Involvement of 5-HT₃ and 5-HT₄ receptors in the regulation of circadian clock gene expression in mouse small intestine

J Pharmacol Sci. 2014;124(2):267-75. doi: 10.1254/jphs.13253fp. Epub 2014 Feb 4.


Several lines of evidence suggest that 5-HT receptors play a critical role in the expression of clock genes in the suprachiasmatic nucleus, the main circadian oscillator in hamsters. The contributions of 5-HT-receptor subtypes in the intestine, where they are expressed at high concentrations, are however not yet clarified. The 5-HT synthesis inhibitor, p-chlorophenylalanine, attenuated the daily rhythm of Per1 and Per2 gene expression in the intestine. Injection of 5-HT and agonists of the 5-HT3 and 5-HT4 receptors increased Per1/Per2 expression and decreased Bmal1 expression in a dose-dependent manner. Although treatment with antagonists of 5-HT3 and 5-HT4 alone did not affect clock gene expression, co-injection of these antagonists with 5-HT blocked the 5-HT-induced changes in clock gene expression. Increased tissue levels of 5-HT due to treatment with the antidepressants clomipramine and fluvoxamine did not affect clock gene expression. The present results suggest that the 5-HT system in the small intestine may play a critical role in regulating circadian rhythms through 5-HT3/5-HT4-receptor activation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ARNTL Transcription Factors / genetics*
  • ARNTL Transcription Factors / metabolism*
  • Animals
  • Circadian Clocks / genetics*
  • Cricetinae
  • Dose-Response Relationship, Drug
  • Gene Expression / genetics*
  • Intestine, Small / metabolism*
  • Male
  • Mice
  • Mice, Inbred ICR
  • Period Circadian Proteins / genetics*
  • Period Circadian Proteins / metabolism*
  • Receptors, Serotonin, 5-HT3 / metabolism
  • Receptors, Serotonin, 5-HT3 / physiology*
  • Receptors, Serotonin, 5-HT4 / metabolism
  • Receptors, Serotonin, 5-HT4 / physiology*
  • Serotonin / physiology
  • Serotonin 5-HT3 Receptor Agonists / pharmacology
  • Serotonin 5-HT4 Receptor Agonists / pharmacology


  • ARNTL Transcription Factors
  • Arntl protein, mouse
  • Per1 protein, mouse
  • Per2 protein, mouse
  • Period Circadian Proteins
  • Receptors, Serotonin, 5-HT3
  • Serotonin 5-HT3 Receptor Agonists
  • Serotonin 5-HT4 Receptor Agonists
  • Receptors, Serotonin, 5-HT4
  • Serotonin