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Compartmentalization of the MAPK scaffold protein KSR1 modulates synaptic plasticity in hippocampal neurons
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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. doi:10.1096/fj.10-173153 ISSN 0892-6638.
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Official URL: http://dx.doi.org/10.1096/fj.10-173153
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 | ||||
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| Subjects: | Q Science > QP Physiology | ||||
| Divisions: | Faculty of Science, Engineering and Medicine > Science > Life Sciences (2010- ) Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School > Biomedical Sciences > Translational & Experimental Medicine > Metabolic and Vascular Health (- until July 2016) Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School |
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| 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 | ||||
| Dates: |
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| Volume: | Vol.25 | ||||
| Number: | No.7 | ||||
| Page Range: | pp. 2362-2372 | ||||
| DOI: | 10.1096/fj.10-173153 | ||||
| Status: | Peer Reviewed | ||||
| Publication Status: | Published | ||||
| Access rights to Published version: | Restricted or Subscription Access |
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