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J. Biol. Chem., Vol. 280, Issue 17, 16705-16713, April 29, 2005

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Regulation of Neuroprotective Activity of Myocyte-enhancer Factor 2 by cAMP-Protein Kinase A Signaling Pathway in Neuronal Survival^*

Xuemin Wang, Xiaoli Tang, Mingtao Li¶, John Marshall||, and Zixu Mao**

From the Department of Medicine, Brown University Medical School and Rhode Island Hospital, Providence, Rhode Island 02903, the ^¶Department of Pharmacology, Zhongshan Medical College, SUN yat-sen University, Number 74, Guangzhou 510080, China, and the ^||Department of Molecular Pharmacology, Physiology, and Biotechnology, Brown University Medical School, Providence, Rhode Island 02912

The transcription factor myocyte-enhancer factor 2 (MEF2) has been shown to be required for the survival of different types of neurons. However, the death- or survival-inducing second messenger pathways that regulate MEF2 activity remain to be fully elucidated. Membrane depolarization by KCl induces neuronal survival that is dependent upon MEF2-mediated gene transactivation. Here we report that membrane depolarizationinduced activation of MEF2 requires the cAMP-protein kinase A (PKA) pathway. Inhibition of the activity of cAMP-PKA pathway attenuates membrane depolarization-induced activation of MEF2 activity and neuronal survival, whereas enhancing the activity of this pathway prevents KCl withdrawal-induced inhibition of MEF2 and neuronal apoptosis. Moreover, PKA directly phosphorylates MEF2 at Thr-20 in vitro to increase MEF2 DNA binding activity. A mutation of Thr-20 to Ala renders MEF2 resistant to PKA phosphorylation in vitro and reduces its DNA binding activity. Transfection of this T20A mutant blocks survival and induces apoptosis in cultured cortical and cerebellar granule neurons. This study identifies the transcription factor MEF2 as a target of cAMP-PKA pathway and demonstrates that PKA phosphorylation of MEF2 is a key step in modulating its DNA binding activity and ability to promote neuronal survival.

Received for publication, February 17, 2005 , and in revised form, February 25, 2005.

^* This work was supported in part by National Institutes of Health Grants HD39446 (to Z. M.) and NS39063 (to J. M.) and National Nature Science Foundation of China Grant 3070299 (to M. L.). 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.

Both authors contributed equally to this work.

^** Present address: Depts. of Pharmacology and Neurology, Emory University School of Medicine, Atlanta, GA 30322. To whom correspondence should be addressed. Tel.: 404–712-8581; E-mail: zmao{at}pharm.emory.edu.

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