Phillips, Matthew B
(2021)
Regulation of NMDA Receptor channel block and desensitization by intracellular calcium.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
N-methyl-D-aspartate receptors (NMDARs) are ligand-gated ion channels found at nearly all vertebrate excitatory synapses that contribute to a multitude of nervous system functions. Unique biophysical properties, including high Ca2+ permeability, voltage-dependent Mg2+ block, and slow gating kinetics, allow NMDARs to control the magnitude and timing of Ca2+ influx following synaptic events. Ca2+ influx through NMDARs drives an array of signaling pathways that regulate critical neuronal functions such as synaptic plasticity and cell survival. Abnormal NMDAR activity is involved in a remarkable range of nervous system disorders including schizophrenia, major depressive disorder, stroke, neuropathic pain, and neurodegenerative diseases. Specifically, NMDAR overactivation can lead to accumulation of toxic levels of Ca2+¬¬¬ that initate cell death signaling pathways. Because of the core involvement of NMDARs in normal brain physiology as well as brain pathologies, NMDARs are attractive targets for neurotherapeutic drugs. The NMDAR channel blocker memantine, a clinically approved treatment for Alzheimer’s disease, displays a combination of clinical utility and tolerability unique amongst NMDAR antagonists. We recently discovered that memantine enhances NMDAR desensitization by stabilizing a Ca2+-dependent desensitized receptor state. Stabilization of a Ca2+-dependent state by memantine offers a rational mechanism by which memantine can target specific NMDAR subpopulations involved in disease: preferential inhibition of NMDARs in neurons experiencing long durations of high Ca2+ influx. Therefore, we systematically investigated the relation between channel blocker potency, intracellular Ca2+ concentration ([Ca2+]i, and NMDAR desensitization. We found that while potency of memantine depended on [Ca2+]i, the potency of another clinically useful channel blocker, ketamine, was [Ca2+]i-independent. Utilizing this discrepancy, we compared the memantine and ketamine binding sites and identified a residue in the NMDAR transmembrane domain that strongly contributes to NMDAR desensitization and memantine potency. Lastly, we characterized novel NMDAR channel blockers and discovered that potency of a memantine derivative was also dependent on [Ca2+]i. The data presented in this dissertation provide key insight into how [Ca2+]i affects channel blocker activity and NMDAR desensitization, and ultimately improve our understanding of the structural and functional mechanisms underlying the effects of channel blocking drugs on NMDAR function.
Share
| Citation/Export: |
|
| Social Networking: |
|
Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
|
| Date: |
8 October 2021 |
| Date Type: |
Publication |
| Defense Date: |
6 July 2021 |
| Approval Date: |
8 October 2021 |
| Submission Date: |
21 July 2021 |
| Access Restriction: |
No restriction; Release the ETD for access worldwide immediately. |
| Number of Pages: |
247 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
Dietrich School of Arts and Sciences > Neuroscience |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
neuroscience, NMDA, ion channel, pharmacology, memantine, ketamine, channel block, calcium |
| Date Deposited: |
08 Oct 2021 19:22 |
| Last Modified: |
08 Oct 2021 19:22 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/41449 |
Metrics
Monthly Views for the past 3 years
Plum Analytics
Actions (login required)
 |
View Item |
![[feed]](/images/feed-icon-32x32.png){kind=icon}