Faculty Collaboration Database

Compartmentalization of the MAPK scaffold protein KSR1 modulates synaptic plasticity in hippocampal neurons. FASEB J 2011 Jul;25(7):2362-72

Date

04/08/2011

Pubmed ID

21471251

DOI

10.1096/fj.10-173153

Scopus ID

2-s2.0-79960180835 (requires institutional sign-in at Scopus site)   19 Citations

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.

Author List

Canal F, Palygin O, Pankratov Y, Corrêa SA, Müller J

MESH terms used to index this publication - Major topics in bold

Amino Acid Sequence
Animals
Benzamides
Binding Sites
Blotting, Western
Cells, Cultured
Dendritic Spines
Excitatory Postsynaptic Potentials
Feedback, Physiological
HEK293 Cells
Hippocampus
Humans
Male
Mice
Mice, Inbred C57BL
Mitogen-Activated Protein Kinase 1
Mitogen-Activated Protein Kinase 3
Molecular Sequence Data
Mutation
Neuronal Plasticity
Neurons
Phosphorylation
Protein Kinases
Sequence Homology, Amino Acid
Synapses