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Gene Review

Htr4  -  5-hydroxytryptamine (serotonin) receptor 4...

Rattus norvegicus

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

  • The purpose of this investigation was to determine whether a nutritionally essential amino acid, l-lysine, acts like a serotonin receptor 4 (5-HT4) antagonist, and if l-lysine is beneficial in animal models of serotonin (5-HT)-induced anxiety, diarrhea, ileum contractions, and tachycardia and in stress-induced fecal excretion [1].
  • Orally applied l-lysine (1 g/kg of body weight) inhibited (P < 0.12) diarrhea triggered by coadministration of restraint stress and 5-hydroxytryptophane (10 mg/kg of body weight), and significantly blocked anxiety induced by the 5-HT4 receptor agonist (3.0 mmol/liter) in rats in vivo [1].
  • In addition, stereotaxic microinjections of herpes simplex viruses, transformed to overexpress 5-HT4 receptors, increase DRN 5-HT neuronal mean activity when performed in the medial prefrontal cortex (mPFC) but not in the striatum or in the hippocampus [2].
  • 5-HT4 agents were unable to alter haloperidol's effects on striatal messenger RNA levels or catalepsy [3].
  • In the TMM, relaxation of carbachol-induced contracture by 5-HT4 receptor agonism of longitudinal muscle was recorded [4].

Psychiatry related information on Htr4


High impact information on Htr4

  • No effects of l-lysine or the 5-HT4 receptor agonist on plasma corticosterone and heart rate were recorded. l-Lysine may be a partial 5-HT4 receptor antagonist and suppresses 5-HT4 receptor-mediated intestinal pathologies and anxiety in rats [1].
  • L-Lysine acts like a partial serotonin receptor 4 antagonist and inhibits serotonin-mediated intestinal pathologies and anxiety in rats [1].
  • 5HT4 receptors couple positively to tetrodotoxin-insensitive sodium channels in a subpopulation of capsaicin-sensitive rat sensory neurons [10].
  • Here we show that although induction of LTP is unaffected by either pharmacological activation or inhibition of 5-HT4, application of the 5-HT4 receptor agonist, RS67333, completely blocks learning-induced depotentiation of LTP in the hippocampal CA1 region of freely moving rats, suggesting a role for 5-HT4 receptors in behavioural metaplasticity [11].
  • The effects of 5HT on ICJ transit were inhibited by the intraperitoneal (ip) infusion of atropine, the 5HT receptor antagonists, methysergide, ketanserin, zacopride, and the 5HT4 agonist, SC53116 [12].

Chemical compound and disease context of Htr4


Biological context of Htr4


Anatomical context of Htr4

  • To verify whether this procognitive action occurs via the activation of the cholinergic nucleus basalis magnocellularis (NBM)-cortical pathways, we examined the effects of RS67333, a selective partial agonist of the 5-HT4 receptor, on rat performance in a place recognition task upon local administration of the drug into the NBM area [20].
  • BACKGROUND: We recently identified a facilitory control exerted by serotonin4 (5-HT4) receptors on the in vivo firing activity of dorsal raphe nucleus (DRN) serotonergic (5-HT) neurons [2].
  • A series of indole-3-carboxamides, indazole-3-carboxamides, and benzimidazolone-3-carboxamides was synthesized and evaluated for antagonist affinity at the 5-HT4 receptor in the rat esophagus [18].
  • Lasting increase in serotonin 5-HT1A but not 5-HT4 receptor subtypes in the kindled rat dentate gyrus: dissociation from local presynaptic effects [21].
  • They were evaluated using radioligand binding assays with [3H]GR 113808, a 5-HT4 receptor selective ligand, in the rat striatum and the electrically stimulated myenteric plexus longitudinal muscle of the guinea pig [22].

Associations of Htr4 with chemical compounds

  • Benzimidazole derivatives. 4. The recognition of the voluminous substituent attached to the basic amino group of 5-HT4 receptor antagonists [23].
  • These increases remain stable when the compounds are administered continuously during 3 and 21 days; the effects of the 3-day treatment are blocked by the 5-HT4 receptor antagonist GR 125487 (1000 microg/kg, intravenous [i.v.]) [2].
  • METHODS AND RESULTS: Here we show that the subacute intraperitoneal (IP) injection of the 5-HT4 receptor agonists prucalopride (2.5 mg/kg) and RS 67333 (1.5 mg/kg) 30 minutes before the beginning of recordings augment the mean firing rate of DRN neurons by 40% and 66%, respectively [2].
  • Additional evidence for the involvement of cAMP in the signaling by 5-HT4 receptors was obtained using the general phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine [24].
  • 8c is an antagonist equipotent to the 5-HT4 receptor antagonist SDZ 205-557 (1) [22].

Physical interactions of Htr4

  • Most of the synthesized compounds exhibited moderate-to-very high affinity (in many cases subnanomolar) for the 5-HT4 binding site and no significant affinity for the 5-HT3 receptor [25].

Regulatory relationships of Htr4

  • These data suggest that 5-HT4 receptor activation enhances the ability of 5-HT3 receptor activation to induce intestinal allodynia [26].

Other interactions of Htr4

  • Enhanced [35S]GTPgammaS binding was not detected in the presence of 5-HT1F, 5-HT2, 5-HT4, and 5-HT7 receptor agonists [27].
  • In conclusion, the stimulation of glucose transport by 5-HT in cardiomyocytes is not mediated by a 5-HT1, 5-HT2, 5-HT3 or 5-HT4 receptor, nor by an adrenergic or dopaminergic receptor, but is likely to occur through the degradation of by a monoamine oxidase and concomitant formation of H2O2 [28].
  • 5-HT1A and 5-HT4 receptor colocalization on hippocampal pyramidal cells [29].
  • Our data indicate that 5-HT has significant ability to modulate membrane excitability in STN neurons; modulation is accomplished by decreasing potassium conductance by activating 5-HT4 and 5-HT2C receptors [30].
  • The highest density of 5-HT4 receptors labeled with [3H]GR113808 was found in the olfactory tubercle, substantia nigra, ventral pallium and striatum of rat and guinea pig, and similar regions of pig-tail macaque monkey [31].

Analytical, diagnostic and therapeutic context of Htr4


  1. L-Lysine acts like a partial serotonin receptor 4 antagonist and inhibits serotonin-mediated intestinal pathologies and anxiety in rats. Smriga, M., Torii, K. Proc. Natl. Acad. Sci. U.S.A. (2003) [Pubmed]
  2. Frontocortical 5-HT4 receptors exert positive feedback on serotonergic activity: viral transfections, subacute and chronic treatments with 5-HT4 agonists. Lucas, G., Compan, V., Charnay, Y., Neve, R.L., Nestler, E.J., Bockaert, J., Barrot, M., Debonnel, G. Biol. Psychiatry (2005) [Pubmed]
  3. Molecular and behavioral effects mediated by Gs-coupled adenosine A2a, but not serotonin 5-Ht4 or 5-Ht6 receptors following antipsychotic administration. Ward, R.P., Dorsa, D.M. Neuroscience (1999) [Pubmed]
  4. Pharmacological analyses of endo-6-methoxy-8-methyl-8-azabicyclo[3.2.1]oct-3-yl-2,3-dihydro-2-oxo-1 H- benzimidazole-1-carboxylate hydrochloride (DAU 6285) at the 5-hydroxytryptamine4 receptor in the tunica muscularis mucosae of rat esophagus and ileum of guinea pig: role of endogenous 5-hydroxytryptamine. Waikar, M.V., Hegde, S.S., Ford, A.P., Clarke, D.E. J. Pharmacol. Exp. Ther. (1993) [Pubmed]
  5. 5-HT4 receptors in the hippocampus modulate rat locomotor activity. Takahashi, H., Takada, Y., Urano, T., Takada, A. Hippocampus. (2002) [Pubmed]
  6. BIMU1 increases associative memory in rats by activating 5-HT4 receptors. Marchetti-Gauthier, E., Roman, F.S., Dumuis, A., Bockaert, J., Soumireu-Mourat, B. Neuropharmacology (1997) [Pubmed]
  7. Anxiolytic-like actions of the selective 5-HT4 receptor antagonists SB 204070A and SB 207266A in rats. Kennett, G.A., Bright, F., Trail, B., Blackburn, T.P., Sanger, G.J. Neuropharmacology (1997) [Pubmed]
  8. 5-HT4 receptors improve social olfactory memory in the rat. Letty, S., Child, R., Dumuis, A., Pantaloni, A., Bockaert, J., Rondouin, G. Neuropharmacology (1997) [Pubmed]
  9. Regional distribution and ontogeny of 5-HT4 binding sites in rat brain. Waeber, C., Sebben, M., Bockaert, J., Dumuis, A. Behav. Brain Res. (1996) [Pubmed]
  10. 5HT4 receptors couple positively to tetrodotoxin-insensitive sodium channels in a subpopulation of capsaicin-sensitive rat sensory neurons. Cardenas, C.G., Del Mar, L.P., Cooper, B.Y., Scroggs, R.S. J. Neurosci. (1997) [Pubmed]
  11. The 5-hydroxytryptamine4 receptor exhibits frequency-dependent properties in synaptic plasticity and behavioural metaplasticity in the hippocampal CA1 region in vivo. Kemp, A., Manahan-Vaughan, D. Cereb. Cortex (2005) [Pubmed]
  12. Effects of serotonin on rat ileocolonic transit and fluid transfer in vivo: possible mechanisms of action. Oosterbosch, L., von der Ohe, M., Valdovinos, M.A., Kost, L.J., Phillips, S.F., Camilleri, M. Gut (1993) [Pubmed]
  13. The action of SDZ 205,557 at 5-hydroxytryptamine (5-HT3 and 5-HT4) receptors. Eglen, R.M., Alvarez, R., Johnson, L.G., Leung, E., Wong, E.H. Br. J. Pharmacol. (1993) [Pubmed]
  14. p-Chloroamphetamine, a serotonin-releasing drug, elicited in rats a hyperglycemia mediated by the 5-HT1A and 5-HT2B/2C receptors. Yamada, J., Sugimoto, Y., Yoshikawa, T. Eur. J. Pharmacol. (1998) [Pubmed]
  15. Hyperglycemia induced by the 5-HT receptor agonist, 5-methoxytryptamine, in rats: involvement of the peripheral 5-HT2A receptor. Yamada, J., Sugimoto, Y., Yoshikawa, T., Horisaka, K. Eur. J. Pharmacol. (1997) [Pubmed]
  16. Effects of the 5-HT2C/2B receptor agonist 1-(3-chlorophenyl) piperazine on plasma glucose levels of rats. Sugimoto, Y., Yamada, J., Yoshikawa, T., Horisaka, K. Eur. J. Pharmacol. (1996) [Pubmed]
  17. Synthesis of 2-piperazinylbenzothiazole and 2-piperazinylbenzoxazole derivatives with 5-HT3 antagonist and 5-HT4 agonist properties. Monge, A., Peña, M.C., Palop, J.A., Calderó, J.M., Roca, J., García, E., Romero, G., del Río, J., Lasheras, B. J. Med. Chem. (1994) [Pubmed]
  18. Synthesis and structure-activity relationships of potent and orally active 5-HT4 receptor antagonists: indazole and benzimidazolone derivatives. Schaus, J.M., Thompson, D.C., Bloomquist, W.E., Susemichel, A.D., Calligaro, D.O., Cohen, M.L. J. Med. Chem. (1998) [Pubmed]
  19. Pharmacological characterization of two novel and potent 5-HT4 receptor agonists, RS 67333 and RS 67506, in vitro and in vivo. Eglen, R.M., Bonhaus, D.W., Johnson, L.G., Leung, E., Clark, R.D. Br. J. Pharmacol. (1995) [Pubmed]
  20. Acquisition, retention, and recall of memory after injection of RS67333, a 5-HT(4) receptor agonist, into the nucleus basalis magnocellularis of the rat. Orsetti, M., Dellarole, A., Ferri, S., Ghi, P. Learn. Mem. (2003) [Pubmed]
  21. Lasting increase in serotonin 5-HT1A but not 5-HT4 receptor subtypes in the kindled rat dentate gyrus: dissociation from local presynaptic effects. Cagnotto, A., Crespi, D., Mancini, L., Manzoni, C., Presti, M.L., Gariboldi, M., Vezzani, A., Mennini, T. J. Neurochem. (1998) [Pubmed]
  22. Arylcarbamate derivatives of 1-piperidineethanol as potent ligands for 5-HT4 receptors. Soulier, J.L., Yang, D., Brémont, B., Croci, T., Guzzi, U., Langlois, M. J. Med. Chem. (1997) [Pubmed]
  23. Benzimidazole derivatives. 4. The recognition of the voluminous substituent attached to the basic amino group of 5-HT4 receptor antagonists. López-Rodríguez, M.L., Benhamú, B., Murcia, M., Alvaro, E., Campillo, M., Pardo, L. J. Comput. Aided Mol. Des. (2003) [Pubmed]
  24. Cyclic AMP and protein kinase A mediate 5-hydroxytryptamine type 4 receptor regulation of calcium-activated potassium current in adult hippocampal neurons. Torres, G.E., Chaput, Y., Andrade, R. Mol. Pharmacol. (1995) [Pubmed]
  25. Benzimidazole derivatives. Part 1: Synthesis and structure-activity relationships of new benzimidazole-4-carboxamides and carboxylates as potent and selective 5-HT4 receptor antagonists. López-Rodríguez, M.L., Benhamú, B., Viso, A., Morcillo, M.J., Murcia, M., Orensanz, L., Alfaro, M.J., Martín, M.I. Bioorg. Med. Chem. (1999) [Pubmed]
  26. 5-HT4 receptor antagonism potentiates inhibition of intestinal allodynia by 5-HT3 receptor antagonism in conscious rats. Smith, M.I., Banner, S.E., Sanger, G.J. Neurosci. Lett. (1999) [Pubmed]
  27. 5-Hydroxytryptamine1A and 5-hydroxytryptamine1B receptors stimulate [35S]guanosine-5'-O-(3-thio)triphosphate binding to rodent brain sections as visualized by in vitro autoradiography. Waeber, C., Moskowitz, M.A. Mol. Pharmacol. (1997) [Pubmed]
  28. 5-hydroxytryptamine stimulates glucose transport in cardiomyocytes via a monoamine oxidase-dependent reaction. Fischer, Y., Thomas, J., Kamp, J., Jüngling, E., Rose, H., Carpéné, n.u.l.l., Kammermeier, H. Biochem. J. (1995) [Pubmed]
  29. 5-HT1A and 5-HT4 receptor colocalization on hippocampal pyramidal cells. Roychowdhury, S., Haas, H., Anderson, E.G. Neuropharmacology (1994) [Pubmed]
  30. Modulation of spontaneous firing in rat subthalamic neurons by 5-HT receptor subtypes. Xiang, Z., Wang, L., Kitai, S.T. J. Neurophysiol. (2005) [Pubmed]
  31. Quantitative autoradiography of 5-HT4 receptors in brains of three species using two structurally distinct radioligands, [3H]GR113808 and [3H]BIMU-1. Jakeman, L.B., To, Z.P., Eglen, R.M., Wong, E.H., Bonhaus, D.W. Neuropharmacology (1994) [Pubmed]
  32. Receptor mechanisms involved in the 5-HT-induced inotropic action in the rat isolated atrium. Läer, S., Remmers, F., Scholz, H., Stein, B., Müller, F.U., Neumann, J. Br. J. Pharmacol. (1998) [Pubmed]
  33. Localization of 5-HT4 receptor mRNA in rat brain by in situ hybridization histochemistry. Vilaró, M.T., Cortés, R., Gerald, C., Branchek, T.A., Palacios, J.M., Mengod, G. Brain Res. Mol. Brain Res. (1996) [Pubmed]
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