title: Epac activation induces histone deacetylase nuclear export via a Ras-dependent signalling pathway.
abstract: Epac (Exchange protein directly activated by cAMP) is a sensor for cAMP and represents a novel mechanism for governing cAMP signalling. Epac is a guanine nucleotide exchange factor (GEF) for the Ras family of small GTPases, Rap. Previous studies demonstrated that, in response to a prolonged beta-adrenergic stimulation Epac induced cardiac myocyte hypertrophy. The aim of our study was to further characterize Epac downstream effectors involved in cardiac myocyte growth. Here, we found that Epac led to the activation of the small G protein H-Ras in primary neonatal cardiac myocytes. A Rap GTPase activating protein (RapGAP) partially inhibited Epac-induced H-Ras activation. Interestingly, we found that H-Ras activation involved the GEF domain of Epac. However, Epac did not directly induce exchange activity on this small GTPase protein. Instead, the effect of Epac on H-Ras activation was dependent on a signalling cascade involving phospholipase C (PLC)/inositol 1,3,5 triphosphate receptor (IP3R) and an increase intracellular calcium. In addition, we found that Epac activation induced histone deacetylase type 4 (HDAC4) translocation. Whereas HDAC5 alone was unresponsive to Epac, it became responsive to Epac in the presence of HDAC4 in COS cells. Consistent with its effect on HDAC cytoplasmic shuttle, Epac activation also increased the prohypertrophic transcription factor MEF2 in a CaMKII dependent manner in primary cardiac myocytes. Thus, our data show that Epac activates a prohypertrophic signalling pathway which involves PLC, H-Ras, CaMKII and HDAC nuclear export.
authors.affiliation: Inserm, UMR-S 769, Signalisation et Physiopathologie Cardiaque, Châtenay-Malabry, France.
authors.forename: Mélanie
authors.initials: M
authors.lastname: Métrich
authors.forename: Anne-Coline
authors.initials: AC
authors.lastname: Laurent
authors.forename: Magali
authors.initials: M
authors.lastname: Breckler
authors.forename: Nicolas
authors.initials: N
authors.lastname: Duquesnes
authors.forename: Isabelle
authors.initials: I
authors.lastname: Hmitou
authors.forename: Delphine
authors.initials: D
authors.lastname: Courillau
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Blondeau
authors.forename: Bertrand
authors.initials: B
authors.lastname: Crozatier
authors.forename: Frank
authors.initials: F
authors.lastname: Lezoualc'h
authors.forename: Eric
authors.initials: E
authors.lastname: Morel
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D002118:Calcium / Q000378:metabolism; D006332:Cardiomegaly / Q000378:metabolism; D020134:Catalytic Domain; D002467:Cell Nucleus / Q000378:metabolism*; D002478:Cells, Cultured; D020662:Guanine Nucleotide Exchange Factors / Q000737:chemistry / Q000378:metabolism*; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000378:metabolism; D064326:MEF2 Transcription Factors; D032383:Myocytes, Cardiac / Q000201:enzymology / Q000378:metabolism*; D018006:Myogenic Regulatory Factors / Q000378:metabolism; D050778:NFATC Transcription Factors / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism*; D051381:Rats; D015398:Signal Transduction; D010738:Type C Phospholipases / Q000378:metabolism
chemical_list: D020662:Guanine Nucleotide Exchange Factors; D053496:Inositol 1,4,5-Trisphosphate Receptors; D064326:MEF2 Transcription Factors; D018006:Myogenic Regulatory Factors; D050778:NFATC Transcription Factors; C116122:RAPGEF3 protein, human; D010738:Type C Phospholipases; D006655:Histone Deacetylases; D016283:Proto-Oncogene Proteins p21(ras); D002118:Calcium