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Gene Review

Htr4  -  5 hydroxytryptamine (serotonin) receptor 4

Mus musculus

Synonyms: 5-HT, 5-HT-4, 5-HT4, 5-hydroxytryptamine receptor 4, 5HTR4, ...
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Disease relevance of Htr4


Psychiatry related information on Htr4

  • Based on these findings, it could be inferred that the increase of brain Allo content elicited by fluoxetine and norfluoxetine, rather than the inhibition selective of 5-HT reuptake, may be operative in the fluoxetine-induced remission of the behavioral abnormalities associated with mood disorders [5].
  • Substantial evidence links alcohol drinking and serotonin (5-HT) functioning in animals [2].
  • These findings have implications for understanding the potential long-term consequences of genetic and pharmacological disruption of 5-HT neurotransmission on cerebral functions during critical periods of postnatal development [6].
  • It is suggested that 5-HT represents a dietary responsive endogenous factor regulating predatory behavior in carnivores [7].
  • Thus, altered 5-HT innervation and/or uptake in the DMX may contribute to abnormal 5-HT modulation of this major autonomic nucleus in patients with Rett syndrome [8].

High impact information on Htr4


Chemical compound and disease context of Htr4


Biological context of Htr4

  • These data suggest that both sequestration and phosphorylation by beta ARK, or another specific agonist-dependent receptor kinase, are involved in homologous desensitization of 5-HT4 receptors coupled to adenylyl cyclase [17].
  • Using degenerate oligonucleotide primers, we identified a rat brain PCR fragment which encoded a '5-HT receptor-like' amino acid sequence [18].
  • The neurotransmitter serotonin (5HT) activates a variety of second messenger signaling systems and through them indirectly regulates the function of ion channels [19].
  • Infection-induced up-regulation of 5-HT2A expression was correlated with the smooth muscle hypercontractility to 5-HT [20].
  • In addition, molecular biology techniques have provided new tools with which to study the function of 5-HT receptors [21].

Anatomical context of Htr4


Associations of Htr4 with chemical compounds

  • Neurons exposed to other agents, like isoproterenol, vasoactive intestinal peptide, or forskolin, that increase cAMP levels did not undergo any desensitization of 5-HT4 receptors [17].
  • When permeabilized neurons were loaded with heparin, an inhibitor of the beta-adrenergic receptor kinase (beta ARK), 5-HT4 receptor desensitization was reduced by 30-40% [17].
  • Activation of protein kinase A with either 8-bromo-cAMP or dibutyryl-cAMP or application of inhibitors of protein kinase A-dependent phosphorylation did not change the rate of 5-HT4-induced desensitization [17].
  • IL-1beta induced an SB203580-sensitive decrease in 5-HT K(m) with no significant change in V(max) [24].
  • Thus, the neurosteroid-induced positive allosteric modulation of GABA action at GABAA receptors is facilitated by fluoxetine or its congeners (i.e., paroxetine, fluvoxamine, sertraline), which may not block 5-HT reuptake at the doses currently prescribed in the clinic [5].

Physical interactions of Htr4


Regulatory relationships of Htr4

  • In RN46A cells, IL-1beta stimulated 5-HT uptake in a dose- and time-dependent manner, peaking in 20 min at 100 ng/ml [24].

Other interactions of Htr4

  • 5-HT and 5-HT(1P) agonists evoked a G protein-mediated long-lasting inward current that was neither mimicked by 5-HT(4) agonists nor blocked by 5-HT(4) antagonists [23].
  • The C57BLKS/J db/db mouse develops hyperglycemia and has delayed gastric emptying that is improved with tegaserod, a partial 5-HT4 agonist [28].
  • In mouse hippocampal neurons, activation of the endogenous 5-HT7 receptors significantly increased neurite length, whereas stimulation of 5-HT4 receptors led to a decrease in the length and number of neurites [29].
  • Serotonin-induced contractions were partially inhibited by atropine, the 5-HT4 antagonist GR113808, and the 5-HT2 antagonist cinanseron but not tetrodotoxin [28].
  • 5HT1c receptor antagonists (mianserin and cyproheptadine), 5-HT3 receptor antagonist (zacopride) and 5-HT4 receptor antagonist (ICS 205-930) increased the latency of audiogenic seizures and decreased the severity of convulsions in young (20-27 days old) DBA/2 mice [30].

Analytical, diagnostic and therapeutic context of Htr4

  • The 5-HT4 receptor: molecular cloning and pharmacological characterization of two splice variants [18].
  • Microdialysis sampling during a 10-min FS showed that NA and 5-HT release were elevated to 213% and 156%, respectively, in the GalOE/P group, whereas in the WT group the increases were only 127% and 119%, respectively [31].
  • In the present study, we combined receptor binding autoradiography with neurochemical ablation of 5-HT axons or electrolytic lesions of the dorsal thalamus in an effort to determine the neural elements upon which the 5-HT1B receptors were located [32].
  • This view is consistent with earlier studies showing that pharmacological activation of the 5-HT system is anxiogenic in animal models and also in humans [33].
  • Carbon fiber microelectrodes were used to measure individual secretory events of histamine and 5-hydroxytryptamine (5-HT) from VMAT2-expressing mast cells as a model system for quantal release [34].


  1. Attenuated response to stress and novelty and hypersensitivity to seizures in 5-HT4 receptor knock-out mice. Compan, V., Zhou, M., Grailhe, R., Gazzara, R.A., Martin, R., Gingrich, J., Dumuis, A., Brunner, D., Bockaert, J., Hen, R. J. Neurosci. (2004) [Pubmed]
  2. Elevated alcohol consumption in null mutant mice lacking 5-HT1B serotonin receptors. Crabbe, J.C., Phillips, T.J., Feller, D.J., Hen, R., Wenger, C.D., Lessov, C.N., Schafer, G.L. Nat. Genet. (1996) [Pubmed]
  3. A single amino-acid difference confers major pharmacological variation between human and rodent 5-HT1B receptors. Oksenberg, D., Marsters, S.A., O'Dowd, B.F., Jin, H., Havlik, S., Peroutka, S.J., Ashkenazi, A. Nature (1992) [Pubmed]
  4. Reevaluation of reserpine-induced suppression of contact sensitivity. Evidence that reserpine interferes with T lymphocyte function independently of an effect on mast cells. Mekori, Y.A., Weitzman, G.L., Galli, S.J. J. Exp. Med. (1985) [Pubmed]
  5. Fluoxetine and norfluoxetine stereospecifically and selectively increase brain neurosteroid content at doses that are inactive on 5-HT reuptake. Pinna, G., Costa, E., Guidotti, A. Psychopharmacology (Berl.) (2006) [Pubmed]
  6. Developmental disruption of serotonin transporter function impairs cerebral responses to whisker stimulation in mice. Esaki, T., Cook, M., Shimoji, K., Murphy, D.L., Sokoloff, L., Holmes, A. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  7. Neural control of predatory aggression in wild and domesticated animals. Nikulina, E.M. Neuroscience and biobehavioral reviews. (1991) [Pubmed]
  8. Serotonin transporter abnormality in the dorsal motor nucleus of the vagus in Rett syndrome: potential implications for clinical autonomic dysfunction. Paterson, D.S., Thompson, E.G., Belliveau, R.A., Antalffy, B.A., Trachtenberg, F.L., Armstrong, D.D., Kinney, H.C. J. Neuropathol. Exp. Neurol. (2005) [Pubmed]
  9. Increased stress response and beta-phenylethylamine in MAOB-deficient mice. Grimsby, J., Toth, M., Chen, K., Kumazawa, T., Klaidman, L., Adams, J.D., Karoum, F., Gal, J., Shih, J.C. Nat. Genet. (1997) [Pubmed]
  10. Aplysia CREB2 represses long-term facilitation: relief of repression converts transient facilitation into long-term functional and structural change. Bartsch, D., Ghirardi, M., Skehel, P.A., Karl, K.A., Herder, S.P., Chen, M., Bailey, C.H., Kandel, E.R. Cell (1995) [Pubmed]
  11. Regulation of serotonin-2C receptor G-protein coupling by RNA editing. Burns, C.M., Chu, H., Rueter, S.M., Hutchinson, L.K., Canton, H., Sanders-Bush, E., Emeson, R.B. Nature (1997) [Pubmed]
  12. The pharmacology and clinical pharmacology of 3,4-methylenedioxymethamphetamine (MDMA, "ecstasy"). Green, A.R., Mechan, A.O., Elliott, J.M., O'Shea, E., Colado, M.I. Pharmacol. Rev. (2003) [Pubmed]
  13. Leptin increases serotonin turnover by inhibition of brain nitric oxide synthesis. Calapai, G., Corica, F., Corsonello, A., Sautebin, L., Di Rosa, M., Campo, G.M., Buemi, M., Mauro, V.N., Caputi, A.P. J. Clin. Invest. (1999) [Pubmed]
  14. No hypothermic response to serotonin in 5-HT7 receptor knockout mice. Hedlund, P.B., Danielson, P.E., Thomas, E.A., Slanina, K., Carson, M.J., Sutcliffe, J.G. Proc. Natl. Acad. Sci. U.S.A. (2003) [Pubmed]
  15. Transgenic mice with high levels of superoxide dismutase activity are protected from the neurotoxic effects of 2'-NH2-MPTP on serotonergic and noradrenergic nerve terminals. Andrews, A.M., Ladenheim, B., Epstein, C.J., Cadet, J.L., Murphy, D.L. Mol. Pharmacol. (1996) [Pubmed]
  16. Airway hyperresponsiveness in transgenic mice overexpressing platelet activating factor receptor is mediated by an atropine-sensitive pathway. Nagase, T., Ishii, S., Shindou, H., Ouchi, Y., Shimizu, T. Am. J. Respir. Crit. Care Med. (2002) [Pubmed]
  17. Characterization of homologous 5-hydroxytryptamine4 receptor desensitization in colliculi neurons. Ansanay, H., Sebben, M., Bockaert, J., Dumuis, A. Mol. Pharmacol. (1992) [Pubmed]
  18. The 5-HT4 receptor: molecular cloning and pharmacological characterization of two splice variants. Gerald, C., Adham, N., Kao, H.T., Olsen, M.A., Laz, T.M., Schechter, L.E., Bard, J.A., Vaysse, P.J., Hartig, P.R., Branchek, T.A. EMBO J. (1995) [Pubmed]
  19. Primary structure and functional expression of the 5HT3 receptor, a serotonin-gated ion channel. Maricq, A.V., Peterson, A.S., Brake, A.J., Myers, R.M., Julius, D. Science (1991) [Pubmed]
  20. Contribution of 5-HT2A receptor in nematode infection-induced murine intestinal smooth muscle hypercontractility. Zhao, A., Urban, J.F., Morimoto, M., Elfrey, J.E., Madden, K.B., Finkelman, F.D., Shea-Donohue, T. Gastroenterology (2006) [Pubmed]
  21. New players in the 5-HT receptor field: genes and knockouts. Lucas, J.J., Hen, R. Trends Pharmacol. Sci. (1995) [Pubmed]
  22. Olfactory bulbectomy in mice leads to increased BDNF levels and decreased serotonin turnover in depression-related brain areas. Hellweg, R., Zueger, M., Fink, K., H??rtnagl, H., Gass, P. Neurobiol. Dis. (2007) [Pubmed]
  23. Expression and function of 5-HT4 receptors in the mouse enteric nervous system. Liu, M., Geddis, M.S., Wen, Y., Setlik, W., Gershon, M.D. Am. J. Physiol. Gastrointest. Liver Physiol. (2005) [Pubmed]
  24. The proinflammatory cytokines interleukin-1beta and tumor necrosis factor-alpha activate serotonin transporters. Zhu, C.B., Blakely, R.D., Hewlett, W.A. Neuropsychopharmacology (2006) [Pubmed]
  25. T cell-dependent mast cell degranulation and release of serotonin in murine delayed-type hypersensitivity. Askenase, P.W., Bursztajn, S., Gershon, M.D., Gershon, R.K. J. Exp. Med. (1980) [Pubmed]
  26. Pharmacological characterization of 5-hydroxytryptamine4(5-HT4) receptors positively coupled to adenylate cyclase in adult guinea pig hippocampal membranes: effect of substituted benzamide derivatives. Bockaert, J., Sebben, M., Dumuis, A. Mol. Pharmacol. (1990) [Pubmed]
  27. 5-HT6 receptors positively coupled to adenylyl cyclase in striatal neurones in culture. Sebben, M., Ansanay, H., Bockaert, J., Dumuis, A. Neuroreport (1994) [Pubmed]
  28. Regional gastric contractility alterations in a diabetic gastroparesis mouse model: effects of cholinergic and serotoninergic stimulation. James, A.N., Ryan, J.P., Crowell, M.D., Parkman, H.P. Am. J. Physiol. Gastrointest. Liver Physiol. (2004) [Pubmed]
  29. 5-HT7 receptor is coupled to G alpha subunits of heterotrimeric G12-protein to regulate gene transcription and neuronal morphology. Kvachnina, E., Liu, G., Dityatev, A., Renner, U., Dumuis, A., Richter, D.W., Dityateva, G., Schachner, M., Voyno-Yasenetskaya, T.A., Ponimaskin, E.G. J. Neurosci. (2005) [Pubmed]
  30. Effects of 5-HT receptor antagonists on seizure susceptibility and locomotor activity in DBA/2 mice. Semenova, T.P., Ticku, M.K. Brain Res. (1992) [Pubmed]
  31. Enhanced hippocampal noradrenaline and serotonin release in galanin-overexpressing mice after repeated forced swimming test. Yoshitake, T., Wang, F.H., Kuteeva, E., Holmberg, K., Yamaguchi, M., Crawley, J.N., Steiner, R., Bartfai, T., Ogren, S.O., Hökfelt, T., Kehr, J. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
  32. Serotonin 1B receptors in the developing somatosensory and visual cortices are located on thalamocortical axons. Bennett-Clarke, C.A., Leslie, M.J., Chiaia, N.L., Rhoades, R.W. Proc. Natl. Acad. Sci. U.S.A. (1993) [Pubmed]
  33. Increased anxiety of mice lacking the serotonin1A receptor. Parks, C.L., Robinson, P.S., Sibille, E., Shenk, T., Toth, M. Proc. Natl. Acad. Sci. U.S.A. (1998) [Pubmed]
  34. Differential quantal release of histamine and 5-hydroxytryptamine from mast cells of vesicular monoamine transporter 2 knockout mice. Travis, E.R., Wang, Y.M., Michael, D.J., Caron, M.G., Wightman, R.M. Proc. Natl. Acad. Sci. U.S.A. (2000) [Pubmed]
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