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dc.contributor.authorDemmerly, Arianna L.
dc.date.accessioned2017-02-07T23:19:53Z
dc.date.available2017-02-07T23:19:53Z
dc.date.issued2016-12
dc.identifier.urihttp://hdl.handle.net/11122/7290
dc.descriptionThesis (Ph.D.) University of Alaska Fairbanks, 2016en_US
dc.description.abstractInappropriate expression of nicotinic acetylcholine receptors in the central nervous system is associated with nicotine addiction, Alzheimer's disease, Parkinson's disease and other disorders. Modulators (drugs) have the potential to restore circuit properties that arise from inappropriate expression of nicotinic receptor's. Compounds that interact with allosteric sites have a distinct advantage over agonists and partial agonists, in that, they retain normal activation patterns by allowing binding of the endogenous ligand. Positive allosteric modulators boost the receptors ability to respond to agonist. Studies of these modulators constitute a first step toward the identification and development of better compounds that minimize signaling errors at cholinergic synapses. We have used single molecule methods to investigate the action of a novel positive allosteric modulator, desformylflustrabromine (dFBr), on nicotinic receptors. Our studies were focused on the α4β2 subtype of nicotinic receptors in the brain. These receptors exist in two forms with low sensitivity (α4₃β2₂) or, alternatively, high sensitivity (α4₂β2₃) to agonist. Our experiments allowed us to develop detailed gating models for high and low sensitivity receptors, as well as gain new insights regarding the mechanisms that underlie potentiation by allosteric modulators. We found that dFBr potentiates low sensitivity receptors by destabilizing desensitized states of the receptor. In contrast, potentiation of high sensitivity receptors arises from a synchronization of openings following an application of agonist due to an increase in the opening rate. Based on our results we now have a better understanding of the advantages of dFBr on high and low sensitivity receptors.en_US
dc.language.isoen_USen_US
dc.titleMechanisms of modulation of nicotinic acetylcholine receptorsen_US
dc.typeThesisen_US
dc.type.degreephden_US
dc.identifier.departmentDepartment of Chemistryen_US
dc.contributor.chairEdmonds, Brian
dc.contributor.committeeSchulte, Marvin
dc.contributor.committeeDunlap, Kriya
dc.contributor.committeeKuhn, Thomas
refterms.dateFOA2020-03-05T12:06:30Z


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