The research proposed here concerns N-methyl-D-aspartate receptors (NMDARs), brain proteins that are activated by the neurotransmitter glutamate and that mediate communication between neurons. NMDARs are required for many normal brain functions, such as memory formation, and also are involved in many human diseases, including Alzheimer's Disease and schizophrenia. The long-term objectives of the proposed research are to understand at a deep level how NMDARs function, what they look like, and how drugs that bind to them can either improve or exacerbate nervous system diseases. A powerful combination of techniques will be used: recording of the electrical activity of NMDARs in neurons within brain slices and from cells modified to express specific types of NMDARs;use of molecular biological techniques to change the chemical makeup of receptors and investigate how the changes affect receptor function;recording of the electrical activity of single receptors;use of computational techniques to create models of the physical makeup of receptors to improve understanding of their structure;use of other computational techniques to create functional models of receptors to improve understanding of how they work. Several specific research goals are proposed. The first is to investigate how NMDAR subunits interact with each other. NMDARs are composed of four separate subunits that work together in a tightly integrated manner. Some regions where subunits interact with each other have been studied, but others have not. In the proposed research, the functional role of a newly-discovered region where subunits interact will be studied. The second goal is to develop a better model of the structure of NMDARs based on knowledge of the structure of related proteins and on computer simulations. Accomplishing these first two goals together will greatly improve understanding of the basic mechanism by which NMDARs mediate neuronal communication. The final goal is to understand how drugs that bind to NMDARs work. One drug that will be studied is used to treat Alzheimer's disease, whereas the other drug causes normal humans to display the symptoms of schizophrenia. Both drugs bind to NMDARs, but they have very different effects. The goal is to understand the important differences between the actions of the drugs to provide insight into the drug characteristics that allow one to help Alzheimer's disease patients, and the other to mimic schizophrenia.

Public Health Relevance

In the proposed research, the structure and function of a brain protein that is essential to many nervous system functions, including memory formation, will be studied. In addition, we will study two similar drugs that bind to the same brain protein, but that have very different effects on people: one drug is used to treat Alzheimer's disease, and the other drug causes normal people to act like schizophrenics. By determining the differences in how these drugs act, we can learn more about treatment of Alzheimer's disease and causes of schizophrenia.

National Institute of Health (NIH)
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Neurotransporters, Receptors, and Calcium Signaling Study Section (NTRC)
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Nadler, Laurie S
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University of Pittsburgh
Schools of Arts and Sciences
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Johnson, Jon W; Glasgow, Nathan G; Povysheva, Nadezhda V (2015) Recent insights into the mode of action of memantine and ketamine. Curr Opin Pharmacol 20:54-63
Plowey, Edward D; Johnson, Jon W; Steer, Erin et al. (2014) Mutant LRRK2 enhances glutamatergic synapse activity and evokes excitotoxic dendrite degeneration. Biochim Biophys Acta 1842:1596-603
Clarke, Richard J; Glasgow, Nathan G; Johnson, Jon W (2013) Mechanistic and structural determinants of NMDA receptor voltage-dependent gating and slow Mg2+ unblock. J Neurosci 33:4140-50
Kotermanski, Shawn E; Johnson, Jon W; Thiels, Edda (2013) Comparison of behavioral effects of the NMDA receptor channel blockers memantine and ketamine in rats. Pharmacol Biochem Behav 109:67-76
Povysheva, Nadezhda V; Johnson, Jon W (2012) Tonic NMDA receptor-mediated current in prefrontal cortical pyramidal cells and fast-spiking interneurons. J Neurophysiol 107:2232-43
Siegler Retchless, Beth; Gao, Wei; Johnson, Jon W (2012) A single GluN2 subunit residue controls NMDA receptor channel properties via intersubunit interaction. Nat Neurosci 15:406-13, S1-2
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Goss, James R; Cascio, Michael; Goins, William F et al. (2011) HSV delivery of a ligand-regulated endogenous ion channel gene to sensory neurons results in pain control following channel activation. Mol Ther 19:500-6
Gielen, Marc; Siegler Retchless, Beth; Mony, Laetitia et al. (2009) Mechanism of differential control of NMDA receptor activity by NR2 subunits. Nature 459:703-7
Kotermanski, Shawn E; Johnson, Jon W (2009) Mg2+ imparts NMDA receptor subtype selectivity to the Alzheimer's drug memantine. J Neurosci 29:2774-9

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