Roles of Epac in synaptic plasticity, neurodevelopment, and cell death. (A) Effects of 8-CPT-induced activation and gene deletion of Epac. The 8-CPT activates both Epac1 and Epac2 in neural tissues. Note the stronger effect of 8-CPT on Epac1 activation (thick arrow) than Epac2 (thin arrow). Activation of Epac protein including Epac1 and Epac2 isoforms contributes to LTP maintenance via extracellular signal-regulated kinase 1/2 (ERK) activation, PACAP-mediated LTD induction via activation of p38 mitogen-activated protein kinases (MAPK), apoptosis by p38 MAPK-induced upregulation of Bim (Bcl-2-interacting mediator known as a Bcl-2 like protein 11), and inhibition of mTOR-independent autophagy activation through Rap2B/PLCε/inositol 1,4,5-trisphosphate (IP3) signaling pathway. However, effects of 8-CPT-induced Epac activation on neurite outgrowth and synaptic glutamate release are quite different and are not determined yet in neural tissue. (B) Role of Epac1 in neurite and axonal growth. Epac1 is involved in axonal growth through Rap1/ERK/cAMP-response element binding protein (CREB) signaling pathway. In Rap-independent manner, Epac1 plays a role in enhancement or inhibition of neurite growth via Rit/CREB activation or accumulation itself near plasma membrane regardless of binding to cAMP, respectively. (C) Role Epac2 and Epac2A isoform in neural tissues. Epac2 involves in adult neurogenesis and glial differentiation, apoptotic cell death and induces synaptic spine shrinkage and neurite outgrowth. The asymmetric expression of Ras/Epac2/Rap in dendritic compartments of cortical neurons affects the distribution of phosphorylated BRaf (p-BRaf) in dendrites and then maintenance of basal dendrite complexity in cortical neurons. However, the effect of Epac2 on LTP induction and maintenance is a controversial issue showing different results according to neural tissues. Epac2A isoform is required for LTD induction but not LTP in the hippocampus and astrocyte differentiation during development. LTP, long-term potentiation; LTD, long-term depression.
