dc.creator | Kozek, Krystian Andrzej | |
dc.date.accessioned | 2020-08-24T11:53:24Z | |
dc.date.available | 2020-10-16 | |
dc.date.issued | 2018-10-16 | |
dc.identifier.uri | https://etd.library.vanderbilt.edu/etd-10162018-095738 | |
dc.identifier.uri | http://hdl.handle.net/1803/15526 | |
dc.description.abstract | G protein-gated, inwardly-rectifying, potassium (K+) (GIRK) channels are important regulators of cellular excitability throughout the body. GIRK channels are composed of four subunits and exist as homomeric and heteromeric channels. Although the vast majority of neuronally-expressed GIRK channels contain GIRK1, GIRK2, and GIRK3 subunits, a discrete population of dopaminergic neurons in the ventral tegmental area do not express GIRK1. Selectively targeting GIRK channels with subunit-selective pharmacological probes may improve our understanding of the role of GIRK channels in reward and addiction circuitry. In an effort to discover activators of GIRK2 channels, we conducted a 100,000-compound high-throughput screen and discovered that VU0529331 activated GIRK2 channels. We learned that VU0529331 increased currents through GIRK1/2 and GIRK2 channels in a concentration-dependent manner without altering K+ selectivity or inward rectification. We established that VU0529331 activity was independent of Gi/o protein-coupled receptor signaling and discovered that VU0529331 also activated homomeric GIRK4, Kir6.1/SUR2a, and Kir6.1/SUR2b channels. VU0529331 is the first reported synthetic small molecule known to activate heteromeric and homomeric GIRK channels. Going forward, this molecule establishes a foundation on which more efficacious and potent analogs can be generated. Together with known GIRK modulators, VU0529331 will enable the investigation of specific GIRK channel roles throughout physiology and disease. | |
dc.format.mimetype | application/pdf | |
dc.subject | Kir3 | |
dc.subject | drug discovery | |
dc.subject | pharmacology | |
dc.subject | electrophysiology | |
dc.subject | channel | |
dc.subject | potassium | |
dc.subject | thallium flux | |
dc.subject | high-throughput screen | |
dc.subject | Kir | |
dc.subject | GIRK | |
dc.subject | ion channel | |
dc.title | Discovery and characterization of G protein-gated, inwardly-rectifying, potassium channel modulators | |
dc.type | dissertation | |
dc.contributor.committeeMember | Charles C. Hong | |
dc.contributor.committeeMember | Danny G. Winder | |
dc.contributor.committeeMember | Corey R. Hopkins | |
dc.contributor.committeeMember | C. David Weaver | |
dc.type.material | text | |
thesis.degree.name | PHD | |
thesis.degree.level | dissertation | |
thesis.degree.discipline | Pharmacology | |
thesis.degree.grantor | Vanderbilt University | |
local.embargo.terms | 2020-10-16 | |
local.embargo.lift | 2020-10-16 | |
dc.contributor.committeeChair | Jerod S. Denton | |