The NR1 M3 Domain Mediates Allosteric Coupling in the N-Methyl-D-aspartate Receptor
N -Methyl- d -aspartate (NMDA) receptors play a critical role in both development of the central nervous system and adult neuroplasticity. However, although the NMDA receptor presents a valuable therapeutic target, the relationship between its structure and functional properties has yet to be fully...
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Veröffentlicht in: | Molecular pharmacology 2008-08, Vol.74 (2), p.454-465 |
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Sprache: | eng |
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Zusammenfassung: | N -Methyl- d -aspartate (NMDA) receptors play a critical role in both development of the central nervous system and adult neuroplasticity.
However, although the NMDA receptor presents a valuable therapeutic target, the relationship between its structure and functional
properties has yet to be fully elucidated. To further explore the mechanism of receptor activation, we characterized two gain-of-function
mutations within the NR1 M3 segment, a transmembrane domain proposed to couple ligand binding and channel opening. Both mutants
(A7Q and A7Y) displayed significant glycine-independent currents, indicating that their M3 domains may preferentially adopt
a more activated conformation. Substituted cysteine modification experiments revealed that the glycine binding clefts of both
A7Q and A7Y are inaccessible to modifying reagents and resistant to competitive antagonism. These data suggest that perturbation
of M3 can stabilize the ligand binding domain in a closed cleft conformation, even in the absence of agonist. Both mutants
also displayed significant glutamate-independent current and insensitivity to glutamate-site antagonism, indicating partial
activation by either glycine or glutamate alone. Furthermore, A7Q and A7Y increased accessibility of the NR2 M3 domain, providing
evidence for intersubunit coupling at the transmembrane level and suggesting that these NR1 mutations dominate the properties
of the intact heteromeric receptor. The equivalent mutations in NR2 did not exhibit comparable phenotypes, indicating that
the NR1 and NR2 M3 domains may play different functional roles. In summary, our data demonstrate that the NR1 M3 segment is
functionally coupled to key structural domains in both the NR1 and NR2 subunits. |
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ISSN: | 0026-895X 1521-0111 |
DOI: | 10.1124/mol.107.044115 |