• Login as Editor
    View Item 
    •   Yeshiva Academic Institutional Repository
    • Albert Einstein College of Medicine (AECOM)
    • Albert Einstein College of Medicine: Doctoral Dissertations
    • View Item
    •   Yeshiva Academic Institutional Repository
    • Albert Einstein College of Medicine (AECOM)
    • Albert Einstein College of Medicine: Doctoral Dissertations
    • View Item
    JavaScript is disabled for your browser. Some features of this site may not work without it.

    Role of calcineurin Abeta phosphatase in beta-adrenergic signaling and function

    Thumbnail

    Date
    2008
    Author
    Suk, Hee Yun
    Metadata
    Show full item record
    Share
    Abstract
    The beta-adrenergic receptors (betaAR) are a large family of the G-protein coupled receptors which regulate a broad spectrum of physiological responses including the sympathetic and the parasympathetic nervous system. Upon activation by ligands, beta-adrenergic receptors which are coupled to G&agr;s, activate adenylyl cyclase to produce cyclic AMP (cAMP). Since cAMP regulates many cellular functions, its regulation is a balance between production and degradation. Degradation of cAMP is catalyzed by 3'S'-cyclic nucleotide phosphodiesterases (PDEs). Compartmentalization and localization of PDEs are, in part, regulated by phosphorylation and interaction with beta-arrestin.;Calcineurin is a serine/threonine protein phosphatase that is activated upon a sustained increase in calcium. Calcineurin holoenzyme consists of a catalytic A subunit, a regulatory B subunit, and calmodulin. Calcineurin has been localized to the cytosol, the nucleus, and the plasma membrane. The most well known substrate of calcineurin is transcription factor Nuclear Factor of Activated T-cells. The role of calcineurin at the plasma membrane, however, remains elusive.;In this study, I explored a novel role of calcineurin in beta-adrenergic signaling. I hypothesize that calcineurin Abeta contributes to beta-adrenergic signaling via regulation of PDE. I found that mouse embryonic fibroblasts from calcineurin Abeta null (CnAbeta-/-) mice exhibit potentiated cAMP levels and reduced PDE activity upon beta-adrenergic stimulation. Membrane fractionation studies demonstrated that calcineurin contributes to potentiated membrane recruitment of beta-arrestin and PDE4D. These data indicate that the loss of calcineurin results in increased cAMP accumulation and decreased PDE activity that is, in part, due to reduced membrane localization of beta arrestin and PDE4D.;Functionally, increased cAMP accumulation potentiates beta-adrenergic signaling's physiological response. I found that beta-adrenergic stimulation via fasting and with beta3AR agonist, CL316,243, increased lipolysis and accumulation of free fatty acids and triglycerides. In the heart, stimulation of beta-adrenergic receptors with general betaAR agonist, isoproterenol led to temporary hypotension. Duration of hypotension was potentiated in CnAbeta-/- mice. These in vivo studies demonstrate that the loss of calcineurin Abeta in mice results in increased beta-adrenergic signaling response.;In summary, I show that ablation of CnAbeta results in enhanced beta-adrenergic signaling leading to dysregulation of many physiological functions.
    Permanent Link(s)
    https://ezproxy.yu.edu/login?url=http://gateway.proquest.com/openurl?url_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation&res_dat=xri:pqm&rft_dat=xri:pqdiss:3304646
    https://hdl.handle.net/20.500.12202/964
    Citation
    Source: Dissertation Abstracts International, Volume: 69-03, Section: B, page: 1475.;Advisors: Chi-Wing Chow.
    *This is constructed from limited available data and may be imprecise.
    Collections
    • Albert Einstein College of Medicine: Doctoral Dissertations [1674]

    Yeshiva University Libraries copyright © 2021  DuraSpace
    YAIR Self-Deposit | YAIR User's Guide | Take Down Policy | Contact Us
    Yeshiva University
     

     

    Browse

    AllCommunities & CollectionsBy Issue DateAuthorsTitlesSubjectsThis CollectionBy Issue DateAuthorsTitlesSubjects

    My Account

    Login as Editor

    Statistics

    View Usage Statistics

    Yeshiva University Libraries copyright © 2021  DuraSpace
    YAIR Self-Deposit | YAIR User's Guide | Take Down Policy | Contact Us
    Yeshiva University