Canal, F., Palygin, Oleg, Pankratov, Yuriy, Corrêa, Sônia A. L. and Müller, Jürgen. (2011) Compartmentalization of the MAPK scaffold protein KSR1 modulates synaptic plasticity in hippocampal neurons. The FASEB Journal, Vol.25 (No.7). pp. 2362-2372. ISSN 0892-6638

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Abstract

ERK1/2 is required for certain forms of synaptic plasticity, including the long-term potentiation of synaptic strength. However, the molecular mechanisms regulating synaptically localized ERK1/2 signaling are poorly understood. Here, we show that the MAPK scaffold protein kinase suppressor of Ras 1 (KSR1) is directly phosphorylated by the downstream kinase ERK1/2. Quantitative Western blot analysis further demonstrates that expression of mutated, feedback-deficient KSR1 promotes sustained ERK1/2 activation in HEK293 cells in response to EGF stimulation, compared to a more transient activation in control cells expressing wild-type KSR1. Immunocytochemistry and confocal imaging of primary hippocampal neurons from newborn C57BL6 mice further show that feedback phosphorylation of KSR1 significantly reduces its localization to dendritic spines. This effect can be reversed by tetrodotoxin (1 μM) or PD184352 (2 μM) treatment, further suggesting that neuronal activity and phosphorylation by ERK1/2 lead to KSR1 removal from the postsynaptic compartment. Consequently, electrophysiological recordings in hippocampal neurons expressing wild-type or feedback-deficient KSR1 demonstrate that KSR1 feedback phosphorylation restricts the potentiation of excitatory postsynaptic currents. Our findings, therefore, suggest that feedback phosphorylation of the scaffold protein KSR1 prevents excessive ERK1/2 signaling in the postsynaptic compartment and thus contributes to maintaining physiological levels of synaptic excitability.—Canal, F., Palygin, O., Pankratov, Y., Corrêa, S. A. L., Müller, J. Compartmentalization of the MAPK scaffold protein KSR1 modulates synaptic plasticity in hippocampal neurons.

Item Type:	Journal Article
Subjects:	Q Science > QP Physiology
Divisions:	Faculty of Science > Life Sciences (2010- ) Faculty of Medicine > Warwick Medical School > Translational & Systems Medicine > Metabolic and Vascular Health Faculty of Medicine > Warwick Medical School
Library of Congress Subject Headings (LCSH):	Mitogen-activated protein kinases, Hippocampus (Brain), Neurons
Journal or Publication Title:	The FASEB Journal
Publisher:	Federation of American Societies for Experimental Biology
ISSN:	0892-6638
Official Date:	July 2011
Volume:	Vol.25
Number:	No.7
Page Range:	pp. 2362-2372
Identification Number:	10.1096/fj.10-173153
Status:	Peer Reviewed
Publication Status:	Published
Access rights to Published version:	Restricted or Subscription Access
URI:	http://wrap.warwick.ac.uk/id/eprint/39483

Data sourced from Thomson Reuters' Web of Knowledge

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