U 73343 The interaction of EPAC with Rim has an important r
The interaction of EPAC2 with Rim1 has an important role in regulating neurotransmitter release. In addition, a recent EPAC2 knockout mice model study provides evidence that EPAC2 promotes transmitter release by maintaining the readily releasable pool (RRP) at mossy fiber (MF) synapses in the hippocampus. Growing evidence demonstrates that EPAC participates in neurite growth and neuronal differentiation., In PC12 and NS-1 cells, EPAC2 is necessary for mediating growth arrest and neurite extension during neuronal differentiation through the mitogen activated protein kinase (MAPK) pathways including p38 and extracellular signal-regulated kinase (ERK). Studies based on EPAC1 and EPAC2 knockout mouse model have revealed that EPAC proteins exert significant physiological roles in learning, memory and social interactions in brain. Furthermore, EPAC2-deficent mice show reduced dendritic spine motility and density in cortical neurons, and display defects in social interactions and ultrasonic vocalizations. Thus, targeting EPAC signaling pathways may present a novel strategy for the treatment of CNS diseases. In the heart, EPAC can enhance cardiac contractility by regulating intracellular Ca concentration through PLCε, PKC, RyR and Ca/calmodulin-dependent protein kinase II (CaMKII) signaling pathways., In the hypertrophic heart, EPAC (mainly EPAC1) is found to be overexpressed. It suggests that EPAC may play an important role in cardiac hypertrophy. Activation of EPAC can prevent HO-induced production of reactive oxygen radical and inhibit the activation of caspase-3 and apoptosis in cardiomyocytes. Recently, it was reported that the activation of β-adrenergic receptors (β-AR) could lead to EPAC2-dependent sarcoplasmic reticulum (SR) Ca leak and arrhythmia through U 73343 of RyR2 by CaMKIIδ or PKA. Of note, the distributions between EPAC1 and EPAC2 in mice myocytes are significantly different. EPAC1 is limited in nuclear signaling while EPAC2 is found to gather around the T tubules, indicating that EPAC2 is involved in the arrhythmogenic SR Ca leak. EPAC also plays a critical role in the development of cardiac fibrosis. The important involvement of EPAC in cardiovascular functions offers a new direction for the discovery of new treatment of cardiovascular diseases. The roles of EPAC in vascular functions involve the regulation of smooth muscle cells migration and proliferation, vascular tone, endothelial barrier (EB) function and inflammation. In smooth muscle cells, EPAC enhances smooth muscle cells migration in the process of vascular remodeling and neointimal formation in response to femoral artery mechanical injuring. Further evidence supports that EPAC enhances smooth muscle cell migration through inducing integrin β1 activation and regulating extracellular matrix components scretion. Besides, EPAC can induce vasorelaxation or vasoconstriction through distinct regulation of intracellular Ca concentration and K., , In vivo studies reveal that knockout of the EPAC1 gene can attenuate neointima formation by inhibition of smooth muscle cells migration, in the meantime, Ca concentration and cofilin-mediated lamellipodia formation are decreased. Most recently, Cheng and co-workers found that EPAC1 involved in neointima formation through PI3K/AKT signaling pathway and mitochondrial fission in response to vascular injury in the mouse carotid artery ligation model. Therefore, EPAC is a promise therapeutic target for vascular diseases. In addition, EPAC exhibits anti-inflammatory activity against interleukin 6 (IL-6) receptor signaling through up-regulating the expression of suppressor of cytokine signaling 3 (SOCS3) in VECs. Both in vitro and in vivo studies revealed that inhibition of EPAC led to the expression vascular cell adhesion molecule 1 (VCAM-1) decrease and mediated the effect of Phosphodiesterase 4 (PDE4) activity. These findings indicate that EPAC-PDE4 signaling pathway may provide a novel means for the treatment of vascular inflammation inclusive of atherosclerosis and in-stent restenosis. Moreover, recent hyperalgesia priming and EPAC knockout mouse model studies uncovered a key role of EPAC1 in chronic inflammatory pain under the control of EPAC1 phosphorylation mediated by GPCR kinase 2 (GRK2)., It is worth to mention that EPAC is also associated with airway diseases via modulating airway smooth muscle cell functions., , Taken together, EPAC is an emerging therapeutic target for the drug discovery of cardiovascular diseases, inflammation and airway diseases.