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J. Biol. Chem., Vol. 280, Issue 1, 660-668, January 7, 2005

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Depolarization Activates ERK and Proline-rich Tyrosine Kinase 2 (PYK2) Independently in Different Cellular Compartments in Hippocampal Slices^*

Jean-Christophe Corvol, Emmanuel Valjent, Madeleine Toutant, Hervé Enslen, Théano Irinopoulou, Sima Lev, Denis Hervé, and Jean-Antoine Girault¶

From the Signal Transduction and Plasticity in the Nervous System Unit, INSERM/Université Pierre et Marie Curie U536, Institut du Fer à Moulin, 75005 Paris, France and the Department of Neurobiology, Weizmann Institute of Science, Rehovot 76100, Israel

In the hippocampus, extracellular signal-regulated kinase (ERK) and the non-receptor protein proline-rich tyrosine kinase 2 (PYK2) are activated by depolarization and involved in synaptic plasticity. Both are also activated under pathological conditions following ischemia, convulsions, or electroconvulsive shock. Although in non-neuronal cells PYK2 activates ERK through the recruitment of Src-family kinases (SFKs), the link between these pathways in the hippocampus is not known. We addressed this question using K⁺-depolarized rat hippocampal slices. Depolarization increased the phosphorylation of PYK2, SFKs, and ERK. These effects resulted from Ca²⁺ influx through voltage-gated Ca²⁺ channels and were diminished by GF109203X, a protein kinase C inhibitor. Inhibition of SFKs with PP2 decreased PYK2 tyrosine phosphorylation dramatically, but not its autophosphorylation on Tyr-402. Moreover, PYK2 autophosphorylation and total tyrosine phosphorylation were profoundly altered in fyn-/- mice, revealing an important functional relationship between Fyn and PYK2 in the hippocampus. In contrast, ERK activation was unaltered by PP2, Fyn knock-out, or LY294002, a phosphatidyl-inositol-3-kinase inhibitor. ERK activation was prevented by MEK inhibitors that had no effect on PYK2. Immunofluorescence of hippocampal slices showed that PYK2 and ERK were activated in distinct cellular compartments in somatodendritic regions and nerve terminals, respectively, with virtually no overlap. Activation of ERK was critical for the rephosphorylation of a synaptic vesicle protein, synapsin I, following depolarization, underlining its functional importance in nerve terminals. Thus, in hippocampal slices, in contrast to cell lines, depolarization-induced activation of non-receptor tyrosine kinases and ERK occurs independently in distinct cellular compartments in which they appear to have different functional roles.

Received for publication, October 4, 2004

^* This work was supported by grants from INSERM, Human Frontiers Science Program, Fondation Schlumberger pour l'Enseignement et la Recherche (Dotation Gruener-Schlumberger), Fondation Liliane Bettencourt-Schueller, Fondation pour la Recherche Médicale, and Association pour la Recherche contre le Cancer to Jean-Antoine Girault. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ To whom correspondence should be addressed: INSERM/UPMC U536, Institut du Fer à Moulin, 17 Rue du Fer à Moulin, 75005 Paris France. Tel.: 33-1-4587-6158; Fax: 33-1-4587-6159; E-mail: girault{at}fer-a-moulin.inserm.fr.

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