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.
© 2017 by The American Society for Biochemistry and Molecular Biology, Inc.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adrenergic beta-2 Receptor Antagonists / pharmacology
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Alzheimer Disease / enzymology
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Alzheimer Disease / genetics
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Alzheimer Disease / metabolism
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Alzheimer Disease / pathology
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Amyloid beta-Peptides / genetics
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Amyloid beta-Peptides / metabolism*
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Amyloid beta-Protein Precursor / genetics
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Amyloid beta-Protein Precursor / metabolism
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Calcium Signaling* / drug effects
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Cell Line, Tumor
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Cyclic AMP-Dependent Protein Kinases / chemistry
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Cyclic AMP-Dependent Protein Kinases / metabolism
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Enzyme Activation / drug effects
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Humans
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Mutation
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Nerve Tissue Proteins / agonists
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Nerve Tissue Proteins / chemistry
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Nerve Tissue Proteins / genetics
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Nerve Tissue Proteins / metabolism
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Neurons / drug effects
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Neurons / enzymology*
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Neurons / metabolism
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Neurons / pathology
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Oxidation-Reduction
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Oxidative Stress / drug effects
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Phosphorylation / drug effects
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Protein Multimerization / drug effects
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Protein Processing, Post-Translational* / drug effects
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Proteolysis / drug effects
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Receptors, Adrenergic, beta-2 / chemistry
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Receptors, Adrenergic, beta-2 / genetics
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Receptors, Adrenergic, beta-2 / metabolism*
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Recombinant Proteins / chemistry
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Recombinant Proteins / metabolism
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Ryanodine Receptor Calcium Release Channel / chemistry
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Ryanodine Receptor Calcium Release Channel / metabolism*
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Tacrolimus Binding Proteins / antagonists & inhibitors
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Tacrolimus Binding Proteins / metabolism
Substances
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ADRB2 protein, human
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APP protein, human
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Adrenergic beta-2 Receptor Antagonists
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Amyloid beta-Peptides
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Amyloid beta-Protein Precursor
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Nerve Tissue Proteins
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Receptors, Adrenergic, beta-2
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Recombinant Proteins
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RyR2 protein, human
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Ryanodine Receptor Calcium Release Channel
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Cyclic AMP-Dependent Protein Kinases
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Tacrolimus Binding Proteins
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tacrolimus binding protein 1B