Functional Evaluation and Development of Novel Agonists and Modulators of Neuronal Ion Channels

<p>This dissertation describes studies of activation of neuronal ion channels and evaluating new ligands to modulate this process. In chapter two, we expanded the binding model of cytisine to the α4β2 nicotinic acetylcholine receptor. We also determined how C(10)-modification of cytisine impac...

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Main Author: Blom, Antoinette Elisabeth Maria
Format: Others
Language:en
Published: 2019
Online Access:https://thesis.library.caltech.edu/11716/1/AEM_Blom_2019_0530_Full_Thesis.pdf
Blom, Antoinette Elisabeth Maria (2019) Functional Evaluation and Development of Novel Agonists and Modulators of Neuronal Ion Channels. Dissertation (Ph.D.), California Institute of Technology. doi:10.7907/RG56-G044. https://resolver.caltech.edu/CaltechTHESIS:06072019-145818414 <https://resolver.caltech.edu/CaltechTHESIS:06072019-145818414>
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spelling ndltd-CALTECH-oai-thesis.library.caltech.edu-117162021-05-26T05:01:28Z https://thesis.library.caltech.edu/11716/ Functional Evaluation and Development of Novel Agonists and Modulators of Neuronal Ion Channels Blom, Antoinette Elisabeth Maria <p>This dissertation describes studies of activation of neuronal ion channels and evaluating new ligands to modulate this process. In chapter two, we expanded the binding model of cytisine to the α4β2 nicotinic acetylcholine receptor. We also determined how C(10)-modification of cytisine impacts the key binding interactions between cytisine and its binding site. To achieve this, we used non-canonical amino acid mutagenesis to probe the electrostatic binding interactions of a novel series of C(10)-cytisine derivatives. In order to perform similar studies in the α3β4 nAChR subtype, we describe the heterologous expression of mouse and human α3β4 nAChRs in Xenopus Laevis oocytes in appendix one. Chapter three describes the development and functional evaluation of a novel series of pyrrolidinoindolines for agonism and modulation of the GABAA receptor. Additionally, we performed mutagenesis studies to identify the binding site of these novel ligands. Appendix two describes a different screen for activation or modulation of GABA<sub>A</sub> receptors using a set of phenolic compounds implicated in Autism Spectrum Disorder. Chapter four shifts focus to voltage-gated ion channels: in this chapter, the ultimate goal was to photochemically control the activation of VGSCs and make progress towards developing a RubpyC17-based photoswitch that could be used in an artificial retina. To this end, we determined the functional effects of several ruthenium bipyridine analogs on voltage-gated sodium and potassium channels.</p> 2019 Thesis NonPeerReviewed application/pdf en other https://thesis.library.caltech.edu/11716/1/AEM_Blom_2019_0530_Full_Thesis.pdf Blom, Antoinette Elisabeth Maria (2019) Functional Evaluation and Development of Novel Agonists and Modulators of Neuronal Ion Channels. Dissertation (Ph.D.), California Institute of Technology. doi:10.7907/RG56-G044. https://resolver.caltech.edu/CaltechTHESIS:06072019-145818414 <https://resolver.caltech.edu/CaltechTHESIS:06072019-145818414> https://resolver.caltech.edu/CaltechTHESIS:06072019-145818414 CaltechTHESIS:06072019-145818414 10.7907/RG56-G044
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language en
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description <p>This dissertation describes studies of activation of neuronal ion channels and evaluating new ligands to modulate this process. In chapter two, we expanded the binding model of cytisine to the α4β2 nicotinic acetylcholine receptor. We also determined how C(10)-modification of cytisine impacts the key binding interactions between cytisine and its binding site. To achieve this, we used non-canonical amino acid mutagenesis to probe the electrostatic binding interactions of a novel series of C(10)-cytisine derivatives. In order to perform similar studies in the α3β4 nAChR subtype, we describe the heterologous expression of mouse and human α3β4 nAChRs in Xenopus Laevis oocytes in appendix one. Chapter three describes the development and functional evaluation of a novel series of pyrrolidinoindolines for agonism and modulation of the GABAA receptor. Additionally, we performed mutagenesis studies to identify the binding site of these novel ligands. Appendix two describes a different screen for activation or modulation of GABA<sub>A</sub> receptors using a set of phenolic compounds implicated in Autism Spectrum Disorder. Chapter four shifts focus to voltage-gated ion channels: in this chapter, the ultimate goal was to photochemically control the activation of VGSCs and make progress towards developing a RubpyC17-based photoswitch that could be used in an artificial retina. To this end, we determined the functional effects of several ruthenium bipyridine analogs on voltage-gated sodium and potassium channels.</p>
author Blom, Antoinette Elisabeth Maria
spellingShingle Blom, Antoinette Elisabeth Maria
Functional Evaluation and Development of Novel Agonists and Modulators of Neuronal Ion Channels
author_facet Blom, Antoinette Elisabeth Maria
author_sort Blom, Antoinette Elisabeth Maria
title Functional Evaluation and Development of Novel Agonists and Modulators of Neuronal Ion Channels
title_short Functional Evaluation and Development of Novel Agonists and Modulators of Neuronal Ion Channels
title_full Functional Evaluation and Development of Novel Agonists and Modulators of Neuronal Ion Channels
title_fullStr Functional Evaluation and Development of Novel Agonists and Modulators of Neuronal Ion Channels
title_full_unstemmed Functional Evaluation and Development of Novel Agonists and Modulators of Neuronal Ion Channels
title_sort functional evaluation and development of novel agonists and modulators of neuronal ion channels
publishDate 2019
url https://thesis.library.caltech.edu/11716/1/AEM_Blom_2019_0530_Full_Thesis.pdf
Blom, Antoinette Elisabeth Maria (2019) Functional Evaluation and Development of Novel Agonists and Modulators of Neuronal Ion Channels. Dissertation (Ph.D.), California Institute of Technology. doi:10.7907/RG56-G044. https://resolver.caltech.edu/CaltechTHESIS:06072019-145818414 <https://resolver.caltech.edu/CaltechTHESIS:06072019-145818414>
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