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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...

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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
Descripción
Sumario: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.