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.