Alternative titles; symbols
HGNC Approved Gene Symbol: HTR4
Cytogenetic location: 5q32 Genomic coordinates (GRCh38): 5:148,451,032-148,654,527 (from NCBI)
The serotonin 5-hydroxytryptamine-4 receptor was first characterized by Dumuis et al. (1988) in mouse colliculi neurons. Subsequently, Eglen et al. (1995) showed that 5-HTR4 mediates widespread effects in central and peripheral nervous systems.
Blondel et al. (1997) used PCR, based on primers to the central region of rat 5-HT4 receptor, to clone a human 5-HT4 receptor, which they called 5-HT4A. Sequence analysis showed that this cDNA encodes a 387-amino acid polypeptide with 7 putative transmembrane domains and several potential regulatory sites. Blondel et al. (1997) found that 5-HT4A is the same length as, and 93% identical to, the shorter of the 2 alternately spliced forms of the rat 5-HT4 receptor. RT-PCR analysis showed that the 5-HT4A mRNA is expressed in human ileum, brain, and atrium, but not in the ventricle.
See also HTR2C (312861) for discussion of other related receptor families.
Serotonin acts as a stimulant to atrial cardiac cells in only a few mammalian species including human, monkey, and pig but not rodents. Cells from human atrium respond to 5-HT stimulation by producing an L-type calcium current. Blondel et al. (1997) showed that COS-7 cells expressing the 5-HT4 receptor responded to serotonin stimulation with pharmacologic profiles similar to those seen in human atrial myocytes, suggesting to the authors that 5-HT4A is the protein responsible for the serotonin responsiveness of the human atrium.
Manzke et al. (2003) reported that serotonin 4-alpha receptors are strongly expressed in respiratory pre-Boetzinger complex neurons of the brainstem and that their selected activation protects spontaneous respiratory activity. Treatment of rats with a 5-HT4 receptor-specific agonist overcame fentanyl-induced respiratory depression and reestablished stable respiratory rhythm without loss of fentanyl's analgesic effect. Manzke et al. (2003) concluded that a fine-tuned recovery from opioid-induced respiratory depression is possible, through adjustment of intracellular cyclic AMP levels through the convergent signaling pathways in neurons.
Claeysen et al. (1997) cloned the human HTR4 gene from heart and mapped the gene to 5q31-q33 by fluorescence in situ hybridization.
Ohtsuki et al. (2002) performed mutation and association analyses of the HTR4 gene in 96 Japanese patients, 48 with mood disorders (see 125480) and 48 with schizophrenia. Eight polymorphisms and 4 rare variants were identified. Four polymorphisms at or in close proximity to exon d showed significant association with bipolar disorder with odds ratios of 1.5 to 2; these included g.83097C/T (HTR4-SVR (splice variant region) SNP1), g.83159G/A (HTR4-SVRSNP2), g.83164(T)9-10 (HTR4-SVRSNP3), and g.83198A/G (HTR4-SVRSNP4). These polymorphisms were in linkage disequilibrium, and only 3 common haplotypes were observed. One haplotype (SVRSNP1, SVRSNP4 C-A) was significantly associated with bipolar disorder (P = 0.002). The genotypic and haplotypic associations with bipolar disorder were confirmed by the transmission disequilibrium test in the NIMH Genetics Initiative bipolar pedigrees with ratios of transmitted to not transmitted alleles of 1.5 to 2.0 (P = 0.01). The same haplotype that showed association with bipolar disorder was suggested to be associated with schizophrenia in the case-control analysis (P = 0.003) but was not confirmed when Japanese schizophrenia families were tested. The polymorphisms associated with mood disorder were located within the region that encodes the divergent C-terminal tails of the 5-HT4 receptor.
In fed and food-deprived mice, Jean et al. (2007) showed that direct stimulation of Htr4 receptors in the nucleus accumbens reduced the physiologic drive to eat and increased Cart (602606) mRNA levels. Injection of HTR4 antagonist or siRNA-mediated Htr4 knockdown targeted to the nucleus accumbens induced hyperphagia only in fed mice and did not affect Cart mRNA expression. Injection of Cart peptide or siRNA-mediated Cart knockdown targeted to the nucleus accumbens reduced or increased food consumption, respectively. Jean et al. (2007) concluded that HTR4-induced anorexia is mediated by CART in the nucleus accumbens.
Blondel, O., Vandecasteele, G., Gastineau, M., Leclerc, S., Dahmoune, Y., Langlois, M., Fischmeister, R. Molecular and functional characterization of a 5-HT(4) receptor cloned from human atrium. FEBS Lett. 412: 465-474, 1997. [PubMed: 9276448] [Full Text: https://doi.org/10.1016/s0014-5793(97)00820-x]
Claeysen, S., Faye, P., Sebben, M., Lemaire, S., Bockaert, J., Dumuis, A., Taviaux, S. Assignment of 5-hydroxytryptamine receptor (HTR4) to human chromosome 5 bands q31-to-q33 by in situ hybridization. Cytogenet. Cell Genet. 78: 133-134, 1997. [PubMed: 9371406] [Full Text: https://doi.org/10.1159/000134646]
Dumuis, A., Bouhelal, R., Sebben, M., Cory, R., Bockaert, J. A nonclassical 5-hydroxytryptamine receptor positively coupled with adenylate cyclase in the central nervous system. Molec. Pharm. 34: 880-887, 1988. [PubMed: 2849052]
Eglen, R. M., Wong, E. H. F., Dumuis, A., Bockaert, J. Central 5-HT4 receptors. Trends Pharm. Sci. 16: 391-398, 1995. [PubMed: 8578609] [Full Text: https://doi.org/10.1016/s0165-6147(00)89081-1]
Jean, A., Conductier, G., Manrique, C., Bouras, C., Berta, P., Hen, R., Charnay, Y., Bockaert, J., Compan, V. Anorexia induced by activation of serotonin 5-HT(4) receptors is mediated by increases in CART in the nucleus accumbens. Proc. Nat. Acad. Sci. 104: 16335-16340, 2007. [PubMed: 17913892] [Full Text: https://doi.org/10.1073/pnas.0701471104]
Manzke, T., Guenther, U., Ponimaskin, E. G., Haller, M., Dutschmann, M., Schwarzacher, S., Richter, D. W. 5-HT4(a) receptors avert opioid-induced breathing depression without loss of analgesia. Science 301: 226-229, 2003. [PubMed: 12855812] [Full Text: https://doi.org/10.1126/science.1084674]
Ohtsuki, T., Ishiguro, H., Detera-Wadleigh, S. D., Toyota, T., Shimizu, H., Yamada, K., Yoshitsugu, K., Hattori, E., Yoshikawa, T., Arinami, T. Association between serotonin 4 receptor gene polymorphisms and bipolar disorder in Japanese case-control samples and the NIMH Genetics Initiative bipolar pedigrees. Molec. Psychiat. 7: 954-961, 2002. [PubMed: 12399948] [Full Text: https://doi.org/10.1038/sj.mp.4001133]