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dc.contributor.authorHerguedas, Beatriz
dc.contributor.authorKohegyi, Bianka K
dc.contributor.authorDohrke, Jan-Niklas
dc.contributor.authorWatson, Jake F
dc.contributor.authorZhang, Danyang
dc.contributor.authorHo, Hinze
dc.contributor.authorShaikh, Saher A
dc.contributor.authorLape, Remigijus
dc.contributor.authorKrieger, James M
dc.contributor.authorGreger, Ingo H
dc.date.accessioned2022-02-09T13:22:24Z
dc.date.available2022-02-09T13:22:24Z
dc.date.issued2022-02-08
dc.date.submitted2021-08-06
dc.identifier.issn2041-1723
dc.identifier.others41467-022-28404-7
dc.identifier.other28404
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/333786
dc.description.abstractAMPA-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.
dc.languageen
dc.publisherSpringer Science and Business Media LLC
dc.subjectArticle
dc.subject/631/535/1258/1259
dc.subject/631/378/2586
dc.subject/631/57/2283
dc.subject/631/45/269/1149
dc.subject/9
dc.subject/9/74
dc.subject/101
dc.subject/101/28
dc.subject/13
dc.subjectarticle
dc.titleMechanisms underlying TARP modulation of the GluA1/2-γ8 AMPA receptor.
dc.typeArticle
dc.date.updated2022-02-09T13:22:23Z
prism.issueIdentifier1
prism.publicationNameNat Commun
prism.volume13
dc.identifier.doi10.17863/CAM.81203
dcterms.dateAccepted2022-01-13
rioxxterms.versionofrecord10.1038/s41467-022-28404-7
rioxxterms.versionVoR
rioxxterms.licenseref.urihttp://creativecommons.org/licenses/by/4.0/
dc.contributor.orcidHerguedas, Beatriz [0000-0003-2044-4795]
dc.contributor.orcidWatson, Jake F [0000-0002-8698-3823]
dc.contributor.orcidHo, Hinze [0000-0003-1082-9851]
dc.contributor.orcidShaikh, Saher A [0000-0002-6162-5472]
dc.contributor.orcidKrieger, James M [0000-0001-6194-6244]
dc.contributor.orcidGreger, Ingo H [0000-0002-7291-2581]
dc.identifier.eissn2041-1723
pubs.funder-project-idRCUK | Biotechnology and Biological Sciences Research Council (BBSRC) (BB/N002113/1)
pubs.funder-project-idRCUK | Medical Research Council (MRC) (MC_U105174197)
cam.issuedOnline2022-02-08


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