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Extracellular signal-regulated kinase and glycogen synthase kinase 3beta regulate gephyrin postsynaptic aggregation and GABAergic synaptic function in a calpain-dependent mechanism

Tyagarajan, SK and Ghosh, H and Yevenes, GE and Imanishi, SY and Zeilhofer, HU and Gerrits, B and Fritschy, J (2013) Extracellular signal-regulated kinase and glycogen synthase kinase 3beta regulate gephyrin postsynaptic aggregation and GABAergic synaptic function in a calpain-dependent mechanism. Journal of Biological Chemistry. pp. 9634-9647.

Abstract

Molecular mechanisms of plasticity at GABAergic synapses are currently poorly understood. To identify signaling cascades that converge onto GABAergic postsynaptic density proteins, we performed MS analysis using gephyrin isolated from rat brain and identified multiple novel phosphorylation and acetylation residues on gephyrin. Here, we report the characterization of one of these phosphoresidues, Ser-268, which when dephosphorylated leads to the formation of larger postsynaptic scaffolds. Using a combination of mutagenesis, pharmacological treatment, and biochemical assays, we identify ERK as the kinase phosphorylating Ser-268 and describe a functional interaction between residues Ser-268 and Ser-270. We further demonstrate that alterations in gephyrin clustering via ERK modulation are reflected by amplitude and frequency changes in miniature GABAergic postsynaptic currents. We unravel novel mechanisms for activity- and ERK-dependent calpain action on gephyrin, which are likely relevant in the context of cellular signaling affecting GABAergic transmission and homeostatic synaptic plasticity in pathology. 2013 by The American Society for Biochemistry and Molecular Biology, Inc

Item Type: Article
Additional Information: pubid: 94 nvp_institute: NIBR contributor_address: (Tyagarajan, Ghosh, Yevenes, Zeilhofer, Fritschy) Institute of Pharmacology and Toxicology, University of Zurich, Winterthurerstr. 190, CH-8057 Zurich, Switzerland (Zeilhofer) Institute of Pharmaceutical Sciences, ETH Zurich, Zurich, 8093, Switzerland (Gerrits) Functional Genomics Center Zurich, 8057 Zurich, Switzerland (Tyagarajan, Ghosh, Zeilhofer, Fritschy) Neuroscience Center Zurich, Zurich, 8057, Switzerland (Imanishi) Turku Centre for Biotechnology, University of Turku, Abo Akademi University, 20520 Turku, Finland (Gerrits) Novartis Institute for Biomedical Research, Fabrikstr. 22, 4002 Basel, Switzerland
Date Deposited: 13 Oct 2015 13:13
Last Modified: 13 Oct 2015 13:13
URI: https://oak.novartis.com/id/eprint/21935

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