title: Identification of a novel signaling pathway and its relevance for GluA1 recycling.
abstract: We previously showed that the serum- and glucocorticoid-inducible kinase 3 (SGK3) increases the AMPA-type glutamate receptor GluA1 protein in the plasma membrane. The activation of AMPA receptors by NMDA-type glutamate receptors eventually leads to postsynaptic neuronal plasticity. Here, we show that SGK3 mRNA is upregulated in the hippocampus of new-born wild type Wistar rats after NMDA receptor activation. We further demonstrate in the Xenopus oocyte expression system that delivery of GluA1 protein to the plasma membrane depends on the small GTPase RAB11. This RAB-dependent GluA1 trafficking requires phosphorylation and activation of phosphoinositol-3-phosphate-5-kinase (PIKfyve) and the generation of PI(3,5)P(2). In line with this mechanism we could show PIKfyve mRNA expression in the hippocampus of wild type C57/BL6 mice and phosphorylation of PIKfyve by SGK3. Incubation of hippocampal slices with the PIKfyve inhibitor YM201636 revealed reduced CA1 basal synaptic activity. Furthermore, treatment of primary hippocampal neurons with YM201636 altered the GluA1 expression pattern towards reduced synaptic expression of GluA1. Our findings demonstrate for the first time an involvement of PIKfyve and PI(3,5)P(2) in NMDA receptor-triggered synaptic GluA1 trafficking. This new regulatory pathway of GluA1 may contribute to synaptic plasticity and memory.
authors.affiliation: Department of Biochemistry I-Cation Channel Group, Ruhr University Bochum, Bochum, Germany.
authors.forename: Guiscard
authors.initials: G
authors.lastname: Seebohm
authors.forename: Sebastian
authors.initials: S
authors.lastname: Neumann
authors.forename: Carsten
authors.initials: C
authors.lastname: Theiss
authors.forename: Tanja
authors.initials: T
authors.lastname: Novkovic
authors.forename: Elaine V
authors.initials: EV
authors.lastname: Hill
authors.forename: Jeremy M
authors.initials: JM
authors.lastname: Tavaré
authors.forename: Florian
authors.initials: F
authors.lastname: Lang
authors.forename: Michael
authors.initials: M
authors.lastname: Hollmann
authors.forename: Denise
authors.initials: D
authors.lastname: Manahan-Vaughan
authors.forename: Nathalie
authors.initials: N
authors.lastname: Strutz-Seebohm
mesh_terms: D000631:Aminopyridines / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006575:Heterocyclic Compounds, 3-Ring / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D017874:Immediate-Early Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009865:Oocytes / Q000378:metabolism; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism; D010766:Phosphorylation; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D018091:Receptors, AMPA / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D015398:Signal Transduction; D015854:Up-Regulation; D014981:Xenopus / Q000254:growth & development / Q000378:metabolism; D020691:rab GTP-Binding Proteins / Q000378:metabolism; D000099184:Serum-Glucocorticoid Regulated Kinases; D000099193:rab11 GTP-Binding Proteins
chemical_list: D000631:Aminopyridines; D004791:Enzyme Inhibitors; D006575:Heterocyclic Compounds, 3-Ring; D017874:Immediate-Early Proteins; D018129:Phosphatidylinositol Phosphates; D017853:Phosphotransferases (Alcohol Group Acceptor); D017346:Protein Serine-Threonine Kinases; D012333:RNA, Messenger; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate; D020691:rab GTP-Binding Proteins; D000099184:Serum-Glucocorticoid Regulated Kinases; D000099193:rab11 GTP-Binding Proteins; C540576:6-amino-N-(3-(4-(4-morpholinyl)pyrido(3',2'-4,5)furo(3,2-d)pyrimidin-2-yl)phenyl)-3-pyridinecarboxamide; C106336:phosphatidylinositol 3,5-diphosphate; C544731:PIKfyve protein, rat