Article
- The EMBO Journal (2007) 26, 4891 - 4901
- doi:10.1038/sj.emboj.7601911
Published online: 1 November 2007
Subject Categories:
ERK activation causes epilepsy by stimulating NMDA receptor activity
Abdolrahman S Nateri1,2, Gennadij Raivich3, Christine Gebhardt4, Clive Da Costa1, Heike Naumann5, Martin Vreugdenhil6, Milan Makwana3, Sebastian Brandner5, Ralf H Adams7, John GR Jefferys6, Oliver Kann4 and Axel Behrens1
- Mammalian Genetics Laboratory, Cancer Research UK, London Research Institute, Lincoln's Inn Fields Laboratories, London, UK
- Division of Pre-Clinical Oncology, Digestive Diseases Centre, Queen's Medical Centre, School of the Medical and Surgical Sciences, University of Nottingham, Nottingham, UK
- Perinatal Brain Repair Group, Departments of Anatomy & Obstetrics and Gynaecology, University College London, London, UK
- Institute for Neurophysiology, Charité—Universitätsmedizin Berlin, Berlin, Germany
- Division of Neuropathology, Department of Neurodegenerative Disease, Institute of Neurology, London, UK
- Division of Neuroscience, Department of Neurophysiology, Medical School, University of Birmingham, Edgbaston, UK
- Vascular Development Laboratory, Cancer Research UK, London Research Institute, Lincoln's Inn Fields Laboratories, London, UK
Correspondence to:
Axel Behrens, Mammalian Genetics Laboratory, Cancer Research UK, London Research Institute, Lincoln's Inn Fields Laboratories, 44, Lincoln's Inn Fields, London WC2A 3PX, UK. Tel.: +44 207 269 3361; Fax: +44 207 269 3581; E-mail: axel.behrens@cancer.org.uk
Received 10 August 2007; Accepted 10 October 2007
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.
Keywords:
- cre/loxP,
- ephrins,
- epilepsy,
- ERK,
- MEK1,
- NMDA receptor
MORE ARTICLES LIKE THIS
These links to content published by NPG are automatically generated
REVIEWS
Epileptogenesis in the immature brain: emerging mechanisms
Nature Reviews Neurology Review (01 Jul 2009)
NEWS AND VIEWS
Epilepsy and the too-well-connected brain
Nature Medicine News and Views (01 Sep 1997)
Shaking down new epilepsy genes
Nature Medicine News and Views (01 May 1996)
RESEARCH
Nature Medicine Article (01 Oct 1998)
Journal of Cerebral Blood Flow & Metabolism Original Article
