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.
| Identifer | oai:union.ndltd.org:VANDERBILT/oai:VANDERBILTETD:etd-01102017-105359 |
| Date | 03 February 2017 |
| Creators | Ramos-Hunter, Susan Joanne |
| Contributors | Gary A. Sulikowski, David Weaver, John McLean, Craig Lindsley, Gary A. Sulikowski, David Weaver, John McLean, Craig Lindsley |
| Publisher | VANDERBILT |
| Source Sets | Vanderbilt University Theses |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.vanderbilt.edu/available/etd-01102017-105359/ |
| Rights | unrestricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to Vanderbilt University or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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