2025-09-24 カリフォルニア大学サンフランシスコ校(UCSF)
Three distinct snapshots obtained with cryo-electron microscopy illustrate the arrangement of two of the four symmetrical subunits that make a functional NMDA receptor. During activation, as the receptor transitions from Closed, to Primed, to Open, subtle rearrangements occur in the transmembrane helix that lines the ion-permeable pore (highlighted in color). Image: G. Popescu and J. Abbott
<関連情報>
- https://www.buffalo.edu/news/releases/2025/09/UB-Jacobs-School-NMDA-receptor.html
- https://www.science.org/doi/10.1126/sciadv.adx4647
NMDA受容体活性化のクライオ電子顕微鏡写真が連続的な再配置を明らかにする Cryo-EM snapshots of NMDA receptor activation illuminate sequential rearrangements
Jamie A. Abbott, Junhoe Kim, Beiying Liu, Gabriela K. Popescu, […] , and Farzad Jalali-Yazdi
Science Advances Published:24 Sep 2025
DOI:https://doi.org/10.1126/sciadv.adx4647
Abstract
Canonical N-methyl-d-aspartate receptors (NMDARs) are glutamate-gated ion channels with critical roles in the development and function of the nervous system. The excitatory currents they produce reflect stochastic transitions between multiple agonist-bound closed- and open-pore states. We leveraged the intrinsically high open probability (Po) of NMDARs composed of GluN1 and GluN2A subunits, together with judiciously chosen mutants and ligands, to achieve conditions in which receptors had a Po near unity. Using single-particle cryo–electron microscopy (cryo-EM), we captured three activated receptor states, each with distinct conformations of the gate-forming M3 helices. Separately, we carried out single-channel electrophysiology, together with statistical modeling, to relate the cryo-EM structures to the gating reaction. NMDAR channel opening involves bending of the pore-forming M3 helices to produce a transient open-channel conformation, subsequently stabilized by new interactions between the D2-M3 linkers with the pre-M1 helices and the pre-M4 loops, to yield the stable open channel.
