Studies on the Role of the N-terminal Domain of Nr1 in the Redox Modulation of Nr2a-containing Nmda Receptors

The NMDA receptor is the subject of intense study due to its critical role in many neuronal processes and neuropathologies. This receptor is modulated by a wide variety of endogenous and exogenous agents, including reducing and oxidizing (redox) agents. Despite a wealth of physiological information, details of the structural basis of modulation are only beginning to emerge. It has been proposed that the amino terminal domain (ATD) of NMDA receptor subunits may serve as a modulatory domain, as several agents appear to have sites of action in this region of the receptor. NR1/NR2A receptors contain cysteines in the ATD of both NR1 and NR2 that confer unique redox sensitivity to these receptors; however, the ATD redox sensitivity of NR1/NR2A receptors remains largely unexplored. The goal of this dissertation was to explore the impact of reducing and oxidizing agents on NMDA receptor function, focusing on the amino terminal domain redox sites. Here we demonstrate that a clinically efficacious neuroprotective agent, ebselen, is active as an oxidizing agent of the NMDA receptor. Additionally, these studies demonstrate a novel modulation of NR1/NR2A redox mutants by the polyamine spermine and explore a relationship between redox and spermine modulation of NR1/NR2A mutant receptors. The losing battle she fought against leukemia was the most profound experience of my graduate training. The price that Mom paid in enduring the rigors of chemotherapy and hospitalization in order to grant us a few more months with her was very high indeed. For that I am very deeply grateful. The apostle Paul writes to the Romans (Chapter 5), " Not only so, but we also rejoice in our sufferings, because we know that suffering produces perseverance; perseverance, character; and character, hope. And hope does not disappoint us." Without my mother's loving influence, I could not have developed the tenacity required for undertaking a dissertation. I would also like to thank my father Ken Herin; my brother Greg and his family, Shannon, Jeanene and Katelynn; my grandparents; the ever-faithful and funny Dr. Diek Wheeler; Pittsburgh Mennonite Church; and people that were both obvious and surprising sources of inspiration. The study of the brain is no less than the search for the composition of our souls. Neurobiologists, educators, and social scholars furiously debate the relative importance of nurture versus nature in determining one's abilities. My humble opinion (and that of a few prominent scholars) is that one cannot meaningfully separate talent from …