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NR3A modulates the outer vestibule of the "NMDA" receptor channel

Center for Neuroscience and Aging, Burnham Institute for Medical Research, La Jolla, California 92037, USA.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.75). 01/2007; 26(51):13156-66. DOI: 10.1523/JNEUROSCI.2552-06.2006
Source: PubMed

ABSTRACT 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.

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    • "The presence of GluN3A results in two distinct independent conductance states: the typical large conductance state, similar to what is found in conventional receptors, and the second significantly smaller, which exhibits a slight increase in mean opening time [14] [17] [38]. Ca 2+ permeability in GluN3A-containing NMDAR is significantly reduced [13] [14] [38] due to the constriction of the outer vestibule [37]. Another prominent feature of GluN3A-containing receptors is the insensitivity to Mg 2+ block at hyperpolarized potential: even with varying concentrations of Mg 2+ , GluN3A prevents a Mg 2+ block [13] [38] (Figure 1); these properties are further characterized in other reviews on GluN3; see [39] [40] [41]. "
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    • "In addition, a DRPEER motif in NR1 (Watanabe et al., 2002), a tryptophan residue in the M2 regions of NR2 subunits (Williams et al., 1998) and the common SYTANLAAF motif in TM3 (Yuan et al., 2005; Wada et al., 2006) affect the Mg 2+ block. Comparing the sequences of NR1, NR2 and NR3 subunits reveals a remarkable conservation of these regions, although especially within the QRN site and the SYTANLAAF motif several exchanges between NR1, NR2 and NR3 subunits are found. "
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