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    Modulation of neuronal ryanodine receptor-mediated calcium signaling by calsenilin

    Grillo, Michael Anthony
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    [PDF] Modulation of neuronal ryanodine receptor-mediated calcium signaling by calsenilin (3.316Mb)
    Date
    2013
    Format
    Thesis
    Metadata
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    Abstract
    Calsenilin is calcium (Ca2+) ion Ca2+ binding protein found in the nucleus, plasma membrane, and endoplasmic reticulum of neuronal cells. Calsenilin was first found to interact with two proteins involved in early-onset familial Alzheimer disease (AD), presenilin 1 and presenilin 2. Several studies have shown overexpression of calsenilin to alter Ca2+ signaling and cell viability in several neuronal cell models of AD. In this study, we show that calsenilin directly interacts with the ryanodine receptor (RyR) modulating Ca2+ release from this intracellular Ca2+-activated Ca2+ release channel. Co-expression, co-localization, and protein-protein interaction of calsenilin and RyR in primary neurons and in central nervous system tissue were determined using immunoblotting, immunohistochemistry and co-immunoprecipitation. Mechanisms of intracellular Ca2+- signaling controlled by the interaction of calsenilin and RyR, including changes in the release of Ca2+ from intracellular stores, were measured with single channel electrophysiology and live-cell optical imaging techniques. Immunohistochemical studies showed a high degree of co-localization between calsenilin and the RyR in neurons of the central nervous system. Additionally, iv successful immunoprecipitation of a RyR-calsenilin protein complex from brain tissue provided evidence of a functional interaction. Using electrophysiological and Ca2+ imaging techniques the modulatory effects of calsenilin on Ca2+ release in a single RyR channel or in a cellular system with a population of RyR channels, respectively, whereby RyR-mediated intracellular Ca2+ release by calsenilin was determined under physiological and pathophysiological intracellular Ca2+ concentrations. Calsenilin directly interacts with the RyR, modulating Ca2+ induced Ca2+ release (CICR) pathways in neuronal cells. Further characterization of this interaction and its pharmacological and molecular biological control could provide insight into altered Ca2+ signaling in neurodegenerative and other diseases controlled by CICR and aid in developing novel alternative therapies using these newly identified mechanisms as targets.
    Table of Contents
    Introduction -- Materials and methods -- Results -- Discussion -- References -- Vita
    URI
    https://hdl.handle.net/10355/45498
    Degree
    Ph.D.
    Thesis Department
    Cell Biology and Biophysics (UMKC)
     
    Molecular Biology and Biochemistry (UMKC)
     
    Collections
    • Cell Biology and Biophysics Electronic Theses and Dissertations (UMKC)
    • Molecular Biology and Biochemistry Electronic Theses and Dissertations (UMKC)
    • 2013 UMKC Dissertations - Freely Available Online

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