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On December 26, the journal Cell Report published an online paper entitled "Structural Foundations of Proton Sensitivity of Human Origin GluN1/GluN2A NMDA Receptors", which was jointly completed by the Institute of Neuroscience of the Chinese Academy of Sciences, the Center for Excellence in Brain Science and Intelligent Technology, the Zhang Xing Research Group of the Frozen Electron Center of Zhejiang University, and the Luo Cheng Research Group of the Shanghai Institute of Pharmaceutical Research of the Chinese Academy of Sciences.
the study is the first to analyze the three-dimensional structure of the frozen electron mirror at the near-atomic resolution of the human-derived NMDA (N-methyl-D-aspartic acid, n-methyl-D-as-tenine) receptor GluN1/GluN2A subtype near-atomic resolution, and to explore the molecular mechanism and structural basis of its proton sensitivity.
as one of the core members of the excitatory ionic glutamate receptor family, NMDA receptors play an important role in neurodevelopment and the plasticity of formation, learning and memory.
NMDA impairments are closely related to many neurological disorders, such as cerebral ischemia, depression, stroke, schizophrenia, Parkinson's disease and Alzheimer's disease.
therefore, NMDA receptors have been a hot research topic and drug target in the field of neuropharmacology.
in the topology, NMDA receptors form heterogeneous quadpolymer ion channel proteins.
two GluN1s are necessary sub-bases, and the composition of two GluN2 (2A-2D) sub-systems determines the biophysical properties of the ion channels.
GluN2A and GluN2B are mainly expressed in the cortex and hippocampus regions, which are closely related to learning/memory.
GluN2B is the dominant expression in the pre-birth brain of an animal, gradually decreased after birth, and distributed in the synaptic region;
previous studies have focused on three-dimensional structure and conformation alsomes of the GluN1/GluN2B subtype, which is less well known for gluN1/GluN2A subtypes, which dominate the expression on adult synaptic post-film.
Note: The three-dimensional structure of the frozen electroscopy of the source GluN1/GluN2A subtype NMDA receptor.
glutamate and hydrogen ions in the pre-synaptic vesicles are released together into the synaptic gap, glutamate can act on the agonists binding the domain to open the ion channel, while hydrogen ions can act on the N-end domain of gluN2A sub-sub-sub-cells, acting to inhibit the excessive opening of the ion channels.
during the transmission of the excitatory synaptic signal, the synaptic pre-film releases the glutamate while releasing hydrogen ions, which inhibit the channel activity of the NMDA receptor.
but so far, the mechanism of hydrogen ioninhibits the activity of NMDA receptors is not clear. Zhang Jinbao, a research intern in the
's Group, analyzed the three-dimensional pixel of human-source gluN1/GluN2A NMDA receptors through the screening of multiple mutants, purified and obtained stable expression of the human source GluN1/GluN2A NMDA receptor, and together with Chang Shenghai, an electromirror platform engineer at Zhejiang University, analyzed the three-dimensional conformation of the human source GluN1/GluN2A subtype NMDA receptors under different pH conditions through single-particle cryoscope technology.
by conformation differences at relatively high/low pH conditions, the researchers not only demonstrated that proton sensors mainly have gluN2A sub-sub-subkeys in the N-end domain (N-terminal domain, GluN2A-NTD), but also analyzed the mechanism of the proton sensor's structural adjustment of the ion channels.
the N-end domain of gluN2A sub-base remains open and reversed in the high pH conditions, and during protonization, the N-end domain shifts to close and de-reverse the conformation.
at the same time, the researchers found that the conformational changes in the N-end domain affect the conformation altruism of the agonisant binding domain through the alterging effect, which in turn causes the closing of the gated channel (shown below).
at the same time, Xu Wang, a ph.d. student at Shanghai Pharmaceutical Institute, verified the above results through molecular dynamics simulation.
this work enriches the structural biology and neuropharmacology of NMDA receptors and provides important theoretical basis for drug design, screening and research and development of new drugs.
the research was funded by the National Key Research and Development Program, the National Natural Science Foundation, the Chinese Academy of Sciences' Strategic Pilot Science and Technology Project, the Shanghai Qixing Program and the Youth Thousand People Program.
Source: Institute of Neuroscience.