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    Phosphorylation-Dependent Regulation of Connexion 37-Mediated Vascular Growth and Remodeling

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    Author
    Jacobsen, Nicole L.
    Issue Date
    2017
    Advisor
    Burt, Janis M.
    
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    Publisher
    The University of Arizona.
    Rights
    Copyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.
    Abstract
    Gap junction channels (GJChs) support the coordination of vascular responses required for the control of normal vascular function by providing a pathway for intercellular diffusion of ions and small molecules. Made of connexin proteins, dysregulation (changes in expression, localization, and function) of gap junction channels or hemichannels (HChs) contribute to and/or exacerbate vascular disease. Specifically, Cx37 is enriched at endothelial cell borders under laminar flow conditions, but is downregulated in regions of oscillatory shear stress, like that occurring downstream of an atherosclerotic plaque. We showed that Cx37 limits vasculogenesis and ischemia-induced angiogenesis, likely by reducing proliferation and enhancing cell death of endothelial cells. Moreover, these Cx37-mediated growth effects require a functional pore-forming domain and the presence of its own carboxyl-terminus (CT). As phosphorylation has been shown to influence channel conductance and growth regulatory properties of other connexins, we hypothesized that differential phosphorylation of the Cx37 carboxyl-terminus regulates channel function and its growth effects. Using alanine (or phenylalanine) and aspartate substitutions to mimic dephosphorylated or phosphorylated amino acid residues, respectively, we show herein that Cx37 may serve as a molecular switch that contributes to cell fate decisions (quiescence versus cell cycle progression and cell death) in a phosphorylation-dependent manner. Moreover, Cx37 GJCh and HCh function is modulated by site-specific phosphorylation within the CT. While channel function is necessary for Cx37-mediated growth effects, it appears that protein-protein interactions (rather than channel-dependent functions) with phosphorylation-specific conformations of Cx37 and growth regulatory elements determine growth phenotype.
    Type
    text
    Electronic Dissertation
    Degree Name
    Ph.D.
    Degree Level
    doctoral
    Degree Program
    Graduate College
    Physiological Sciences
    Degree Grantor
    University of Arizona
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