. Excitatory receptors activated by the neurotransmitter L-glutamate mediate most excitatory synaptic transmission in vertebrate nervous systems. In the proposed research the glutamate receptor subtypes activated by N-methyl-D-aspartate (NMDA receptors) will be studied. NMDA receptors are essential for many basic nervous system functions, including learning and development, and are involved in a remarkable range of nervous system diseases, including numerous mental disorders. The long-term objectives of the proposed research are to understand the functional and structural properties of NMDA receptors responsible for their multiple roles in brain function. ? ? Possibly because of their involvement in multiple neural systems, NMDA receptors are subject to many forms of physiological regulation. One of the most powerful forms of regulation is block of the ion channel of NMDA receptors by extracellular magnesium ions (Mg2+o). The properties of channel block by Mg2+o are fundamental determinants of NMDA receptor involvement in brain function. Several drugs of pharmaceutical importance also block the channels of NMDA receptors. Interaction of Mg2+o and channel-blocking drugs with NMDA receptors in turn also is highly regulated. In the proposed research, we will investigate several of the mechanisms by which channel block of NMDA receptors is regulated, including: the types of subunits that constitute an NMDA receptor, permeation of the channel by Mg2+o, receptor binding of permeant ions, and inherent voltage dependence of receptor function. We will integrate electrophysiological, computational, molecular, and structural analyses to achieve these objectives. The research will deepen our understanding of NMDA receptor regulation, function, and dysfunction under a wide range of conditions, and provide insight into the relation between the structure and properties of NMDA receptors. ? ? DESCRIPTION OF

Public Health Relevance

. Imbalanced NMDA receptor activity has been linked to many nervous system disorders, including schizophrenia, Parkinson's disease, Alzheimer's disease, Huntington's disease, stroke, epilepsy, depression, post-traumatic stress disorder, and bipolar disorder. The improved understanding of NMDA receptors that will be provided by the proposed research has enormous potential to help prevent, and ameliorate the consequences of, many forms of brain dysfunction. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
2R01MH045817-16
Application #
7267281
Study Section
Special Emphasis Panel (ZRG1-MDCN-C (02))
Program Officer
Nadler, Laurie S
Project Start
1990-08-01
Project End
2012-04-30
Budget Start
2007-05-01
Budget End
2008-04-30
Support Year
16
Fiscal Year
2007
Total Cost
$285,309
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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