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Gating motions underlie AMPA receptor secretion from the endoplasmic reticulum
Author(s) -
Penn Andrew C,
Williams Stephen R,
Greger Ingo H
Publication year - 2008
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1038/emboj.2008.222
Subject(s) - endoplasmic reticulum , biology , gating , ampa receptor , secretion , microbiology and biotechnology , stim1 , receptor , neuroscience , genetics , biochemistry , glutamate receptor
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.