title: Cell surface expression of GluR5 kainate receptors is regulated by an endoplasmic reticulum retention signal.
abstract: Kainate receptors (KARs) are mediators of excitatory neurotransmission in the mammalian central nervous system, and their efficient targeting and trafficking is critical for normal synaptic function. A key step in the delivery of KARs to the neuronal plasma membrane is the exit of newly assembled receptors from the endoplasmic reticulum (ER). Here we report the identification of a novel ER retention signal in the alternatively spliced C-terminal domain of the GluR5-2b subunit, which controls receptor trafficking in both heterologous cells and neurons. The ER retention motif consists of a critical arginine (Arg-896) and surrounding amino acids, disruption of which promotes ER exit and surface expression of the receptors, as well as altering their physiological properties. The Arg-896-mediated ER retention of GluR5 is regulated by a mutation that mimics phosphorylation of Thr-898, but not by PDZ interactions. Furthermore, two positively charged residues (Arg-900 and Lys-901) in the C terminus were also found to regulate ER export of the receptors. Taken together, our results identify novel trafficking signals in the C-terminal domain of GluR5-2b and demonstrate that alternative splicing is an important mechanism regulating KAR function.
authors.affiliation: Department of Molecular Pharmacology, Physiology and Biotechnology, Brown University, Providence, Rhode Island 02912, USA.
authors.forename: Zhao
authors.initials: Z
authors.lastname: Ren
authors.forename: Nathan J
authors.initials: NJ
authors.lastname: Riley
authors.forename: Leigh A
authors.initials: LA
authors.lastname: Needleman
authors.forename: James M
authors.initials: JM
authors.lastname: Sanders
authors.forename: Geoffrey T
authors.initials: GT
authors.lastname: Swanson
authors.forename: John
authors.initials: J
authors.lastname: Marshall
mesh_terms: D017398:Alternative Splicing; D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D001120:Arginine / Q000737:chemistry; D019921:Biotinylation; D015153:Blotting, Western; D019556:COS Cells; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism*; D004594:Electrophysiology; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D005434:Flow Cytometry; D017353:Gene Deletion; D005786:Gene Expression Regulation; D005822:Genetic Vectors; D006801:Humans; D015151:Immunoblotting; D008856:Microscopy, Fluorescence; D008969:Molecular Sequence Data; D009154:Mutation; D009474:Neurons / Q000378:metabolism; D010766:Phosphorylation; D017434:Protein Structure, Tertiary; D051381:Rats; D017207:Rats, Sprague-Dawley; D018092:Kainic Acid Receptors / Q000096:biosynthesis* / Q000737:chemistry*; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D014162:Transfection
chemical_list: D001120:Arginine; D018092:Kainic Acid Receptors