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Regulation of NMDA Receptor channel block and desensitization by intracellular calcium

Phillips, Matthew B (2021) Regulation of NMDA Receptor channel block and desensitization by intracellular calcium. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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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.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Phillips, Matthew Bmatt.phillips@pitt.edumbp25
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee MemberAizenman,
Committee MemberMeriney,
Committee MemberJacob,
Committee MemberWills,
Committee MemberJones,
Committee ChairJohnson,
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


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