Gating motions underlie AMPA receptor secretion from the endoplasmic reticulum

Penn, Andrew C, Williams, Stephen R and Greger, Ingo H (2008) Gating motions underlie AMPA receptor secretion from the endoplasmic reticulum. EMBO Journal, 27 (22). pp. 3056-3068. ISSN 0261-4189

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Ion channel biogenesis involves an intricate interplay between subunit folding and assembly. Channel stoichiometries vary and give rise to diverse functions, which impacts on neuronal signalling. AMPA glutamate receptor (AMPAR) assembly is modulated by RNA processing. Here, we provide mechanistic insight into this process. First, we show that a single alternatively spliced residue within the ligand-binding domain alters AMPAR secretion from the ER. Local contacts differ between Leu758 of the GluR2-flop splice form as compared with the flip-specific Val758, which is transmitted globally to alter resensitization kinetics. Detailed biochemical and functional analysis of mutants suggest that AMPARs sample the gating cascade prior to ER export. Irreversibly locking the receptor within various states of the cascade severely attenuates ER transit. Alternative RNA processing by contrast, shifts equilibria between transition states reversibly and thereby modulates secretion kinetics. These data reveal how RNA processing tunes AMPAR biogenesis, and imply that gating transitions in the ER determine iGluR secretory traffic. © 2008 European Molecular Biology Organization | All Rights Reserved.

Item Type: Article
Schools and Departments: School of Life Sciences > Neuroscience
Subjects: R Medicine > RC Internal medicine > RC0321 Neurosciences. Biological psychiatry. Neuropsychiatry
Depositing User: Stephanie Turley
Date Deposited: 04 Dec 2015 14:40
Last Modified: 18 Feb 2016 13:00
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