Regulation of the amyloid precursor protein ectodomain shedding by the 5-HT4 receptor and Epac

FEBS Lett. 2005 Feb 14;579(5):1136-42. doi: 10.1016/j.febslet.2005.01.010.


The serotonin 5-hydroxytryptamine (5-HT4) receptor is of potential interest for the treatment of Alzheimer's disease because it increases memory and learning. In this study, we investigated the effect of zinc metalloprotease inhibitors on the amyloid precursor protein (APP) processing induced by the serotonin 5-HT4 receptor in vitro. We show that secretion of the non-amyloidogenic form of APP, sAPPalpha induced by the 5-HT4(e) receptor isoform was not due to a general boost of the constitutive secretory pathway but rather to its specific effect on alpha-secretase activity. Although the h5-HT4(e) receptor increased IP3 production, inhibition of PKC did not modify its effect on sAPPalpha secretion. In addition, we found that alpha secretase activity is regulated by the cAMP-regulated guanine nucleotide exchange factor, Epac and the small GTPase Rac.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyloid beta-Protein Precursor / chemistry*
  • Amyloid beta-Protein Precursor / metabolism*
  • Animals
  • Cell Line
  • Cricetinae
  • Guanine Nucleotide Exchange Factors / metabolism*
  • Humans
  • Inositol 1,4,5-Trisphosphate / metabolism
  • Metalloproteases / antagonists & inhibitors
  • Metalloproteases / metabolism
  • Receptors, Serotonin, 5-HT4 / metabolism*
  • Serotonin 5-HT4 Receptor Antagonists
  • Zinc / pharmacology


  • Amyloid beta-Protein Precursor
  • Guanine Nucleotide Exchange Factors
  • Serotonin 5-HT4 Receptor Antagonists
  • Receptors, Serotonin, 5-HT4
  • Inositol 1,4,5-Trisphosphate
  • Metalloproteases
  • Zinc