The N-methyl-D-aspartate (NMDA) receptor has four membrane-associated domains, three of which are membrane-spanning (M1, M3, and M4) and one of which is a re-entrant pore loop (M2 The N-methyl-D-aspartate (NMDA) 1 receptor is a subtype of ionotropic glutamate receptor that plays essential roles in neuronal development, synaptic plasticity, and several types of neurological disorders (1). NMDA receptors are heteromers containing NR1 subunits, which bind the co-agonist glycine (2, 3), and NR2 subunits, which bind the agonist glutamate (4, 5). The agonist-binding domains of all ionotropic glutamate receptor subunits consist of two lobes (S1 and S2) that are formed by the region of the extracellular N-terminal domain preceding the first membrane-associated (M) domain and the loop between the M3 and M4 domain, respectively (5-8), and that together form a clamshell structure that undergoes a conformational change to enclose the ligand upon binding (6, 9, 10).Observations from x-ray crystallographic studies on non-NMDA glutamate receptor constructs suggest that the degree of binding domain closure induced by a particular agonist appears to determine both the degree of receptor activation and the extent of desensitization produced by that agonist (10) and that desensitization in these receptors results from the dissociation of dimers of the ligand-binding domains of adjacent subunits (11). NMDA receptors exhibit apparent desensitization sensitive to glycine or intracellular Ca 2ϩ (1, 12) in addition to true glycine-insensitive desensitization (subsequently referred to simply as desensitization). NMDA receptor desensitization is physiologically relevant, as it can influence the amplitude, duration, and following frequency of NMDA receptormediated synaptic events (13-16). Determinants of NMDA receptor desensitization have been localized to two regions in or near the S1 ligand-binding site in the N-terminal domain, one that shows homology to leucine/isoleucine/valine-binding proteins and one located in the region immediately preceding the M1 domain (17, 18), as well as to a highly conserved motif (YTANLAAF) in the C-terminal portion of the M3 domain preceding the S2 ligand-binding lobe (19). The pre-M1 and M3 domains have been suggested to be involved in transducing the conformational changes induced by agonist binding into those responsible for ion channel gating (17,19), but the nature of the conformational changes and molecular determinants underlying NMDA receptor ion channel gating remain unclear. The YTANLAAF motif in M3 has been shown to play an important role in the regulation of ion channel gating, as a point mutation in this region of the NR1 subunit increases mean open time in receptors formed from coexpression with NR2A subunits (19). Mutations at a tryptophan residue in the M2 domain of the NR1 or NR2A subunit have also been reported to subtly affect mean open time and opening frequency (20). We report here that a residue in the M4 domain of the NR2A subunit exerts a powerful regulatory influence on the desens...
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