title: Molecular Mechanism of AMPA Receptor Modulation by TARP/Stargazin.
abstract: AMPA receptors (AMPARs) mediate the majority of fast excitatory transmission in the brain and critically contribute to synaptic plasticity and pathology. AMPAR trafficking and gating are tightly controlled by auxiliary transmembrane AMPAR regulatory proteins (TARPs). Here, using systematic domain swaps with the TARP-insensitive kainate receptor GluK2, we show that AMPAR interaction with the prototypical TARP stargazin/γ2 primarily involves the AMPAR membrane domains M1 and M4 of neighboring subunits, initiated or stabilized by the AMPAR C-tail, and that these interactions are sufficient to enable full receptor modulation. Moreover, employing TARP chimeras disclosed a key role in this process also for the TARP transmembrane domains TM3 and TM4 and extracellular loop 2. Mechanistically, our data support a two-step action in which binding of TARP to the AMPAR membrane domains destabilizes the channel closed state, thereby enabling an efficient opening upon agonist binding, which then stabilizes the open state via subsequent interactions.
authors.affiliation: Department of Biochemistry and Molecular Biology, Institute for Medical Research Israel-Canada (IMRIC), Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 91120, Israel.
authors.forename: Anat
authors.initials: A
authors.lastname: Ben-Yaacov
authors.affiliation: Department of Biochemistry and Molecular Biology, Institute for Medical Research Israel-Canada (IMRIC), Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 91120, Israel.
authors.forename: Moshe
authors.initials: M
authors.lastname: Gillor
authors.affiliation: Department of Biochemistry and Molecular Biology, Institute for Medical Research Israel-Canada (IMRIC), Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 91120, Israel.
authors.forename: Tomer
authors.initials: T
authors.lastname: Haham
authors.affiliation: Department of Biochemistry and Molecular Biology, Institute for Medical Research Israel-Canada (IMRIC), Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 91120, Israel.
authors.forename: Alon
authors.initials: A
authors.lastname: Parsai
authors.affiliation: Department of Biochemistry and Molecular Biology, Institute for Medical Research Israel-Canada (IMRIC), Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 91120, Israel.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Qneibi
authors.affiliation: Department of Biochemistry and Molecular Biology, Institute for Medical Research Israel-Canada (IMRIC), Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 91120, Israel. Electronic address: yaelste@ekmd.huji.ac.il.
authors.forename: Yael
authors.initials: Y
authors.lastname: Stern-Bach
mesh_terms: D000818:Animals; D015220:Calcium Channels / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism*; D021381:Protein Transport / Q000502:physiology; D018091:Receptors, AMPA / Q000378:metabolism*; D018092:Kainic Acid Receptors / Q000378:metabolism; D009435:Synaptic Transmission / Q000502:physiology*; D014981:Xenopus; D029867:Xenopus Proteins / Q000378:metabolism*; D000097806:GluK2 Kainate Receptor
chemical_list: D015220:Calcium Channels; D009687:Nuclear Proteins; D018091:Receptors, AMPA; D018092:Kainic Acid Receptors; D029867:Xenopus Proteins; D000097806:GluK2 Kainate Receptor; C558132:CACNG2 protein, Xenopus; C413185:TARP
keywords: AMPA receptor; Stargazin; TARP; desensitization; gating mechanism; glutamate; ion-channel; kainate