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Originally published In Press as doi:10.1074/jbc.M210037200 on January 3, 2003

J. Biol. Chem., Vol. 278, Issue 11, 8904-8912, March 14, 2003
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Growth Differentiation Factor-15 Prevents Low Potassium-induced Cell Death of Cerebellar Granule Neurons by Differential Regulation of Akt and ERK Pathways*

Srinivasa SubramaniamDagger , Jens StrelauDagger §, and Klaus Unsicker

From the Neuroanatomy and Interdisciplinary Center for Neurosciences (IZN), University of Heidelberg, Im Neuenheimer Feld 307, D-69120 Heidelberg, Germany

Growth differentiation factor-15 (GDF-15) is a novel member of the transforming growth factor-beta superfamily and has been shown to be induced in neurons subsequent to lesions. We have therefore begun to study its putative role in the regulation of neuron survival and apoptosis. Cultured cerebellar granule neurons (CGN) survive when maintained in high K+ (25 mM) but undergo apoptosis when switched to low K+ (5 mM). GDF-15 prevented death of CGN in low K+. This effect could be blocked by phosphatidylinositol 3-kinase/Akt pathway inhibitors LY294002 or wortmannin. In contrast, mitogen-activated protein kinase (MEK)/extracellular-signal-regulated kinase (ERK) pathway inhibitors U0126 and PD98059 potentiated GDF-15 mediated survival and prevented cell death in low K+ even without factor treatment. Immunoblots revealed GDF-15-induced phosphorylation of Akt and glycogen synthase kinase-3beta . This activation was suppressed by phosphatidylinositol 3-kinase inhibitors. Low K+ induced delayed and persistent ERK activation, which was blocked by MEK inhibitors or GDF-15. ERK activation induced c-Jun, a member of the AP-1 transcription factor family. GDF-15 or U0126 prevented c-Jun activation. Furthermore, we show that GDF-15 prevented generation of reactive oxygen species, a known activator of ERK. Together, our data suggest that GDF-15 prevents apoptosis in CGN by activating Akt and inhibiting endogenously active ERK.

* This work was supported by grants from Deutsche Forschungsgemeinschaft (STR 616/1-2) and Bundesministerium für Bildung und Forschung.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Dagger These two authors contributed equally to this work.

§ To whom correspondence should be addressed: Neuroanatomy, IZN, University of Heidelberg, Im Neuenheimer Feld 307, 2. OG, D-69120 Heidelberg, Germany. Tel.: 49-6221-54-8227; Fax: 49-6221-54-5604; E-mail: Jens.Strelau@urz.uni-heidelberg.de.

Copyright © 2003 by The American Society for Biochemistry and Molecular Biology, Inc.
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