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dc.contributor.authorDawe, G Brenten
dc.contributor.authorKadir, Md Fahimen
dc.contributor.authorVenskutonytė, Ramintaen
dc.contributor.authorPerozzo, Amanda Men
dc.contributor.authorYan, Yuhaoen
dc.contributor.authorAlexander, Ryan PDen
dc.contributor.authorNavarrete, Camiloen
dc.contributor.authorSantander, Eduardo Aen
dc.contributor.authorArsenault, Marikaen
dc.contributor.authorFuentes, Christianen
dc.contributor.authorAurousseau, Mark RPen
dc.contributor.authorFrydenvang, Karlaen
dc.contributor.authorBarrera, Nelson Pen
dc.contributor.authorKastrup, Jette Sen
dc.contributor.authorEdwardson, Michaelen
dc.contributor.authorBowie, Dereken
dc.date.accessioned2019-04-16T23:32:01Z
dc.date.available2019-04-16T23:32:01Z
dc.date.issued2019-06en
dc.identifier.issn0896-6273
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/291776
dc.description.abstractNeurotransmitter-gated ion-channels are allosteric proteins that switch on and off in response to agonist binding. Most studies have focused on the agonist-bound, activated channel whilst assigning a lesser role to the apo or resting state. Here, we show that nanoscale mobility of resting AMPA-type ionotropic glutamate receptors (AMPARs) predetermines responsiveness to neurotransmitter, allosteric anions and auxiliary TARP subunits. Mobility at rest is regulated by alternative splicing of the flip/flop cassette of the ligand-binding domain which controls motions in the distant AMPAR amino-terminal domain (NTD). Flip variants promote moderate NTD movement which establishes slower channel desensitization and robust regulation by anions and auxiliary subunits. In contrast, greater NTD mobility imparted by the flop cassette acts as a master-switch to override allosteric regulation. In AMPAR heteromers, TARP stoichiometry further modifies these actions of the flip/flop cassette generating two functionally-distinct classes of partially- and fully-TARPed receptors typical of cerebellar stellate and Purkinje cells.
dc.format.mediumPrint-Electronicen
dc.languageengen
dc.publisherCell Press
dc.rightsAttribution-NonCommercial-NoDerivatives 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by-nc-nd/4.0/
dc.subjectCerebellumen
dc.subjectPurkinje Cellsen
dc.subjectAnimalsen
dc.subjectHumansen
dc.subjectMiceen
dc.subjectMembrane Proteinsen
dc.subjectReceptors, AMPAen
dc.subjectProtein Isoformsen
dc.subjectCryoelectron Microscopyen
dc.subjectMicroscopy, Atomic Forceen
dc.subjectCrystallography, X-Rayen
dc.subjectPatch-Clamp Techniquesen
dc.subjectIon Channel Gatingen
dc.subjectAlternative Splicingen
dc.subjectAllosteric Regulationen
dc.subjectAllosteric Siteen
dc.subjectProtein Structure, Quaternaryen
dc.subjectProtein Structure, Tertiaryen
dc.subjectHEK293 Cellsen
dc.subjectProtein Domainsen
dc.titleNanoscale Mobility of the Apo State and TARP Stoichiometry Dictate the Gating Behavior of Alternatively Spliced AMPA Receptors.en
dc.typeArticle
prism.endingPage992.e5
prism.issueIdentifier5en
prism.publicationDate2019en
prism.publicationNameNeuronen
prism.startingPage976
prism.volume102en
dc.identifier.doi10.17863/CAM.38936
dcterms.dateAccepted2019-03-28en
rioxxterms.versionofrecord10.1016/j.neuron.2019.03.046en
rioxxterms.versionAM
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserveden
rioxxterms.licenseref.startdate2019-06en
dc.contributor.orcidPerozzo, Amanda M [0000-0001-9681-3548]
dc.contributor.orcidBowie, Derek [0000-0001-9491-8768]
dc.identifier.eissn1097-4199
rioxxterms.typeJournal Article/Reviewen
cam.orpheus.successThu Jan 30 10:46:13 GMT 2020 - Embargo updated*
rioxxterms.freetoread.startdate2020-04-17


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Attribution-NonCommercial-NoDerivatives 4.0 International
Except where otherwise noted, this item's licence is described as Attribution-NonCommercial-NoDerivatives 4.0 International