Cargando…

Structural basis of kainate subtype glutamate receptor desensitization

Glutamate receptors are ligand gated tetrameric ion channels that mediate synaptic transmission in the central nervous system. They are instrumental in vertebrate cognition and their dysfunction underlies diverse diseases(1,2). In both the resting and desensitized states of AMPA and kainate subtype...

Descripción completa

Detalles Bibliográficos
Autores principales: Meyerson, Joel R., Chittori, Sagar, Merk, Alan, Rao, Prashant, Han, Tae Hee, Serpe, Mihaela, Mayer, Mark L., Subramaniam, Sriram
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5161608/
https://www.ncbi.nlm.nih.gov/pubmed/27580033
http://dx.doi.org/10.1038/nature19352
_version_ 1782482098682068992
author Meyerson, Joel R.
Chittori, Sagar
Merk, Alan
Rao, Prashant
Han, Tae Hee
Serpe, Mihaela
Mayer, Mark L.
Subramaniam, Sriram
author_facet Meyerson, Joel R.
Chittori, Sagar
Merk, Alan
Rao, Prashant
Han, Tae Hee
Serpe, Mihaela
Mayer, Mark L.
Subramaniam, Sriram
author_sort Meyerson, Joel R.
collection PubMed
description Glutamate receptors are ligand gated tetrameric ion channels that mediate synaptic transmission in the central nervous system. They are instrumental in vertebrate cognition and their dysfunction underlies diverse diseases(1,2). In both the resting and desensitized states of AMPA and kainate subtype glutamate receptors the ion channels are closed while the ligand binding domain, which is physically coupled to the channel, adopts dramatically different conformations(3–6). Without an atomic model for the desensitized state, it is not possible to address a central question in receptor gating: how the resting and desensitized receptor states both display closed ion channels, even though they have major differences in quaternary structure of the ligand binding domain. By determining the cryo-EM structure of the kainate receptor GluK2 subtype in its desensitized state at 3.8 Å resolution, we show that desensitization is characterized by establishment of a ring-like structure in the ligand binding domain layer of the receptor. Formation of this “desensitization ring” is mediated by staggered helix contacts between adjacent subunits, which leads to a pseudo four-fold symmetric arrangement of the ligand binding domains, illustrating subtle changes in symmetry that are at the heart of the gating mechanism. Disruption of the desensitization ring is likely the key switch that enables restoration of the receptor to its resting state, thereby completing the gating cycle.
format Online
Article
Text
id pubmed-5161608
institution National Center for Biotechnology Information
language English
publishDate 2016
record_format MEDLINE/PubMed
spelling pubmed-51616082017-02-28 Structural basis of kainate subtype glutamate receptor desensitization Meyerson, Joel R. Chittori, Sagar Merk, Alan Rao, Prashant Han, Tae Hee Serpe, Mihaela Mayer, Mark L. Subramaniam, Sriram Nature Article Glutamate receptors are ligand gated tetrameric ion channels that mediate synaptic transmission in the central nervous system. They are instrumental in vertebrate cognition and their dysfunction underlies diverse diseases(1,2). In both the resting and desensitized states of AMPA and kainate subtype glutamate receptors the ion channels are closed while the ligand binding domain, which is physically coupled to the channel, adopts dramatically different conformations(3–6). Without an atomic model for the desensitized state, it is not possible to address a central question in receptor gating: how the resting and desensitized receptor states both display closed ion channels, even though they have major differences in quaternary structure of the ligand binding domain. By determining the cryo-EM structure of the kainate receptor GluK2 subtype in its desensitized state at 3.8 Å resolution, we show that desensitization is characterized by establishment of a ring-like structure in the ligand binding domain layer of the receptor. Formation of this “desensitization ring” is mediated by staggered helix contacts between adjacent subunits, which leads to a pseudo four-fold symmetric arrangement of the ligand binding domains, illustrating subtle changes in symmetry that are at the heart of the gating mechanism. Disruption of the desensitization ring is likely the key switch that enables restoration of the receptor to its resting state, thereby completing the gating cycle. 2016-08-31 2016-09-22 /pmc/articles/PMC5161608/ /pubmed/27580033 http://dx.doi.org/10.1038/nature19352 Text en Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms
spellingShingle Article
Meyerson, Joel R.
Chittori, Sagar
Merk, Alan
Rao, Prashant
Han, Tae Hee
Serpe, Mihaela
Mayer, Mark L.
Subramaniam, Sriram
Structural basis of kainate subtype glutamate receptor desensitization
title Structural basis of kainate subtype glutamate receptor desensitization
title_full Structural basis of kainate subtype glutamate receptor desensitization
title_fullStr Structural basis of kainate subtype glutamate receptor desensitization
title_full_unstemmed Structural basis of kainate subtype glutamate receptor desensitization
title_short Structural basis of kainate subtype glutamate receptor desensitization
title_sort structural basis of kainate subtype glutamate receptor desensitization
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5161608/
https://www.ncbi.nlm.nih.gov/pubmed/27580033
http://dx.doi.org/10.1038/nature19352
work_keys_str_mv AT meyersonjoelr structuralbasisofkainatesubtypeglutamatereceptordesensitization
AT chittorisagar structuralbasisofkainatesubtypeglutamatereceptordesensitization
AT merkalan structuralbasisofkainatesubtypeglutamatereceptordesensitization
AT raoprashant structuralbasisofkainatesubtypeglutamatereceptordesensitization
AT hantaehee structuralbasisofkainatesubtypeglutamatereceptordesensitization
AT serpemihaela structuralbasisofkainatesubtypeglutamatereceptordesensitization
AT mayermarkl structuralbasisofkainatesubtypeglutamatereceptordesensitization
AT subramaniamsriram structuralbasisofkainatesubtypeglutamatereceptordesensitization