Molecular determinants of glycine-independent desensitization of NR1/NR2A receptors.
Glycine-independent desensitization is thought to be an important regulatory mechanism for the function of N-methyl-D-aspartate (NMDA) receptors. Previous studies have suggested that the molecular determinants for glycine-independent desensitization are located at two distinct domains of NR2A, i.e., the amino-terminal domain (ATD) and the pre-M1 domain. Since the glycine-independent desensitization described in these earlier studies was a mixture of glycine-independent desensitization and zinc-dependent apparent desensitization, the exact role of these two domains in glycine-independent desensitization remains in question. In the present study, we show that deletion of the ATD of NR2A or mutating the pre-M1 region of NR2A causes no detectable changes in the degree or the time constant of glycine-independent desensitization. Therefore, the ATD and the pre-M1 domain of NR2A play no significant role in glycine-independent desensitization of NR1/NR2A receptors. On the other hand, several residues in the lurcher motif of either NR1 or NR2A are critical for the glycine-independent desensitization of NR1/NR2A receptors. In addition to NR1a(A653T) and NR2A(A651T), NR1a(T648C), NR1a(A649C), NR2A(T646C), and NR2A(A647C) show significantly reduced glycine-independent desensitization. Since all these mutations also alter the proton sensitivity or deactivation time constants of NR1/NR2A receptors, our data suggest that the channel gating and desensitization of NMDA receptors share common molecular determinants and that the lurcher motif of NR1 and NR2A is critical for both processes.
Hu
Bo
B
Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, 2205, USA.
Zheng
Fang
F
D001665:Binding Sites / Q000187:drug effects / Q000502:physiology; D002460:Cell Line; D018698:Glutamic Acid / Q000008:administration & dosage / Q000378:metabolism; D005998:Glycine / Q000008:administration & dosage* / Q000378:metabolism*; D006801:Humans; D016194:Receptors, N-Methyl-D-Aspartate / Q000737:chemistry / Q000378:metabolism*
C409466:NR1 NMDA receptor; C120997:NR2A NMDA receptor; D016194:Receptors, N-Methyl-D-Aspartate; D018698:Glutamic Acid; D005998:Glycine