Mechanisms underlying TARP modulation of the GluA1/2-γ8 AMPA receptor.
Authors
Kohegyi, Bianka K
Dohrke, Jan-Niklas
Zhang, Danyang
Lape, Remigijus
Publication Date
2022-02-08Journal Title
Nat Commun
ISSN
2041-1723
Publisher
Springer Science and Business Media LLC
Volume
13
Issue
1
Language
en
Type
Article
This Version
VoR
Metadata
Show full item recordCitation
Herguedas, B., Kohegyi, B. K., Dohrke, J., Watson, J. F., Zhang, D., Ho, H., Shaikh, S. A., et al. (2022). Mechanisms underlying TARP modulation of the GluA1/2-γ8 AMPA receptor.. Nat Commun, 13 (1) https://doi.org/10.1038/s41467-022-28404-7
Abstract
AMPA-type glutamate receptors (AMPARs) mediate rapid signal transmission at excitatory synapses in the brain. Glutamate binding to the receptor's ligand-binding domains (LBDs) leads to ion channel activation and desensitization. Gating kinetics shape synaptic transmission and are strongly modulated by transmembrane AMPAR regulatory proteins (TARPs) through currently incompletely resolved mechanisms. Here, electron cryo-microscopy structures of the GluA1/2 TARP-γ8 complex, in both open and desensitized states (at 3.5 Å), reveal state-selective engagement of the LBDs by the large TARP-γ8 loop ('β1'), elucidating how this TARP stabilizes specific gating states. We further show how TARPs alter channel rectification, by interacting with the pore helix of the selectivity filter. Lastly, we reveal that the Q/R-editing site couples the channel constriction at the filter entrance to the gate, and forms the major cation binding site in the conduction path. Our results provide a mechanistic framework of how TARPs modulate AMPAR gating and conductance.
Keywords
Article, /631/535/1258/1259, /631/378/2586, /631/57/2283, /631/45/269/1149, /9, /9/74, /101, /101/28, /13, article
Sponsorship
RCUK | Biotechnology and Biological Sciences Research Council (BBSRC) (BB/N002113/1)
RCUK | Medical Research Council (MRC) (MC_U105174197)
Identifiers
s41467-022-28404-7, 28404
External DOI: https://doi.org/10.1038/s41467-022-28404-7
This record's URL: https://www.repository.cam.ac.uk/handle/1810/333786
Rights
Licence:
http://creativecommons.org/licenses/by/4.0/
Statistics
Total file downloads (since January 2020). For more information on metrics see the
IRUS guide.
Recommended or similar items
The current recommendation prototype on the Apollo Repository will be turned off on 03 February 2023. Although the pilot has been fruitful for both parties, the service provider IKVA is focusing on horizon scanning products and so the recommender service can no longer be supported. We recognise the importance of recommender services in supporting research discovery and are evaluating offerings from other service providers. If you would like to offer feedback on this decision please contact us on: support@repository.cam.ac.uk