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.

Evaluation of neurotoxic and neuroprotective pathways affected by antiepileptic drugs in cultured hippocampal neurons

“…In fact, in an in vivo study, phospho-ERK levels were shown to increase after a behavioural seizure detection (Houser et al, 2008). Inhibiting ERK signaling might be useful for seizure control (Nateri et al, 2007).…”

Acute 19-nortestosterone transiently suppresses hippocampal MAPK pathway and the phosphorylation of the NMDA receptor

“…Thus, it appears that the depleted GluN2B protein levels observed in the present study are a consequence of increased internalisation due to decreased phosphorylation of GluN2B Y1472 . Nateri et al [21] suggests that MEK1 overexpression in mice leads to elevated hippocampal GluN2B protein levels through increased ERK phosphorylation and subsequent activation of eIF4E. In that study, GluN2B levels were not associated with those of phosphorylated GluN2B Y1472 .…”

“…Although androgens are reported to stimulate synaptogenesis [40], our results do not support an engagement of eIF4E in the synaptic fraction at least not within the time frame tested in the present investigation. Looking up-stream of NMDAR regulation, ephrinB2 is a protein that stimulates the phosphorylation of GluN2B at Y1472 through Fyn kinase [21,22]. Moreover, it is also known to regulate synaptic plasticity [27].…”

“…This factor, known to be activated by ERK, is essential for mRNA translation and as such considered to be a marker and regulator of A c c e p t e d M a n u s c r i p t 4 synaptodendritic protein synthesis underlying structural plasticity [20]. Furthermore, we determined the protein levels of ephrinB2, an ERK regulated synaptic component that can stimulate the phosphorylation of GluN2B at Y1472 though the src family kinase Fyn [21,22]. The results show that 19NT acutely and transiently decreases phosphorylated GluN2B and ERK through a flutamide sensitive pathway.…”

Stapling Mimics Noncovalent Interactions of γ-Carboxyglutamates in Conantokins, Peptidic Antagonists of N-Methyl-d-Aspartic Acid Receptors

“…Because NMDA receptor targets of conantokins have been strongly implicated in epileptogenesis (34,42,51), the pharmacological activity of the stapled conG analogs was speculated to result from antagonism of these receptor targets. Compared with the native peptide, stapled conG analogs possessed similar efficacy in suppressing seizure activities.…”