Differential effects of Ca2+ and cAMP on transcription mediated by MEF2D and cAMP-response element-binding protein in hippocampal neurons

TY - JOUR

T1 - Differential effects of Ca2+ and cAMP on transcription mediated by MEF2D and cAMP-response element-binding protein in hippocampal neurons

AU - Belfield, Johanna L

AU - Whittaker, Chris

AU - Cader, M Zaeem

AU - Chawla, Sangeeta

PY - 2006

Y1 - 2006

N2 - In neurons, the second messengers Ca(2+) 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 Ca(2+) 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 Ca(2+)-activated MEF2D-mediated gene expression. We have also shown that cAMP inhibits Ca(2+)-induced nuclear export of the MEF2 co-repressor HDAC5 and prevents Ca(2+)-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.

AB - In neurons, the second messengers Ca(2+) 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 Ca(2+) 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 Ca(2+)-activated MEF2D-mediated gene expression. We have also shown that cAMP inhibits Ca(2+)-induced nuclear export of the MEF2 co-repressor HDAC5 and prevents Ca(2+)-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.

KW - Active Transport, Cell Nucleus

KW - Animals

KW - Calcium

KW - Cells, Cultured

KW - Cyclic AMP

KW - Cyclic AMP Response Element-Binding Protein

KW - Hippocampus

KW - Histone Deacetylases

KW - Long-Term Potentiation

KW - Myogenic Regulatory Factors

KW - NFATC Transcription Factors

KW - Neurons

KW - Protein Transport

KW - Rats

KW - Rats, Wistar

KW - Transcription, Genetic

U2 - 10.1074/jbc.M601485200

DO - 10.1074/jbc.M601485200

M3 - Article

C2 - 16870618

SN - 0021-9258

VL - 281

SP - 27724

EP - 27732

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

IS - 38

ER -