State-dependent Ras signaling and AMPA receptor trafficking.
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.
Qin
Yi
Y
Department of Pharmacology and Neuroscience Graduate Program, University of Virginia School of Medicine, Charlottesville, VA 22908, USA.
Zhu
Yinghua
Y
Baumgart
Joel P
JP
Stornetta
Ruth L
RL
Seidenman
Kenneth
K
Mack
Volker
V
van Aelst
Linda
L
Zhu
J Julius
JJ
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*
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