Differential effects of Ca2+ and cAMP on transcription mediated by MEF2D and cAMP-response element-binding protein in hippocampal neurons.
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.
Belfield
Johanna L
JL
Department of Pharmacology, University of Cambridge, Tennis Court Road, Cambridge CB2 1PD, United Kingdom.
Whittaker
Chris
C
Cader
M Zaeem
MZ
Chawla
Sangeeta
S
D021581:Active Transport, Cell Nucleus; D000818:Animals; D002118:Calcium / Q000502:physiology*; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000502:physiology*; D017362:Cyclic AMP Response Element-Binding Protein / Q000502:physiology*; D006624:Hippocampus / Q000378:metabolism*; D006655:Histone Deacetylases / Q000378:metabolism; D017774:Long-Term Potentiation; D064326:MEF2 Transcription Factors; D018006:Myogenic Regulatory Factors / Q000502:physiology*; D050778:NFATC Transcription Factors / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D021381:Protein Transport; D051381:Rats; D017208:Rats, Wistar; D014158:Transcription, Genetic
D017362:Cyclic AMP Response Element-Binding Protein; D064326:MEF2 Transcription Factors; D018006:Myogenic Regulatory Factors; D050778:NFATC Transcription Factors; D000242:Cyclic AMP; C498619:Hdac5 protein, rat; D006655:Histone Deacetylases; D002118:Calcium