NMDA receptors are Ca++-gating inotropic receptors. They are multi- subunit hetero-oligomers assembled from two classes (NR1 and NR2) of subunits. The one NR1 gene is processed into at least seven distinct splice variants and the four NR2 genes produce proteins that combine, in unknown combinations and stoichiometry, with NR1 to form receptors of distinct physiological characteristics depending on subunit composition. We have developed a battery of antibodies that can selectively recognize each of the subunits on immunoblots and can selectively immunoprecipitate a specific subunit. By solubilizing receptors in a gentle detergent, the subunit interactions remain intact and co- immunoprecipitation of multiple subunits with a specific antibody yields information regarding subunit associations in situ. This project proposes: (1) to determine the subunit combinations that assemble into NMDA receptors in various regions of the rat brain, (2) to generate cell lines stably expressing NMDA receptors of defined subunit composition that represent the major species of NMDA receptors expressed, (3) to examine the functional properties of NMDA receptors of defined subunit composition, (4) to measure the stoichiometry of NMDA receptor subunits in assembled NMDA receptors, and (5) to examine the possibility that agrin mediates tyrosine phosphorylation and/or aggregation of NMDA receptors. Results from these studies will increase our knowledge of the structure, function, location, and pharmacology of these receptors. Because NMDA receptors are involved in many important functions such as synaptic plasticity, which is vital for normal CNS development and may underlie the processes of learning, memory, and excitotoxicity, which may be involved in ischemic brain damage as well as several neurological diseases, drugs that affect the function of these receptors could be useful in the treatment of stroke,neurodegenerative diseases, and control of chronic pain to name a few examples. However, until we understand the various types and properties of the receptors that are expressed, side-effects will dominate any drugs that act via these receptors.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
Project #
Application #
Study Section
Neurological Sciences Subcommittee 1 (NLS)
Program Officer
Oliver, Eugene J
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Georgetown University
Schools of Dentistry
United States
Zip Code
Jarabek, Bryan R; Yasuda, Robert P; Wolfe, Barry B (2004) Regulation of proteins affecting NMDA receptor-induced excitotoxicity in a Huntington's mouse model. Brain 127:505-16
Al-Hallaq, Rana A; Jarabek, Bryan R; Fu, Zhanyan et al. (2002) Association of NR3A with the N-methyl-D-aspartate receptor NR1 and NR2 subunits. Mol Pharmacol 62:1119-27
Brown, Kwame M; Wrathall, Jean R; Yasuda, Robert P et al. (2002) Quantitative measurement of glutamate receptor subunit protein expression in the postnatal rat spinal cord. Brain Res Dev Brain Res 137:127-33
Yeh, J; Ferreira, M; Ebert, S et al. (2001) Axotomy and nerve growth factor regulate levels of neuronal nicotinic acetylcholine receptor alpha3 subunit protein in the rat superior cervical ganglion. J Neurochem 79:258-65
Al-Hallaq, R A; Yasuda, R P; Wolfe, B B (2001) Enrichment of N-methyl-D-aspartate NR1 splice variants and synaptic proteins in rat postsynaptic densities. J Neurochem 77:110-9
Prybylowski, K L; Grossman, S D; Wrathall, J R et al. (2001) Expression of splice variants of the NR1 subunit of the N-methyl-D-aspartate receptor in the normal and injured rat spinal cord. J Neurochem 76:797-805
Yeh, J J; Yasuda, R P; Davila-Garcia, M I et al. (2001) Neuronal nicotinic acetylcholine receptor alpha3 subunit protein in rat brain and sympathetic ganglion measured using a subunit-specific antibody: regional and ontogenic expression. J Neurochem 77:336-46
Prybylowski, K; Rumbaugh, G; Wolfe, B B et al. (2000) Increased exon 5 expression alters extrasynaptic NMDA receptors in cerebellar neurons. J Neurochem 75:1140-6
Khan, A M; Stanley, B G; Bozzetti, L et al. (2000) N-methyl-D-aspartate receptor subunit NR2B is widely expressed throughout the rat diencephalon: an immunohistochemical study. J Comp Neurol 428:428-49
Grossman, S D; Wolfe, B B; Yasuda, R P et al. (2000) Changes in NMDA receptor subunit expression in response to contusive spinal cord injury. J Neurochem 75:174-84

Showing the most recent 10 out of 15 publications