Glycine-Independent NMDA Receptor Desensitization: Localization of Structural Determinants

Abstract

In studying chimeras of NR2A and NR2C subunits of the NMDA receptor, we have found that glycine-independent desensitization depends on two regions of the extracellular N-terminal domain. One corresponds to a stretch of approximately 190 amino acids preceding the glutamate-binding domain S1. The other localizes at the interface between the N-terminal segment and the first transmembrane domain of NR2A subunits and involves A555 and S556. Both regions support desensitization in the absence of the other with different time courses. Desensitization did not develop with time in receptors containing the entire N-terminal region of NR2C. The introduction of A555 into the corresponding position of NR2C subunits enabled the receptors to manifest time-dependent increase in desensitization. Thus, this determinant behaves as an allosteric effector for glycine-independent desensitization.

α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid (AMPA) Receptor Channels Lacking the N-terminal Domain

“…Glycine-independent desensitization of NMDA receptors was assigned to two regions in the NR2A subunit, the X domain and an area within the S1 segment (13,17). Moreover, participation of the N-terminal domain in the regulation of NMDA receptor channel function by allosteric modulators, including Zn 2ϩ ions (14,16), ifenprodil (8,15,16), spermine (8), protons (25), and redox agents (26), has been demonstrated.…”

“…First, this domain is implicated as a determinant in the assembly of oligomeric channels (10 -12). Second, the X domain may mediate the allosteric transitions involved in the channel activation, desensitization, or modulation by ions and drugs as has been observed for NMDA receptors (8,(13)(14)(15)(16)(17). Third, the X domain may provide docking sites for extracellular proteins, which serve to cluster the receptors or stabilize their localization.…”

Retina-Driven Dephosphorylation of the NR2A Subunit Correlates with Faster NMDA Receptor Kinetics at Developing Retinocollicular Synapses

“…This desensitization has been studied extensively and is known to involve allosteric changes in the extracellular domain of the NR2A subunit near the agonist binding site (Krupp et al, 1998;Villarroel et al, 1998). However, recent evidence has implicated phosphorylation of the cytoplasmic C terminal of the NR2A subunit in this desensitization.…”

Gating Reaction Mechanisms for NMDA Receptor Channels

“…The rising phase of evoked macroscopic current was Ͻ15 ms (Fig. 4), which is much faster than the time constant of NMDAR desensitization (Ͼ100 ms) (Vicini et al, 1998;Villarroel et al, 1998). To confirm that the rising phase was independent of binding steps, a series of jumps from solutions containing various concentrations of glycine to a solution with 1 mM glutamate plus 100 M glycine was performed (Fig.…”