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J. Biol. Chem., Vol. 281, Issue 38, 27724-27732, September 22, 2006

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Differential Effects of Ca²⁺ and cAMP on Transcription Mediated by MEF2D and cAMP-response Element-binding Protein in Hippocampal Neurons^*

From the Department of Pharmacology, University of Cambridge, Tennis Court Road, Cambridge CB2 1PD, United Kingdom

In neurons, the second messengers Ca²⁺ and cAMP are mediators of transcriptional responses that are important for the development and function of the nervous system. The pro-survival neuronal transcription factors cAMP-response elementbinding protein (CREB) and myocyte enhancer factor-2 (MEF2) both stimulate gene expression in response to activity-dependent increases in the concentration of intracellular Ca²⁺ ions. CREB is also activated by increases in intracellular cAMP. Here we have investigated whether the MEF2 family member MEF2D, similar to CREB, is also activated by cAMP in hippocampal neurons. We have shown that, unlike CREB, MEF2D is not activated by agents that increase intracellular cAMP. Moreover, increases in cAMP inhibit Ca²⁺-activated MEF2D-mediated gene expression. We have also shown that cAMP inhibits Ca²⁺-induced nuclear export of the MEF2 co-repressor HDAC5 and prevents Ca²⁺-stimulated nuclear import of the MEF2 co-activator NFAT3/c4. Our results suggest that cAMP interferes with MEF2D-mediated gene expression at multiple levels by antagonizing the derepression of MEF2D by HDAC5 and by inhibiting recruitment of the co-activator NFAT.

Received for publication, February 15, 2006 , and in revised form, July 12, 2006.

^* This work was supported by a Biotechnology and Biological Sciences Research Council David Phillips Fellowship (to S. C.). 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 Supported by the King's College Durham fund for a vacation scholarship.

² To whom correspondence should be addressed: Dept. of Pharmacology, Tennis Ct. Rd., Cambridge CB2 1PD, UK. Tel.: 44-1223-334060; Fax: 44-1223-334100; E-mail: sc10008{at}cam.ac.uk.

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