title: State-dependent Ras signaling and AMPA receptor trafficking.
abstract: Synaptic trafficking of AMPA-Rs, controlled by small GTPase Ras signaling, plays a key role in synaptic plasticity. However, how Ras signals synaptic AMPA-R trafficking is unknown. Here we show that low levels of Ras activity stimulate extracellular signal-regulated kinase kinase (MEK)-p42/44 MAPK (extracellular signal-regulated kinase [ERK]) signaling, whereas high levels of Ras activity stimulate additional Pi3 kinase (Pi3K)-protein kinase B (PKB) signaling, each accounting for approximately 50% of the potentiation during long-term potentiation (LTP). Spontaneous neural activity stimulates the Ras-MEK-ERK pathway that drives GluR2L into synapses. In the presence of neuromodulator agonists, neural activity also stimulates the Ras-Pi3K-PKB pathway that drives GluR1 into synapses. Neuromodulator release increases with increases of vigilance. Correspondingly, Ras-MEK-ERK activity in sleeping animals is sufficient to deliver GluR2L into synapses, while additional increased Ras-Pi3K-PKB activity in awake animals delivers GluR1 into synapses. Thus, state-dependent Ras signaling, which specifies downstream MEK-ERK and Pi3K-PKB pathways, differentially control GluR2L- and GluR1-dependent synaptic plasticity.
authors.affiliation: Department of Pharmacology and Neuroscience Graduate Program, University of Virginia School of Medicine, Charlottesville, VA 22908, USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Qin
authors.forename: Yinghua
authors.initials: Y
authors.lastname: Zhu
authors.forename: Joel P
authors.initials: JP
authors.lastname: Baumgart
authors.forename: Ruth L
authors.initials: RL
authors.lastname: Stornetta
authors.forename: Kenneth
authors.initials: K
authors.lastname: Seidenman
authors.forename: Volker
authors.initials: V
authors.lastname: Mack
authors.forename: Linda
authors.initials: L
authors.lastname: van Aelst
authors.forename: J Julius
authors.initials: JJ
authors.lastname: Zhu
mesh_terms: D000818:Animals; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D006632:Histamine / Q000494:pharmacology; D066298:In Vitro Techniques; D017774:Long-Term Potentiation; D020935:MAP Kinase Signaling System; D008959:Models, Neurological; D016297:Mutagenesis, Site-Directed; D009473:Neuronal Plasticity; D018377:Neurotransmitter Agents / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D051381:Rats; D018091:Receptors, AMPA / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013569:Synapses / Q000378:metabolism; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D006632:Histamine; D018377:Neurotransmitter Agents; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D018091:Receptors, AMPA; D011993:Recombinant Fusion Proteins; D018631:ras Proteins; C104722:glutamate receptor ionotropic, AMPA 2