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

Johansen B. Amin, Miaomiao He, Ramesh Prasad, Xiaoling Leng, Huan-Xiang Zhou and Lonnie P. Wollmuth ()
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Johansen B. Amin: Stony Brook University
Miaomiao He: Stony Brook University
Ramesh Prasad: University of Illinois at Chicago
Xiaoling Leng: University of Illinois at Chicago
Huan-Xiang Zhou: University of Illinois at Chicago
Lonnie P. Wollmuth: Stony Brook University

Nature Communications, 2023, vol. 14, issue 1, 1-11

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-37260-y

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