title: ERK activation causes epilepsy by stimulating NMDA receptor activity.
abstract: The ERK MAPK signalling pathway is a highly conserved kinase cascade linking transmembrane receptors to downstream effector mechanisms. To investigate the function of ERK in neurons, a constitutively active form of MEK1 (caMEK1) was conditionally expressed in the murine brain, which resulted in ERK activation and caused spontaneous epileptic seizures. ERK activation stimulated phosphorylation of eukaryotic translation initiation factor 4E (eIF4E) and augmented NMDA receptor 2B (NR2B) protein levels. Pharmacological inhibition of NR2B function impaired synaptic facilitation in area cornus ammonicus region 3 (CA3) in acute hippocampal slices derived from caMEK1-expressing mice and abrogated epilepsy in vivo. In addition, expression of caMEK1 caused phosphorylation of the transcription factor, cAMP response element-binding protein (CREB) and increased transcription of ephrinB2. EphrinB2 overexpression resulted in increased NR2B tyrosine phosphorylation, which was essential for caMEK1-induced epilepsy in vivo, since conditional inactivation of ephrinB2 greatly reduced seizure frequency in caMEK1 transgenic mice. Therefore, our study identifies a mechanism of epileptogenesis that links MAP kinase to Eph/Ephrin and NMDA receptor signalling.
authors.affiliation: Mammalian Genetics Laboratory, Cancer Research UK, London Research Institute, Lincoln's Inn Fields Laboratories, London, UK.
authors.forename: Abdolrahman S
authors.initials: AS
authors.lastname: Nateri
authors.forename: Gennadij
authors.initials: G
authors.lastname: Raivich
authors.forename: Christine
authors.initials: C
authors.lastname: Gebhardt
authors.forename: Clive
authors.initials: C
authors.lastname: Da Costa
authors.forename: Heike
authors.initials: H
authors.lastname: Naumann
authors.forename: Martin
authors.initials: M
authors.lastname: Vreugdenhil
authors.forename: Milan
authors.initials: M
authors.lastname: Makwana
authors.forename: Sebastian
authors.initials: S
authors.lastname: Brandner
authors.forename: Ralf H
authors.initials: RH
authors.lastname: Adams
authors.forename: John G R
authors.initials: JG
authors.lastname: Jefferys
authors.forename: Oliver
authors.initials: O
authors.lastname: Kann
authors.forename: Axel
authors.initials: A
authors.lastname: Behrens
mesh_terms: D000818:Animals; D000242:Cyclic AMP / Q000378:metabolism; D004789:Enzyme Activation; D036388:Ephrin-B2 / Q000378:metabolism; D004827:Epilepsy / Q000201:enzymology / Q000209:etiology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D048369:MAP Kinase Kinase 1 / Q000378:metabolism; D020935:MAP Kinase Signaling System; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D010766:Phosphorylation; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: D036388:Ephrin-B2; C121001:NR2B NMDA receptor; D016194:Receptors, N-Methyl-D-Aspartate; D000242:Cyclic AMP; D048049:Extracellular Signal-Regulated MAP Kinases; D048369:MAP Kinase Kinase 1