title: Regulation of AMPA receptor subunit GluA1 surface expression by PAK3 phosphorylation.
abstract: AMPA receptors (AMPARs) are the major excitatory receptors of the brain and are fundamental to synaptic plasticity, memory, and cognition. Dynamic recycling of AMPARs in neurons is regulated through several types of posttranslational modification, including phosphorylation. Here, we identify a previously unidentified signal transduction cascade that modulates phosphorylation of serine residue 863 (S863) in the GluA1 AMPAR subunit and controls surface trafficking of GluA1 in neurons. Activation of the EphR-Ephrin signal transduction pathway enhances S863 phosphorylation. Further, EphB2 can interact with Zizimin1, a guanine-nucleotide exchange factor that activates Cdc42 and stimulates S863 phosphorylation in neurons. Among the numerous targets downstream of Cdc42, we determined that the p21-activated kinase-3 (PAK3) phosphorylates S863 in vitro. Moreover, specific loss of PAK3 expression and pharmacological inhibition of PAK both disrupt activity-dependent phosphorylation of S863 in cortical neurons. EphB2, Cdc42, and PAKs are broadly capable of controlling dendritic spine formation and synaptic plasticity and are implicated in multiple cognitive disorders. Collectively, these data delineate a novel signal cascade regulating AMPAR trafficking that may contribute to the molecular mechanisms that govern learning and cognition.
authors.affiliation: Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205;
authors.forename: Natasha K
authors.initials: NK
authors.lastname: Hussain
authors.affiliation: Shriners Hospitals Pediatric Research Center and Department of Anatomy and Cell Biology, Temple University School of Medicine, Philadelphia, PA 19140.
authors.forename: Gareth M
authors.initials: GM
authors.lastname: Thomas
authors.affiliation: Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205;
authors.forename: Junjie
authors.initials: J
authors.lastname: Luo
authors.affiliation: Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205; rhuganir@jhmi.edu.
authors.forename: Richard L
authors.initials: RL
authors.lastname: Huganir
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism; D008969:Molecular Sequence Data; D010766:Phosphorylation; D051381:Rats; D018091:Receptors, AMPA / Q000737:chemistry / Q000378:metabolism*; D036081:Receptors, Eph Family / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D012694:Serine / Q000378:metabolism; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism; D054462:p21-Activated Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: C579360:DOCK9 protein, rat; D020662:Guanine Nucleotide Exchange Factors; D018091:Receptors, AMPA; D012694:Serine; D036081:Receptors, Eph Family; C515913:Pak3 protein, rat; D054462:p21-Activated Kinases; D020764:cdc42 GTP-Binding Protein
keywords: AMPA; PSD; Zizimin; ephR; synaptic