of sAPPalpha
Maillet M, Robert SJ, Cacquevel M, Gastineau M, Vivien D, Bertoglio J, Zugaza JL, Fischmeister R, Lezoualc'h F
Nat Cell Biol 2003 Jul;5(7):633-9
PMID 12819788
 
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, Chaillan FA, Dumuis A, Bockaert J, Soumireu-Mourat B, Roman FS
Neuropharmacology 2004 Dec;47(7):1021-35
PMID 15555636
 
Rapid anxiolytic effects of a 5-HT receptor agonist are mediated by a neurogenesis-independent mechanism
Mendez-David I, David DJ, Darcet F, Wu MV, Kerdine-Römer S, Gardier AM, Hen R
Neuropsychopharmacology 2014 May;39(6):1366-78
PMID 24287720
 
VRX-03011, a novel 5-HT4 agonist, enhances memory and hippocampal acetylcholine efflux
Mohler EG, Shacham S, Noiman S, Lezoualc'h F, Robert S, Gastineau M, Rutkowski J, Marantz Y, Dumuis A, Bockaert J, Gold PE, Ragozzino ME
Neuropharmacology 2007 Sep;53(4):563-73
PMID 17692343
 
Pharmacological characterization of the 5-hydroxytryptamine receptor coupled to adenylyl cyclase stimulation in human brain
Monferini E, Gaetani P, Rodriguez y Baena R, Giraldo E, Parenti M, Zocchetti A, Rizzi CA
Life Sci 1993;52(9):PL61-5
PMID 8437506
 
SL65
Moser PC, Bergis OE, Jegham S, Lochead A, Duconseille E, Terranova JP, Caille D, Berque-Bestel I, Lezoualc'h F, Fischmeister R, Dumuis A, Bockaert J, George P, Soubrié P, Scatton B
0155, a novel 5-hydroxytryptamine(4) receptor partial agonist with potent cognition-enhancing properties J Pharmacol Exp Ther
PMID 12130738
 
Association between serotonin 4 receptor gene polymorphisms and bipolar disorder in Japanese case-control samples and the NIMH Genetics Initiative Bipolar Pedigrees
Ohtsuki T, Ishiguro H, Detera-Wadleigh SD, Toyota T, Shimizu H, Yamada K, Yoshitsugu K, Hattori E, Yoshikawa T, Arinami T
Mol Psychiatry 2002;7(9):954-61
PMID 12399948
 
Serotonin increases calcium current in human atrial myocytes via the newly described 5-hydroxytryptamine4 receptors
Ouadid H, Seguin J, Dumuis A, Bockaert J, Nargeot J
Mol Pharmacol 1992 Feb;41(2):346-51
PMID 1311410
 
SB203186, a potent 5-HT4 receptor antagonist in porcine sinoatrial node and human and porcine atrium.
Parker SG, HHamburger S, Taylor EM, Kaumann AJ.
Br. J.Pharmacol, 1993 ; 108, 68p.
 
Appearance of a ventricular 5-HT4 receptor-mediated inotropic response to serotonin in heart failure
Qvigstad E, Brattelid T, Sjaastad I, Andressen KW, Krobert KA, Birkeland JA, Sejersted OM, Kaumann AJ, Skomedal T, Osnes JB, Levy FO
Cardiovasc Res 2005 Mar 1;65(4):869-78
PMID 15721867
 
Alterations of Expression of the Serotonin 5-HT4 Receptor in Brain Disorders
Rebholz H, Friedman E, Castello J
Int J Mol Sci 2018 Nov 13;19(11)
PMID 30428567
 
5-Hydroxytryptamine (5-HT)4 receptors in post mortem human brain tissue: distribution, pharmacology and effects of neurodegenerative diseases
Reynolds GP, Mason SL, Meldrum A, De Keczer S, Parnes H, Eglen RM, Wong EH
Br J Pharmacol 1995 Mar;114(5):993-8
PMID 7780656
 
Benzimidazolone derivatives: a new class of 5-hydroxytryptamine4 receptor agonists with prokinetic and acetylcholine releasing properties in the guinea pig ileum
Rizzi CA, Coccini T, Onori L, Manzo L, Tonini M
J Pharmacol Exp Ther 1992 May;261(2):412-9
PMID 1578356
 
Characterization of Serotonin Signaling Components in Patients with Inflammatory.
Shajib S, Chauhan Usha, Adeeb S, Chetty Y, Armstrong D, Smita LS, Halder J.
Journal of the Canadian Association of Gastroenterology, 2018.
 
A randomized trial of 5-hydroxytryptamine4-receptor agonist, YKP10811, on colonic transit and bowel function in functional constipation
Shin A, Acosta A, Camilleri M, Boldingh A, Burton D, Ryks M, Rhoten D, Zinsmeister AR
Clin Gastroenterol Hepatol 2015 Apr;13(4):701-8
PMID 25148765
 
5-HT4 receptor modulation of acetylcholine outflow in guinea pig brain slices
Siniscalchi A, Badini I, Beani L, Bianchi C
Neuroreport 1999 Feb 25;10(3):547-51
PMID 10208587
 
Association of a haplotype in the serotonin 5-HT4 receptor gene (HTR4) with Japanese schizophrenia
Suzuki T, Iwata N, Kitamura Y, Kitajima T, Yamanouchi Y, Ikeda M, Nishiyama T, Kamatani N, Ozaki N
Am J Med Genet B Neuropsychiatr Genet 2003 Aug 15;121B(1):7-13
PMID 12898568
 
Systematic review: cardiovascular safety profile of 5-HT(4) agonists developed for gastrointestinal disorders
Tack J, Camilleri M, Chang L, Chey WD, Galligan JJ, Lacy BE, Müller-Lissner S, Quigley EM, Schuurkes J, De Maeyer JH, Stanghellini V
Aliment Pharmacol Ther 2012 Apr;35(7):745-67
PMID 22356640
 
Characterization of the 5-hydroxytryptamine receptor type involved in inhibition of spontaneous activity of human isolated colonic circular muscle
Tam FS, Hillier K, Bunce KT
Br J Pharmacol 1994 Sep;113(1):143-50
PMID 7812604
 
Enhanced delayed matching performance in younger and older macaques administered the 5-HT4 receptor agonist, RS 17017
Terry AV Jr, Buccafusco JJ, Jackson WJ, Prendergast MA, Fontana DJ, Wong EH, Bonhaus DW, Weller P, Eglen RM
Psychopharmacology (Berl) 1998 Feb;135(4):407-15
PMID 9539266
 
Novartis suspends tegaserod sales at FDA's request
Thompson CA
Am J Health Syst Pharm 2007 May 15;64(10):1020
PMID 17494895
 
5-Hydroxytryptamine effects in the gut: the 3, 4, and 7 receptors
Tonini M
Neurogastroenterol Motil 2005 Oct;17(5):637-42
PMID 16185301
 
Drugs acting on serotonin receptors for the treatment of functional GI disorders
Tonini M, Pace F
Dig Dis 2006;24(1-2):59-69
PMID 16699264
 
Azabicycloalkyl benzimidazolones: interaction with serotonergic 5-HT3 and 5-HT4 receptors and potential therapeutic implications.
Turconi M, Schiantarielli P, Borsini F, Rizzi C A, Ladinsky H, Donepti A.
Drugs Future, 1991 ; 16: 1011-1026.
 
Cloning and expression of a human serotonin 5-HT4 receptor cDNA
Van den Wyngaert I, Gommeren W, Verhasselt P, Jurzak M, Leysen J, Luyten W, Bender E
J Neurochem 1997 Nov;69(5):1810-9
PMID 9349523
 
Selective and functional 5-hydroxytryptamine4 receptor antagonism by SB 207266
Wardle KA, Bingham S, Ellis ES, Gaster LM, Rushant B, Smith MI, Sanger GJ
Br J Pharmacol 1996 Jun;118(3):665-70
PMID 8762092
 
miR-16 and miR-103 impact 5-HT(4) receptor signalling and correlate with symptom profile in irritable bowel syndrome
Wohlfarth C, Schmitteckert S, Härtle JD, Houghton LA, Dweep H, Fortea M, Assadi G, Braun A, Mederer T, Pöhner S, Becker PP, Fischer C, Granzow M, Mönnikes H, Mayer EA, Sayuk G, Boeckxstaens G, Wouters MM, Simrén M, Lindberg G, Ohlsson B, Schmidt PT, Dlugosz A, Agreus L, Andreasson A, D'Amato M, Burwinkel B, Bermejo JL, Röth R, Lasitschka F, Vicario M, Metzger M, Santos J, Rappold GA, Martinez C, Niesler B
Sci Rep 2017 Oct 31;7(1):14680
PMID 29089619
 
Screening for membrane hormone receptor expression in primary aldosteronism
Zwermann O, Suttmann Y, Bidlingmaier M, Beuschlein F, Reincke M
Eur J Endocrinol 2009 Mar;160(3):443-51
PMID 19131502
 

Citation

This paper should be referenced as such :
Gurbanov R, Karadag H
HTR4 (5-hydroxytryptamine receptor 4);
Atlas Genet Cytogenet Oncol Haematol. in press
On line version : http://AtlasGeneticsOncology.org/Genes/HTR4ID52727ch5q32.html


Other Solid tumors implicated (Data extracted from papers in the Atlas) [ 1 ]

Solid Tumors TT_t0508q32q24ID106824


External links

Nomenclature
HGNC (Hugo)HTR4   5299
Cards
AtlasHTR4ID52727ch5q32.txt
Entrez_Gene (NCBI)HTR4  3360  5-hydroxytryptamine receptor 4
Aliases5-HT4; 5-HT4R
GeneCards (Weizmann)HTR4
Ensembl hg19 (Hinxton)ENSG00000164270 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000164270 [Gene_View]  ENSG00000164270 [Sequence]  chr5:148451032-148637061 [Contig_View]  HTR4 [Vega]
ICGC DataPortalENSG00000164270
TCGA cBioPortalHTR4
AceView (NCBI)HTR4
Genatlas (Paris)HTR4
WikiGenes3360
SOURCE (Princeton)HTR4
Genetics Home Reference (NIH)HTR4
Genomic and cartography
GoldenPath hg38 (UCSC)HTR4  -     chr5:148451032-148637061 -  5q32   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)HTR4  -     5q32   [Description]    (hg19-Feb_2009)
GoldenPathHTR4 - 5q32 [CytoView hg19]  HTR4 - 5q32 [CytoView hg38]
ImmunoBaseENSG00000164270
Mapping of homologs : NCBIHTR4 [Mapview hg19]  HTR4 [Mapview hg38]
OMIM602164   
Gene and transcription
Genbank (Entrez)AJ011371 AJ131724 AJ131725 AJ131726 AJ278979
RefSeq transcript (Entrez)NM_000870 NM_001040169 NM_001040172 NM_001040173 NM_001040174 NM_001286410 NM_199453
RefSeq genomic (Entrez)
Consensus coding sequences : CCDS (NCBI)HTR4
Cluster EST : UnigeneHs.483773 [ NCBI ]
CGAP (NCI)Hs.483773
Alternative Splicing GalleryENSG00000164270
Gene ExpressionHTR4 [ NCBI-GEO ]   HTR4 [ EBI - ARRAY_EXPRESS ]   HTR4 [ SEEK ]   HTR4 [ MEM ]
Gene Expression Viewer (FireBrowse)HTR4 [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevestigatorExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)3360
GTEX Portal (Tissue expression)HTR4
Human Protein AtlasENSG00000164270-HTR4 [pathology]   [cell]   [tissue]
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ13639   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtQ13639  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProQ13639
Splice isoforms : SwissVarQ13639
PhosPhoSitePlusQ13639
Domaine pattern : Prosite (Expaxy)G_PROTEIN_RECEP_F1_1 (PS00237)    G_PROTEIN_RECEP_F1_2 (PS50262)   
Domains : Interpro (EBI)5HT4_rcpt    GPCR_Rhodpsn    GPCR_Rhodpsn_7TM   
Domain families : Pfam (Sanger)7tm_1 (PF00001)   
Domain families : Pfam (NCBI)pfam00001   
Domain families : Smart (EMBL)7TM_GPCR_Srsx (SM01381)  
Conserved Domain (NCBI)HTR4
DMDM Disease mutations3360
Blocks (Seattle)HTR4
PDB (RSDB)5EM9   
PDB Europe5EM9   
PDB (PDBSum)5EM9   
PDB (IMB)5EM9   
Structural Biology KnowledgeBase5EM9   
SCOP (Structural Classification of Proteins)5EM9   
CATH (Classification of proteins structures)5EM9   
SuperfamilyQ13639
Human Protein Atlas [tissue]ENSG00000164270-HTR4 [tissue]
Peptide AtlasQ13639
IPIIPI00014378   IPI00064638   IPI00216427   IPI00186777   IPI00216429   IPI00291659   IPI00216428   IPI00984861   IPI00974551   IPI00748585   
Protein Interaction databases
DIP (DOE-UCLA)Q13639
IntAct (EBI)Q13639
FunCoupENSG00000164270
BioGRIDHTR4
STRING (EMBL)HTR4
ZODIACHTR4
Ontologies - Pathways
QuickGOQ13639
Ontology : AmiGOG protein-coupled receptor activity  G protein-coupled serotonin receptor activity  G protein-coupled serotonin receptor activity  protein binding  cytoplasm  endosome  plasma membrane  integral component of plasma membrane  G protein-coupled receptor signaling pathway  G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger  chemical synaptic transmission  membrane  dendrite  neurotransmitter receptor activity  regulation of appetite  G protein-coupled serotonin receptor signaling pathway  
Ontology : EGO-EBIG protein-coupled receptor activity  G protein-coupled serotonin receptor activity  G protein-coupled serotonin receptor activity  protein binding  cytoplasm  endosome  plasma membrane  integral component of plasma membrane  G protein-coupled receptor signaling pathway  G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger  chemical synaptic transmission  membrane  dendrite  neurotransmitter receptor activity  regulation of appetite  G protein-coupled serotonin receptor signaling pathway  
Pathways : KEGGCalcium signaling pathway    Neuroactive ligand-receptor interaction    Serotonergic synapse   
REACTOMEQ13639 [protein]
REACTOME PathwaysR-HSA-418555 [pathway]   
NDEx NetworkHTR4
Atlas of Cancer Signalling NetworkHTR4
Wikipedia pathwaysHTR4
Orthology - Evolution
OrthoDB3360
GeneTree (enSembl)ENSG00000164270
Phylogenetic Trees/Animal Genes : TreeFamHTR4
HOGENOMQ13639
Homologs : HomoloGeneHTR4
Homology/Alignments : Family Browser (UCSC)HTR4
Gene fusions - Rearrangements
Fusion : FusionGDB20754   
Fusion : Fusion_HubHTR4--FAM120AOS    HTR4--FN1    MAN2A1--HTR4    MARCH3--HTR4    SH3TC2--HTR4    ST3GAL1--HTR4   
Fusion : QuiverHTR4
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerHTR4 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)HTR4
dbVarHTR4
ClinVarHTR4
1000_GenomesHTR4 
Exome Variant ServerHTR4
ExAC (Exome Aggregation Consortium)ENSG00000164270
GNOMAD BrowserENSG00000164270
Varsome BrowserHTR4
Genetic variants : HAPMAP3360
Genomic Variants (DGV)HTR4 [DGVbeta]
DECIPHERHTR4 [patients]   [syndromes]   [variants]   [genes]  
CONAN: Copy Number AnalysisHTR4 
Mutations
ICGC Data PortalHTR4 
TCGA Data PortalHTR4 
Broad Tumor PortalHTR4
OASIS PortalHTR4 [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICHTR4  [overview]  [genome browser]  [tissue]  [distribution]  
Somatic Mutations in Cancer : COSMIC3DHTR4
Mutations and Diseases : HGMDHTR4
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD - Leiden Open Variation Database
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
BioMutasearch HTR4
DgiDB (Drug Gene Interaction Database)HTR4
DoCM (Curated mutations)HTR4 (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)HTR4 (select a term)
intoGenHTR4
NCG5 (London)HTR4
Cancer3DHTR4(select the gene name)
Impact of mutations[PolyPhen2] [Provean] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM602164   
Orphanet
DisGeNETHTR4
MedgenHTR4
Genetic Testing Registry HTR4
NextProtQ13639 [Medical]
TSGene3360
GENETestsHTR4
Target ValidationHTR4
Huge Navigator HTR4 [HugePedia]
snp3D : Map Gene to Disease3360
BioCentury BCIQHTR4
ClinGenHTR4
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD3360
Chemical/Pharm GKB GenePA29557
Clinical trialHTR4
Miscellaneous
canSAR (ICR)HTR4 (select the gene name)
DataMed IndexHTR4
Probes
Litterature
PubMed92 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMineHTR4
EVEXHTR4
GoPubMedHTR4
iHOPHTR4
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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