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Title page for ETD etd-01102017-105359


Type of Document Dissertation
Author Ramos-Hunter, Susan Joanne
Author's Email Address susan.j.ramos-hunter@vanderbilt.edu
URN etd-01102017-105359
Title Development of Molecular Tools for the Investigation of G protein-gated Inwardly Rectifying Potassium (GIRK) Channels
Degree PhD
Department Chemistry
Advisory Committee
Advisor Name Title
Gary A. Sulikowski Committee Chair
Craig Lindsley Committee Member
David Weaver Committee Member
John McLean Committee Member
Keywords
  • porcine liver esterase
  • fluorophore
  • molecular tools
  • GIRK Channels
  • small molecule probes
Date of Defense 2016-12-16
Availability unrestricted
Abstract
G protein-gated inwardly rectifying potassium (GIRK) ion channels are part of a larger family of inwardly rectifying potassium channels (Kirs) that regulate diverse biological processes. Kirs regulate solute balance in the kidneys, cardiac rates and rhythms, and neuronal excitability. Specifically, dysfunction in GIRKs expressed throughout the central nervous system (CNS) have been linked to schizophrenia, pain perception, drug addiction, and epilepsy. In the heart and adrenal glands, dysfunctional GIRKs have demonstrated arrhythmia phenotypes and have been linked to adrenal carcinoma. The gathering of valuable information on cellular processes, such as the function and regulation of ion channels will benefit greatly from the development of small molecule probes and fluorescent dyes. Recently, we conducted a high-throughput thallium (Tl+) flux assay and identified a series of small molecules that modulate GIRK1-containing GIRK channels. From these compounds, we developed ML297, a diaryl urea with a potency of 160 nM on GIRK1/2 channels. Further structure-activity relationship studies identified remarkably selective GIRK1/4 (heart-localized) inhibitors and selective GIRK1/2 (CNS-localized) activators. Our current efforts are directed towards further increasing the selectivity and potency of our scaffolds. In parallel, we are also interested in latent fluorescent dyes that are selectively activated by exogenous enzymes expressed in GIRK-containing cell lines. This pro-dye/enzyme system would optimize the signal-to-noise ratio of Tl+ flux assays, which we use extensively to study GIRK channels. Our understanding of function and regulation of GIRK channels will improve with better chemically-synthesized products; potent and selective small molecules and improved dyes will guide the therapeutic potential of modulating GIRK channels.
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