Excitatory receptors activated by the neurotransmitter L-glutamate are responsible for most fast excitatory synaptic communication in vertebrate nervous systems. In the proposed research the glutamate receptor subtypes specifically activated by N-methyl-D-aspartate (NMDA receptors) will be studied. NMDA receptors are required for many basic functions of the nervous system, including development and memory formation. Imbalanced NMDA Receptor activity has been linked to numerous nervous system disorders, including schizophrenia, Parkinson's disease, Alzheimer's disease, Huntington's disease, stroke, and epilepsy. The unique properties of the ion channel formed by NMDA receptors are essential for its central position in nervous system function and dysfunction. The long-term objectives of the proposed research are to understand the ion channel structures and properties that are about central to NMDA receptor function. NMDA receptors are subject to many forms of physiological regulation. One of the most powerful is block of the ion channel of NMDA receptors by extracellular magnesium ions (Mg about). Block by Mg2+ in turn is strongly regulated by both extracellular and intracellular ions that can permeate the channel of NMDA receptors. To achieve he objectives of the proposed research, the following specific aims will be pursued: (1) examine how the important regulatory ion Ca2+ affects block of the channel of NMDA receptors by Mg2+ (2) determine how the effect of permeant ions on Mg2+ block varies among NMDA receptor subtypes; (3) identify amino acids within the structure of NMDA receptors that are involved in forming the site at which permeant ions bind and affect block by Mg2+ These aims will be achieved through a combination of electrophysiological recording from cells and from single NMDA receptors, computational modeling of NMDA receptor activity, and manipulation of the structure of NMDA receptors using molecular biological approaches. The results of the proposed research will extend our understanding of the structure and operation of NMDA receptors, and thus provide insight into their operation in nervous system physiology and disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH045817-15
Application #
7059965
Study Section
Molecular, Cellular and Developmental Neurosciences 2 (MDCN)
Program Officer
Nadler, Laurie S
Project Start
1990-08-01
Project End
2007-04-30
Budget Start
2006-05-01
Budget End
2007-04-30
Support Year
15
Fiscal Year
2006
Total Cost
$285,547
Indirect Cost
Name
University of Pittsburgh
Department
Neurosciences
Type
Schools of Arts and Sciences
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Glasgow, Nathan G; Wilcox, Madeleine R; Johnson, Jon W (2018) Effects of Mg2+ on recovery of NMDA receptors from inhibition by memantine and ketamine reveal properties of a second site. Neuropharmacology 137:344-358
Leiva, Rosana; Phillips, Matthew B; Turcu, Andreea L et al. (2018) Pharmacological and Electrophysiological Characterization of Novel NMDA Receptor Antagonists. ACS Chem Neurosci 9:2722-2730
Wu, Man; White, Hayley V; Boehm, Blake A et al. (2018) New Cav2 calcium channel gating modifiers with agonist activity and therapeutic potential to treat neuromuscular disease. Neuropharmacology 131:176-189
Dimitrion, Peter; Zhi, Yun; Clayton, Dennis et al. (2017) Low-Density Neuronal Cultures from Human Induced Pluripotent Stem Cells. Mol Neuropsychiatry 3:28-36
D'Aiuto, Leonardo; Williamson, Kelly; Dimitrion, Peter et al. (2017) Comparison of three cell-based drug screening platforms for HSV-1 infection. Antiviral Res 142:136-140
Lorenz-Guertin, Joshua M; Wilcox, Madeleine R; Zhang, Ming et al. (2017) A versatile optical tool for studying synaptic GABAA receptor trafficking. J Cell Sci 130:3933-3945
Glasgow, Nathan G; Povysheva, Nadezhda V; Azofeifa, Andrea M et al. (2017) Memantine and Ketamine Differentially Alter NMDA Receptor Desensitization. J Neurosci 37:9686-9704
Divito, Christopher B; Borowski, Jenna E; Glasgow, Nathan G et al. (2017) Glial and Neuronal Glutamate Transporters Differ in the Na+ Requirements for Activation of the Substrate-Independent Anion Conductance. Front Mol Neurosci 10:150
Mesbahi-Vasey, Samaneh; Veras, Lea; Yonkunas, Michael et al. (2017) All atom NMDA receptor transmembrane domain model development and simulations in lipid bilayers and water. PLoS One 12:e0177686
Khlestova, Elizaveta; Johnson, Jon W; Krystal, John H et al. (2016) The Role of GluN2C-Containing NMDA Receptors in Ketamine's Psychotogenic Action and in Schizophrenia Models. J Neurosci 36:11151-11157

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