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J. Biol. Chem., Vol. 281, Issue 39, 29085-29095, September 29, 2006

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Induction of Krox-24 by Endogenous Cannabinoid Type 1 Receptors in Neuro2A Cells Is Mediated by the MEK-ERK MAPK Pathway and Is Suppressed by the Phosphatidylinositol 3-Kinase Pathway^*

E. Scott Graham, Nicola Ball, Emma L. Scotter, Pritika Narayan, Mike Dragunow, and Michelle Glass¹

From the Department of Pharmacology and the National Research Centre for Growth and Development, University of Auckland, Private Bag 92019, Auckland, New Zealand

Neuro2a cells endogenously express cannabinoid type 1 (CB1) receptors. CB1 stimulation with HU210 activated ERK and induced the transcription factor Krox-24. A functional MEK-ERK pathway is an important requirement for CB1-mediated Krox-24 induction as blockade of MEK signaling by UO126 reduces both basal and CB1-mediated activation of Krox-24. CB1 receptor stimulation did not activate either JNK or p38 MAPK pathways or the pro-proliferation phosphatidylinositol 3-kinase (PI3K)-Akt pathway. However, serum removal or blockade of PI3K signaling by LY294002 transiently stimulated basal Krox-24 expression and increased CB1-mediated induction of Krox-24. This was consistent with a transient increase in pMEK, pERK, and pCREB levels following PI3K blockade. These data demonstrate that CB1-mediated activation of the Krox-24 transcription factor is negatively regulated through the PI3K-Akt pathway and reveals several points of signaling cross-talk between these two important kinase pathways.

Received for publication, March 17, 2006 , and in revised form, July 21, 2006.

^* This work was supported by the Royal Society of New Zealand Marsden Fund and the Discovery-1 platform was funded by the National Research Centre for Growth and Development. 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.

¹ To whom correspondence should be addressed. Tel.: 649-373-7599 (Ext. 86247); Fax: 649-373-7556; E-mail: m.glass{at}auckland.ac.nz.

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