Format

Send to

Choose Destination
J Biol Chem. 2017 Jun 16;292(24):10153-10168. doi: 10.1074/jbc.M116.743070. Epub 2017 May 5.

Amyloid β production is regulated by β2-adrenergic signaling-mediated post-translational modifications of the ryanodine receptor.

Author information

1
From the Université Côte d'Azur, CNRS, IPMC, France, "Labex Distalz," 660 route des Lucioles, 06560 Sophia-Antipolis, Valbonne, France.
2
INSERM U1046, CNRS UMR9214, CNRS LIA1185, Université de Montpellier, CHRU Montpellier, 34295 Montpellier, France, and.
3
Department of Physiology and Cellular Biophysics, Clyde and Helen Wu Center for Molecular Cardiology, Columbia University College of Physicians and Surgeons, New York, New York 10032.
4
Department of Physiology and Cellular Biophysics, Clyde and Helen Wu Center for Molecular Cardiology, Columbia University College of Physicians and Surgeons, New York, New York 10032 arm42@columbia.edu.
5
From the Université Côte d'Azur, CNRS, IPMC, France, "Labex Distalz," 660 route des Lucioles, 06560 Sophia-Antipolis, Valbonne, France, mchami@ipmc.cnrs.fr.

Abstract

Alteration of ryanodine receptor (RyR)-mediated calcium (Ca2+) signaling has been reported in Alzheimer disease (AD) models. However, the molecular mechanisms underlying altered RyR-mediated intracellular Ca2+ release in AD remain to be fully elucidated. We report here that RyR2 undergoes post-translational modifications (phosphorylation, oxidation, and nitrosylation) in SH-SY5Y neuroblastoma cells expressing the β-amyloid precursor protein (βAPP) harboring the familial double Swedish mutations (APPswe). RyR2 macromolecular complex remodeling, characterized by depletion of the regulatory protein calstabin2, resulted in increased cytosolic Ca2+ levels and mitochondrial oxidative stress. We also report a functional interplay between amyloid β (Aβ), β-adrenergic signaling, and altered Ca2+ signaling via leaky RyR2 channels. Thus, post-translational modifications of RyR occur downstream of Aβ through a β2-adrenergic signaling cascade that activates PKA. RyR2 remodeling in turn enhances βAPP processing. Importantly, pharmacological stabilization of the binding of calstabin2 to RyR2 channels, which prevents Ca2+ leakage, or blocking the β2-adrenergic signaling cascade reduced βAPP processing and the production of Aβ in APPswe-expressing SH-SY5Y cells. We conclude that targeting RyR-mediated Ca2+ leakage may be a therapeutic approach to treat AD.

KEYWORDS:

Alzheimer disease; amyloid precursor protein (APP); amyloid-β (AB); calcium intracellular release; calstabin2; ryanodine receptor; β 2 adrenergic signaling

PMID:
28476886
PMCID:
PMC5473221
DOI:
10.1074/jbc.M116.743070
[Indexed for MEDLINE]
Free PMC Article

Publication types, MeSH terms, Substances, Grant support

Publication types

MeSH terms

Substances

Grant support

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center