Project I - Zhang &Chen Program Director/Principal Investigator (Last, First, Middle): Lipton, Stuart A. PROJECT SUMMARY (See instructions): The N-methyl-D-aspartate subtype of gluatmate receptor (NMDAR) is essential for normal function of the central nervous system (CNS). However, excessive activation of NMDARs, particulariy of extrasynaptic as opposed to synaptic receptors, mediates, at least in part, neuronal or synaptic damage in many neurological disorders, such as hypoxic-ischemic brain injury and, as recently suggested, in Down syndrome. Blockade of excessive NMDAR activity must be achieved without interference with its normal brain function. We have taken two approaches for clinically-tolerated pharmacological and genetic intervention on NMDARs. One approach is to use Memantine but also NO species to further down regulate the NMDAR by S-nitrosylation. The structural determinants on NMDARs for the action of Memantine and NO-like species will be characterized further under the auspices of this grant. Another approach is to utilize the inhibitory effect of a novel family of NMDAR subunits, composed of NRSA and NRSB, to downregulate NMDARs by affecting channel permeability, in a sense mimicking the effect of the NMDAR antagonist drugs that are also being developed here. We will study the role of the MS domain of NRS subunits that downregulate activity of NMDARs and also design NRS ligand-binding domain (LBD)-based screening assays to discover new compounds that modulate NRS-containing receptors. These agents will be useful for characterizing NRS-containing receptors, and possibly for neuroprotection. Accordingly, the Specific Aims of this proposal are as follows: 1) To study the effect of S-nitrosylation/redox modulation of the loose linker region between the amino-terminal domain (ATD) and the LBD of NMDARs by electrophysiology;2) To develop LBD-derived screening assays to screen for ligands selective for the NRS subunit of the NMDAR. These ligands will be further characterized and refined by secondary assays, chemical modification, and co-crystallization;3) To study the inhibitory effect of peptides derived from the out vestibule (MS) region of NRS subunits on NMDAR permeability.

Public Health Relevance

This grant aims to develop novel, clinically-tolerated NMDA receptor antagonists, called NitroMemantines, in addition to other novel molecules based on the structure of the NRS subunit, which this Team of Investigators discovered, in order to prevent cognitive deficits seen in Down syndrome. We take two approaches, pharmacological and genetic, for safe inhibition of NMDARs to treat pathological conditions without interference with normal function.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Program Projects (P01)
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Special Emphasis Panel (ZHD1-DSR-N (51))
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Sanford-Burnham Medical Research Institute
La Jolla
United States
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Okamoto, Shu-ichi; Lipton, Stuart A (2015) S-Nitrosylation in neurogenesis and neuronal development. Biochim Biophys Acta 1850:1588-93
Zhu, Saiyong; Ambasudhan, Rajesh; Sun, Woong et al. (2014) Small molecules enable OCT4-mediated direct reprogramming into expandable human neural stem cells. Cell Res 24:126-9
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Chan, Shing Fai; Sances, Sam; Brill, Laurence M et al. (2014) ATM-dependent phosphorylation of MEF2D promotes neuronal survival after DNA damage. J Neurosci 34:4640-53
Choi, Min Sik; Nakamura, Tomohiro; Cho, Seung-Je et al. (2014) Transnitrosylation from DJ-1 to PTEN attenuates neuronal cell death in parkinson's disease models. J Neurosci 34:15123-31
Okamoto, Shu-Ichi; Nakamura, Tomohiro; Cieplak, Piotr et al. (2014) S-nitrosylation-mediated redox transcriptional switch modulates neurogenesis and neuronal cell death. Cell Rep 8:217-28
Molokanova, Elena; Akhtar, Mohd Waseem; Sanz-Blasco, Sara et al. (2014) Differential effects of synaptic and extrasynaptic NMDA receptors on A?-induced nitric oxide production in cerebrocortical neurons. J Neurosci 34:5023-8
Marco, Sonia; Giralt, Albert; Petrovic, Milos M et al. (2013) Suppressing aberrant GluN3A expression rescues synaptic and behavioral impairments in Huntington's disease models. Nat Med 19:1030-8
Sunico, Carmen R; Nakamura, Tomohiro; Rockenstein, Edward et al. (2013) S-Nitrosylation of parkin as a novel regulator of p53-mediated neuronal cell death in sporadic Parkinson's disease. Mol Neurodegener 8:29
Talantova, Maria; Sanz-Blasco, Sara; Zhang, Xiaofei et al. (2013) A? induces astrocytic glutamate release, extrasynaptic NMDA receptor activation, and synaptic loss. Proc Natl Acad Sci U S A 110:E2518-27

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