Investigation of Some Small Molecule-Protein and Protein-Protein Interactions in Nicotine Addiction, Opioid Use Disorder, and COVID-19

Author: Grant, Stephen Nicholas

Year: 2022

Degree: Dissertation (Ph.D.)

Advisor: Lester, Henry A.

Committee Members: Tirrell, David A.; Barton, Jacqueline K.; Dougherty, Dennis A.; Lester, Henry A.

Option: Chemistry

DOI: 10.7907/pdtj-8238

Abstract

Nicotine addiction, opioid use disorder, and COVID-19 have made lasting impacts on every aspect of society. These are complicated conditions, and studies in these fields will likely continue for decades, if not centuries. Here, we make contributions to each of these issues using electrophysiology and microscopy. The first chapter goes into the motivation behind this thesis and the major experiments I used in my graduate career. In the second chapter, we introduce a new amino acid into the mouse muscle nicotinic acetylcholine receptor in an attempt to understand the dynamics of receptor activation. In the third chapter, we continue the Lester lab’s work on the neuroscientific effects of menthol and how it plays a role in nicotine addiction. We found the binding site for menthol on the α4β2 nicotinic acetylcholine receptor, which continues our hypothesis that the neuroscientific effects of menthol are detrimental to cigarette smokers. Fortunately, partly because of our studies, mentholated nicotine products are being phased out of the United States. The fourth and fifth chapters investigate μ-opioid receptor trafficking, both the trafficking from the endoplasmic reticulum and endocytosis from the plasma membrane. Both of these events play a role in inducing opioid use disorder and increasing the danger of using opioids. We hope that these studies will help other researchers understand opioid use disorder and fight the opioid epidemic. Finally, we studied the effects of SARS-COV-2 proteins on epithelial sodium channels. These channels are important for regulating lung fluid levels where their improper function may cause pulmonary edema. Pulmonary edema has been observed in COVID-19 patients. Altogether, we believe that we have made meaningful impacts on these important health concerns in this thesis. We look forward to how the scientific communities continue to build on our results.

Files