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The Journal of Neuroscience, December 20, 2006, 26(51):13156-13166; doi:10.1523/JNEUROSCI.2552-06.2006

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Cellular/Molecular
NR3A Modulates the Outer Vestibule of the "NMDA" Receptor Channel

Akira Wada,¹ Hiroto Takahashi,¹ Stuart A. Lipton,^1,2 and H.-S. Vincent Chen^1,3

¹Center for Neuroscience and Aging, Burnham Institute for Medical Research, and Departments of ²Neurosciences and ³Cardiology, University of California, San Diego, La Jolla, California 92037

Correspondence should be addressed to H.-S. Vincent Chen, M.D., Ph.D., Burnham Institute for Medical Research, 10901 North Torrey Pines Road, La Jolla, CA 92037. Email: hsv_chen{at}burnham.org

Classical NMDA receptors (NMDARs), activated by glycine and glutamate, are heteromultimers comprised of NR1 and NR2 subunits. Coexpression of the novel NR3 family of NMDAR subunits decreases the magnitude of NR1/NR2 receptor-mediated currents or forms glycine-activated channels with the NR1 subunit alone. The second (M2) and third (M3) membrane segments of NR1 and NR2 subunits of classical NMDARs form the core of the channel permeation pathway. Structural information regarding NR1/NR3 channels remains unknown. Using the Xenopus oocyte expression system and the SCAM (substituted cysteine accessibility method), we found that M3 segments of both NR1 and NR3A form a narrow constriction in the outer vestibule of the channel, which prevents passage of externally applied sulfhydryl-specific agents. The most internal reactive residue in each M3 segment is the threonine in the conserved SYTANLAAF motif. These threonines appear to be symmetrically aligned. Several NR3A M3 mutations change the behavior of NR1/NR3A channels. Unlike NR1, however, the M3 segment of NR3A does not undergo extensive molecular rearrangement during channel gating by added glycine. Additionally, in the M2 segment, our data suggest that the amino acid at the asparagine (N) site of NR1, but not NR3A, contributes to the selectivity filter of NR1/3A channels. We therefore conclude that NR3A modulates the NR1/NR3A permeation pathway via a novel mechanism of forming a narrow constriction at the outer channel vestibule. This modified channel vestibule may also explain the dominant-negative effect of the NR3 subunit on channel behavior when coexpressed with NR1 and NR2 subunits.

Key words: ligand-gated channel; SCAM; permeability; block; glutamate; size filter

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Received June 17, 2006; revised Oct. 3, 2006; accepted Oct. 31, 2006.

Correspondence should be addressed to H.-S. Vincent Chen, M.D., Ph.D., Burnham Institute for Medical Research, 10901 North Torrey Pines Road, La Jolla, CA 92037. Email: hsv_chen{at}burnham.org

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