Regulation of the amyloid precursor protein ectodomain shedding by the 5-HT4 receptor and Epac.
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.
Robert
Sylvain
S
Laboratoire de Cardiologie Cellulaire et Moléculaire, INSERM U-446, Faculté de Pharmacie, 5 rue J.-B. Clement, F-92296 Chatenay-Malabry, France.
Maillet
Marjorie
M
Morel
Eric
E
Launay
Jean-Marie
JM
Fischmeister
Rodolphe
R
Mercken
Luc
L
Lezoualc'h
Frank
F
D016564:Amyloid beta-Protein Precursor / Q000737:chemistry* / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D006224:Cricetinae; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism*; D006801:Humans; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism; D045726:Metalloproteases / Q000037:antagonists & inhibitors / Q000378:metabolism; D044422:Receptors, Serotonin, 5-HT4 / Q000378:metabolism*; D058832:Serotonin 5-HT4 Receptor Antagonists; D015032:Zinc / Q000494:pharmacology
D016564:Amyloid beta-Protein Precursor; D020662:Guanine Nucleotide Exchange Factors; D058832:Serotonin 5-HT4 Receptor Antagonists; D044422:Receptors, Serotonin, 5-HT4; D015544:Inositol 1,4,5-Trisphosphate; D045726:Metalloproteases; D015032:Zinc