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Conserved Glycine Harboring Disease-associated Mutations Permits Nmda Receptor Slow Deactivation And High Ca2+ Permeability

Title: A Conserved Glycine Harboring Disease-associated Mutations Permits Nmda Receptor Slow Deactivation And High Ca2+ 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
Journal Article
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 Ca2+ 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_libsubv1_wos_000444554800005 (IID), 10.1038/s41467-018-06145-w (DOI)
Keywords: desensitization, molecular-dynamics, tetramerization, currents, domains, channel, ampa receptors, autoantibodies, gating mechanism, transmembrane segment
Publication Note: The publisher’s version of record is available at https://doi.org/10.1038/s41467-018-06145-w
Persistent Link to This Record: http://purl.flvc.org/fsu/fd/FSU_libsubv1_wos_000444554800005
Owner Institution: FSU
Is Part Of: Nature Communications.
2041-1723
Issue: vol. 9

Choose the citation style.
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 Ca2+ Permeability. Nature Communications. Retrieved from http://purl.flvc.org/fsu/fd/FSU_libsubv1_wos_000444554800005