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conserved glycine harboring disease-associated mutations permits NMDA receptor slow deactivation and high Ca permeability.

Title: A conserved glycine harboring disease-associated mutations permits NMDA receptor slow deactivation and high Ca permeability.
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Name(s): Amin, Johansen B, author
Leng, Xiaoling, author
Gochman, Aaron, author
Zhou, Huan-Xiang, author
Wollmuth, Lonnie P, author
Type of Resource: text
Genre: Journal Article
Text
Date Issued: 2018-09-14
Physical Form: computer
online resource
Extent: 1 online resource
Language(s): English
Abstract/Description: A variety of de novo and inherited missense mutations associated with neurological disorders are found in the NMDA receptor M4 transmembrane helices, which are peripheral to the pore domain in eukaryotic ionotropic glutamate receptors. Subsets of these mutations affect receptor gating with dramatic effects, including in one instance halting it, occurring at a conserved glycine near the extracellular end of M4. Functional experiments and molecular dynamic simulations of constructs with and without substitutions at this glycine indicate that it acts as a hinge, permitting the intracellular portion of the ion channel to laterally expand. This expansion stabilizes long-lived open states leading to slow deactivation and high Ca permeability. Our studies provide a functional and structural framework for the effect of missense mutations on NMDARs at central synapses and highlight how the M4 segment may represent a pathway for intracellular modulation of NMDA receptor function.
Identifier: FSU_pmch_30217972 (IID), 10.1038/s41467-018-06145-w (DOI), PMC6138751 (PMCID), 30217972 (RID), 30217972 (EID), 10.1038/s41467-018-06145-w (PII)
Grant Number: R01 NS088479, R35 GM118091, T32 GM007518, R01 NS088479
Publication Note: This NIH-funded author manuscript originally appeared in PubMed Central at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6138751.
Persistent Link to This Record: http://purl.flvc.org/fsu/fd/FSU_pmch_30217972
Host Institution: FSU
Is Part Of: Nature communications.
2041-1723
Issue: iss. 1, vol. 9

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Amin, J. B., Leng, X., Gochman, A., Zhou, H. -X., & Wollmuth, L. P. (2018). A conserved glycine harboring disease-associated mutations permits NMDA receptor slow deactivation and high Ca permeability. Nature Communications. Retrieved from http://purl.flvc.org/fsu/fd/FSU_pmch_30217972