• About
    • Login
    View Item 
    •   Institutional Repository Home
    • Electronic Theses and Dissertations
    • Electronic Theses and Dissertations
    • View Item
    •   Institutional Repository Home
    • Electronic Theses and Dissertations
    • Electronic Theses and Dissertations
    • View Item
    JavaScript is disabled for your browser. Some features of this site may not work without it.

    Browse

    All of Institutional RepositoryCommunities & CollectionsBy Issue DateAuthorsTitlesSubjectsDepartmentThis CollectionBy Issue DateAuthorsTitlesSubjectsDepartment

    My Account

    LoginRegister

    Identifying the role of TALK-1 channels in islet hormone secretion, mitochondrial function, and the ER stress response.

    Graff, Sarah M
    0000-0003-0419-4706
    : http://hdl.handle.net/1803/16758
    : 2021-06-14

    Abstract

    The two-pore domain K+ channel, TALK-1 modulates pancreatic β- and δ-cell Ca2+ ([Ca2+]c) entry and endoplasmic reticulum (ER) Ca2+ ([Ca2+]ER) handling thereby impacting hormone secretion and glucose tolerance. To investigate the cell specific mechanisms of TALK-1 we selectively ablated TALK-1 in β-cells (β-TALK1-KO) or δ-cells (δ-TALK1-KO). Although β-TALK1-KO mice show normal glucose tolerance on a chow diet, following exposure to a high-fat-diet (HFD) β-TALK1-KO mice showed improved glucose tolerance compared to controls. In contrast, δ-TALK1-KO mice did not show any changes in glucose tolerance but had improved fasting blood glucose levels on a HFD. Interestingly, β-TALK1-KO mice on a HFD had lower serum insulin levels compared to controls that was due to reduced islet glucose-stimulated insulin secretion (GSIS). This suggests that -cell TALK-1 channels control of GSIS may influence tissue insulin signaling or sensitivity. We next determined how TALK-1 control of [Ca2+]c handling impacts mitochondrial function. β-TALK1-KO islets have significantly increased [Ca2+]c oscillation frequency and greater [Ca2+]mito, which may result from either elevated [Ca2+]c or increased [Ca2+]ER storage. Ablation of β-cell TALK-1 also caused mitochondrial hyperpolarization and increased ATP production that could not be further enhanced following exposure to a HFD, which suggests that TALK-1 activity tunes beta-cell metabolism. As loss of TALK-1 function improves -cell function, a gain-of-function (GOF) in TALK-1 would be predicted to impair GSIS. To test this, we examined a dominant mutation in TALK-1(L114P), associated with maturity onset diabetes of the young. TALK-1-L114P results in a drastic GOF at the plasma membrane, hyperpolarizing the -cell membrane potential, limiting [Ca2+]c influx, reducing [Ca2+]ER storage, and inhibiting islet GSIS. We also examined a recessive mutation TALK-1(R13Q) that was associated with neonatal diabetes. Interestingly, in contrast to TALK-1(L114P), TALK-1(R13Q) abolished K+ currents at the plasma membrane possibly by limiting TALK-1 trafficking to the membrane. However, TALK-1(R13Q) maintained current on the ER membrane, reduced [Ca2+]ER storage, blunted β-cell glucose-stimulated [Ca2+]c influx, and limited GSIS. As these mutations in TALK-1 activity severely impact -cell function, this suggests that TALK-1 could be a therapeutic target for treating diabetes.
    Show full item record

    Files in this item

    Icon
    Name:
    GRAFF-DISSERTATION-2021.pdf
    Size:
    1.950Mb
    Format:
    PDF
    View/Open

    This item appears in the following collection(s):

    • Electronic Theses and Dissertations

    Connect with Vanderbilt Libraries

    Your Vanderbilt

    • Alumni
    • Current Students
    • Faculty & Staff
    • International Students
    • Media
    • Parents & Family
    • Prospective Students
    • Researchers
    • Sports Fans
    • Visitors & Neighbors

    Support the Jean and Alexander Heard Libraries

    Support the Library...Give Now

    Gifts to the Libraries support the learning and research needs of the entire Vanderbilt community. Learn more about giving to the Libraries.

    Become a Friend of the Libraries

    Quick Links

    • Hours
    • About
    • Employment
    • Staff Directory
    • Accessibility Services
    • Contact
    • Vanderbilt Home
    • Privacy Policy