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Two gates mediate NMDA receptor activity and are under subunit-specific regulation.

ABSTRACT: Kinetics of NMDA receptor (NMDAR) ion channel opening and closing contribute to their unique role in synaptic signaling. Agonist binding generates free energy to open a canonical gate at the M3 helix bundle crossing. Single channel activity is characterized by clusters, or periods of rapid opening and closing, that are separated by long silent periods. A conserved glycine in the outer most transmembrane helices, the M4 helices, regulates NMDAR function. Here we find that the GluN1 glycine mainly regulates single channel events within a cluster, whereas the GluN2 glycine mainly regulates entry and exit from clusters. Molecular dynamics simulations suggest that, whereas the GluN2 M4 (along with GluN2 pre-M1) regulates the gate at the M3 helix bundle crossing, the GluN1 glycine regulates a 'gate' at the M2 loop. Subsequent functional experiments support this interpretation. Thus, the distinct kinetics of NMDARs are mediated by two gates that are under subunit-specific regulation.

SUBMITTER: Amin JB

PROVIDER: S-EPMC10036335 | biostudies-literature | 2023 Mar

REPOSITORIES: biostudies-literature

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Two gates mediate NMDA receptor activity and are under subunit-specific regulation.

Amin Johansen B JB He Miaomiao M Prasad Ramesh R Leng Xiaoling X Zhou Huan-Xiang HX Wollmuth Lonnie P LP

Nature communications 20230323 1

Kinetics of NMDA receptor (NMDAR) ion channel opening and closing contribute to their unique role in synaptic signaling. Agonist binding generates free energy to open a canonical gate at the M3 helix bundle crossing. Single channel activity is characterized by clusters, or periods of rapid opening and closing, that are separated by long silent periods. A conserved glycine in the outer most transmembrane helices, the M4 helices, regulates NMDAR function. Here we find that the GluN1 glycine mainly ...[more]

PMID: 36959168

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Two gates mediate NMDA receptor activity and are under subunit-specific regulation.

Publications

Two gates mediate NMDA receptor activity and are under subunit-specific regulation.

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