Author ORCID Identifier
0000-0003-2739-8437
Date of Graduation
12-2021
Document Type
Dissertation (PhD)
Program Affiliation
Biochemistry and Molecular Biology
Degree Name
Doctor of Philosophy (PhD)
Advisor/Committee Chair
Vasanthi Jayaraman, PhD
Committee Member
Ruth Heidelberger, MD, PhD
Committee Member
Theresa Koehler, PhD
Committee Member
Ilya Levental, PhD
Committee Member
Irina Serysheva, PhD
Abstract
NMDA receptors are ligand-gated ion channels that mediate a number of physiological and pathological phenomena within the mammalian central nervous system. Under the typical course of activation, these receptors bind to glycine and glutamate molecules and undergo a series of conformational changes that results in the opening of a cation-permeable pore in the neuronal plasma membrane. Various aspects of NMDA receptor function are not fully understood, including the phenomenon of negative cooperativity between the glycine- and glutamate-binding sites of the receptor and the mechanism controlling partial agonism. Past studies utilizing static structural snapshots of the receptor or isolated domains of the receptor have provided insufficient insights to fully understand these issues. Herein, I have conducted Förster Resonance Energy Transfer measurements on individual NMDA receptor molecules to observe their conformational landscape under various conditions. These studies have revealed changes in conformation of the receptor that underlie negative cooperativity and partial agonism, thereby affording new insights into the mechanisms controlling these processes.
Keywords
NMDA Receptor, Glutamate Receptors, smFRET, FRET, Allostery, Single-Molecule Methods