Epac protein

Bos JL (2006) Epac proteins multi-purpose cAMP targets. Trends Biochem Sci 31 680-686... 

Robert S, Maillet M, Morel E, et al. Regulation of the amyloid precursor protein ectodomain shedding by the 5-HT4 receptor and Epac. FEBS Lett 2005 579 1136-1142. 

Lin SL, Johnson-Farley NN, Lubinsky DR, Cowen DS. Coupling of neuronal 5-HT7 receptors to activation of extracellular-regulated kinase through a protein kinase A-independent pathway that can utilize Epac. J Neurochem 2003 87 1076-1085. 

Fig. 5.8 A scenario where adenylyl cyclase is activated by a hormoneactivated GPCR. The elevated cellular level of cAMP activates EPAC, the exchange protein directly activated by cAMP. The GDP/GTP exchange activily of EPAC promotes the formation of the active, GTPhound form of the monomeric G protein. Rapl. Rapl recruits and activates RafB, the upstream kinase of the Map kinase pathway. (This scheme is shown with permission of the authors and Nature, ref. 56.)...

EPAC exchange protein directly activated by cAMP... 

A sensor for cAMP requires a conformational change of the protein upon binding of the ligand. This is provided by the two major cAMP-binding proteins the regulatoiy subunit of the cAMP-dependent protein kinase (PKA) or by EPAC (exchange protein directly activated by cAMP). Both proteins were equipped with the standard FRET pair EYFP and ECFP attached to the N- and C-termini, respectively [96]. When expressed in hippocampal neurons or peritoneal macrophages. 

Novara M, Baldelli P, Cavallari D, Carabelli V, Giancippoli A, Carbone E. Exposure to cAMP and beta-adrenergic stimulation recruits Cav3 T-type channels in rat chromaffin cells through Epac cAMP-receptor proteins. J Physiol 2004 558(Pt 2) 433-49. 

Most human CKRs preferentially activate Gaj/o proteins, resulting in the inhibition of cyclic adenosine monophosphate (cAMP) production by the enzyme adenylyl cyclase (AC). cAMP activates exchange proteins activated by cAMP (Epac) and protein kinase A (PKA) and the latter subsequently activates the transcription factor cAMP-responsive element (CRE). The released CPy subunits activate phosphoHpase C-P (PLC-P), resulting in the formation of inositol 1,4,5-triphosphate (IP3) and diacylglycerol (DAG) from phosphatidylinositol-4,5-bisphosphate (PIP2)- IP3 subsequently increases intracellular Ca release from endoplasmic reticulum (ER) stores, which results in the activation of protein kinase C (PKC) and the transcription factor nuclear factor of activated T cells (NFAT) (Neptune Bourne, 1997 Patel et al., 2013). Furthermore, CKRs are phosphorylated on their intracellular domains by G protein-coupled receptor kinases (GRKs) and subsequently recruit P-arrestins (Fig. 12). 

Figure 12 CKR signaling. CKRs preferentially signal via Gai/o proteins and recruit p-arrestin upon receptor activation. Abbreviations AC, adenylyl cyclase ATP, adenosine triphosphate cAMP, cyclic adenosine monophosphate CRE, cAMP-responsive element DAG, diacylglycerol Epac, exchange proteins activated by cAMP GRK, G protein-coupled receptor kinase IP3, inositol 1,4,5-triphosphate NFAT, nuclear factor of activated T-cells PIP2, phosphatidylinositol-4,5-bisphosphate PKA, protein kinase A PKC, protein kinase C PLC-p, phospholipase C-p.

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