Staggering of subunits in NMDAR channels.
Functional N-methyl-D-aspartate receptors (NMDARs) are heteromultimers formed by NR1 and NR2 subunits. The M3 segment, as contributed by NR1, forms the core of the extracellular vestibule, including binding sites for channel blockers, and represents a critical molecular link between ligand binding and channel opening. Taking advantage of the substituted cysteine accessibility method along with channel block and multivalent coordination, we studied the contribution of the M3 segment in NR2C to the extracellular vestibule. We find that the M3 segment in NR2C, like that in NR1, contributes to the core of the extracellular vestibule. However, the M3 segments from the two subunits are staggered relative to each other in the vertical axis of the channel. Compared to NR1, homologous positions in NR2C, including those in the highly conserved SYTANLAAF motif, are located about four amino acids more externally. The staggering of subunits may represent a key structural feature underlying the distinct functional properties of NMDARs.
Sobolevsky
Alexander I
AI
Department of Neurobiology and Behavior, State University of New York at Stony Brook, Stony Brook, NY 11794-5230, USA. asobolevsky@notes2.cc.sunysb.edu
Rooney
LeeAnn
L
Wollmuth
Lonnie P
LP
D000585:Aminacrine / Q000494:pharmacology; D000595:Amino Acid Sequence; D000818:Animals; D002412:Cations / Q000494:pharmacology; D002462:Cell Membrane / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D003545:Cysteine / Q000737:chemistry / Q000235:genetics; D005110:Extracellular Space / Q000737:chemistry / Q000502:physiology; D005260:Female; D018698:Glutamic Acid / Q000494:pharmacology; D015640:Ion Channel Gating / Q000187:drug effects / Q000502:physiology; D007473:Ion Channels / Q000187:drug effects / Q000502:physiology; D046911:Macromolecular Substances; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D008698:Mesylates / Q000494:pharmacology; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D009865:Oocytes / Q000737:chemistry / Q000187:drug effects / Q000502:physiology; D011487:Protein Conformation; D021122:Protein Subunits / Q000737:chemistry / Q000502:physiology*; D016194:Receptors, N-Methyl-D-Aspartate / Q000737:chemistry / Q000502:physiology*; D017386:Sequence Homology, Amino Acid; D012834:Silver / Q000494:pharmacology; D014981:Xenopus / Q000502:physiology
D002412:Cations; D007473:Ion Channels; D046911:Macromolecular Substances; D008698:Mesylates; C409466:NR1 NMDA receptor; C432823:NR2C NMDA receptor; D021122:Protein Subunits; D016194:Receptors, N-Methyl-D-Aspartate; D018698:Glutamic Acid; D012834:Silver; C074502:methanethiosulfonate; D000585:Aminacrine; D003545:Cysteine