NMDA receptor activations produce substantial elevations in intracellular calcium levels, which initiate signaling cascades critical for normal ad pathological brain processes. These include normal synaptic development and plasticity, as well as psychiatric conditions such as addiction and chronic pain, schizophrenia, and neuropathologies such as stroke and Alzheimer's disease. Until recently it was assumed that the amount of calcium in the NMDA receptor current is fixed and controlled solely by gating modulators and channel blockers. This project investigates a newly reported modulatory mechanism by which intracellular signaling cascades can change in a reversible fashion the amount of calcium in the NMDA receptor current. This work seeks to identify the molecular determinants and mechanisms responsible for this new modulation. The resulting knowledge will inform novel strategies to address dysfunctions and pathologies where NMDA receptor- mediated calcium is a cause or an aggravating factor.

Public Health Relevance

The calcium fluxes resulting from NMDA receptor activity are essential to the roles played by these receptors in the physiology of central excitatory synapses and their dysregulation has been implicated in the etiology of psychiatric disorders such as schizophrenia, addiction and chronic pain. In addition, NMDA receptor-mediated calcium influx is the major conduit of glutamate excitotoxicity, a principal mechanism in acute and chronic neurodegenerative conditions such as stroke, Alzheimer, Parkinson, and Huntington's diseases. Results from this application will afford a better understanding of the mechanisms that control NMDA receptor-mediated calcium fluxes and thus will inform more effective strategies to address dysfunctions and pathologies caused by inappropriate calcium influx through NMDA receptors.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS097016-02
Application #
9233219
Study Section
Special Emphasis Panel (ZRG1-MDCN-R (04)M)
Program Officer
Silberberg, Shai D
Project Start
2016-03-01
Project End
2020-02-28
Budget Start
2017-03-01
Budget End
2018-02-28
Support Year
2
Fiscal Year
2017
Total Cost
$313,555
Indirect Cost
$116,680
Name
State University of New York at Buffalo
Department
Biochemistry
Type
Schools of Medicine
DUNS #
038633251
City
Amherst
State
NY
Country
United States
Zip Code
14228
Zheng, Wenjun; Wen, Han; Iacobucci, Gary J et al. (2017) Probing the Structural Dynamics of the NMDA Receptor Activation by Coarse-Grained Modeling. Biophys J 112:2589-2601
Iacobucci, Gary J; Popescu, Gabriela K (2017) NMDA receptors: linking physiological output to biophysical operation. Nat Rev Neurosci 18:236-249
Cummings, Kirstie A; Belin, Sophie; Popescu, Gabriela K (2017) Residues in the GluN1 C-terminal domain control kinetics and pharmacology of GluN1/GluN3A N-methyl-d-aspartate receptors. Neuropharmacology 119:40-47
Bajpai, Vivek K; Kerosuo, Laura; Tseropoulos, Georgios et al. (2017) Reprogramming Postnatal Human Epidermal Keratinocytes Toward Functional Neural Crest Fates. Stem Cells 35:1402-1415
Maneshi, Mohammad Mehdi; Maki, Bruce; Gnanasambandam, Radhakrishnan et al. (2017) Mechanical stress activates NMDA receptors in the absence of agonists. Sci Rep 7:39610
Iacobucci, Gary J; Popescu, Gabriela K (2017) Resident Calmodulin Primes NMDA Receptors for Ca2+-Dependent Inactivation. Biophys J 113:2236-2248