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The Journal of Neuroscience, August 1, 2007, 27(31):8334-8343; doi:10.1523/JNEUROSCI.2155-07.2007

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Cellular/Molecular
NMDA Di-Heteromeric Receptor Populations and Associated Proteins in Rat Hippocampus

Rana A. Al-Hallaq,¹ Thomas P. Conrads,² Timothy D. Veenstra,² and Robert J. Wenthold¹

¹Laboratory of Neurochemistry, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, Maryland 20892, and ²Laboratory of Proteomics and Analytical Technologies, Science Applications International Corporation-Frederick, National Cancer Institute-Frederick, National Institutes of Health, Frederick, Maryland 21702

Correspondence should be addressed to Dr. Rana A. Al-Hallaq, National Institute on Deafness and Other Communication Disorders/National Institutes of Health, 50 South Drive, Mail Stop Code 8027, Building 50, Room 4146, Bethesda, MD 20892-8027. Email: alhallaq{at}nidcd.nih.gov

Subunit composition of NMDA receptors (NMDARs) determines a range of physiological properties, downstream signaling effects, and binding partners. Differential localization of NR2A- or NR2B-containing NMDARs within the neuron and subunit-specific protein associations may explain differences in NR2A and NR2B contributions to synaptic plasticity and excitotoxic cell death. This question is complicated by the existence of tri-heteromeric complexes (NR1/NR2A/NR2B). To date, no quantitative biochemical determinations have been made of the relative abundance of different NMDAR populations in intact hippocampus, the region extensively correlated with NMDAR-dependent long-term potentiation. We investigated subunit composition and subunit-specific interactions in CA1/CA2 of rat hippocampus. Using sequential immunoprecipitations to deplete either NR2B or NR2A, di-heteromeric NR1/NR2A and NR1/NR2B receptor populations were isolated from postnatal day 7 (P7) hippocampus and P42 and 6-month-old CA1/CA2. Quantitative Western blot analysis revealed that 60–70% of NR2A and 70–85% of NR2B subunits were associated in NR1/NR2A or NR1/NR2B di-heteromeric complexes. Isolated di-heteromeric receptor fractions were used to examine NR2A- or NR2B-specific interactions with synapse-associated proteins. Our results indicate that NR2A- or NR2B-containing NMDARs associate similarly with postsynaptic density-95 (PSD-95), synapse-associated protein 102, and PSD-93 at P42. However, NR2A-containing receptors coimmunoprecipitated a greater proportion of the synaptic proteins neuronal nitric oxide synthase, Homer, and ß-catenin. Finally, mass spectrometry analysis of isolated di-heteromeric receptors identified a novel NMDAR interactor, collapsin response mediator protein 2, which preferentially associates with NR2B-containing di-heteromeric NMDARs. In summary, in rat hippocampus, NR2A and NR2B exist primarily in di-heteromeric complexes that interact similarly with PSD-95-related proteins but are associated with different protein complexes.

Key words: tri-heteromeric; MAGUK; PSD-95; CRMP2; detergent solubility; postsynaptic

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Received May 10, 2007; revised June 11, 2007; accepted June 22, 2007.

Correspondence should be addressed to Dr. Rana A. Al-Hallaq, National Institute on Deafness and Other Communication Disorders/National Institutes of Health, 50 South Drive, Mail Stop Code 8027, Building 50, Room 4146, Bethesda, MD 20892-8027. Email: alhallaq{at}nidcd.nih.gov

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