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

被引：46

作者：

Robert, S

Maillet, M

Morel, E

Launay, JM

Fischmeister, R

Mercken, L

Lezoualc'h, F

机构：

[1] Fac Pharm Chatenay Malabry, Lab Cardiol Cellulaire & Mol, INSERM, U446, F-92296 Chatenay Malabry, France

[2] Univ Paris Sud, Fac Pharm, Neuropharmacol Lab, EA3544,IFR 75, F-92296 Chatenay Malabry, France

[3] Hop Lariboisiere, Serv Biochim & Biol Mol, EA 3621, F-75475 Paris, France

[4] Aventis Pharma, Neurodegenerat Dis Grp, Vitry Sur Seine, France

来源：

FEBS LETTERS | 2005年 / 579卷 / 05期

关键词：

serotonin; Alzheimer's disease; amyloid; small G protein; cAMP; G protein-coupled receptor;

D O I：

10.1016/j.febslet.2005.01.010

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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 a-secretase activity. Although the hs-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. (C) 2005 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

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页码：1136 / 1142

页数：7

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