Epacs are members of a family of guanine nucleotide exchange factors (ENSFM00250000000899), which also includes RapGEF5 (GFR, KIAA0277, MR-GEF, Q92565) and RapGEFL1 (Link-GEFII, Q9UHV5). They are activated endogenously by cyclic AMP and with some pharmacological selectivity by 8-pCPT-2'-O-Me-cAMP [4]. Once activated, Epacs induce an enhanced activity of the monomeric G proteins, Rap1 and Rap2 by facilitating binding of guanosine-5'-triphosphate in place of guanosine 5'-diphosphate, leading to activation of phospholipase C [5].

* Key recommended reading is highlighted with an asterisk

* Fujita T, Umemura M, Yokoyama U, Okumura S, Ishikawa Y. (2017) The role of Epac in the heart. Cell. Mol. Life Sci., 74 (4): 591-606. [PMID:27549789]

Parnell E, Palmer TM, Yarwood SJ. (2015) The future of EPAC-targeted therapies: agonism versus antagonism. Trends Pharmacol. Sci., 36 (4): 203-14. [PMID:25744542]

* Robichaux 3rd WG, Cheng X. (2018) Intracellular cAMP Sensor EPAC: Physiology, Pathophysiology, and Therapeutics Development. Physiol. Rev., 98 (2): 919-1053. [PMID:29537337]

* Wang P, Liu Z, Chen H, Ye N, Cheng X, Zhou J. (2017) Exchange proteins directly activated by cAMP (EPACs): Emerging therapeutic targets. Bioorg. Med. Chem. Lett., 27 (8): 1633-1639. [PMID:28283242]

1. Almahariq M, Tsalkova T, Mei FC, Chen H, Zhou J, Sastry SK, Schwede F, Cheng X. (2013) A novel EPAC-specific inhibitor suppresses pancreatic cancer cell migration and invasion. Mol. Pharmacol., 83 (1): 122-8. [PMID:23066090]

2. Chen H, Tsalkova T, Chepurny OG, Mei FC, Holz GG, Cheng X, Zhou J. (2013) Identification and characterization of small molecules as potent and specific EPAC2 antagonists. J. Med. Chem., 56 (3): 952-62. [PMID:23286832]

3. Chen H, Wild C, Zhou X, Ye N, Cheng X, Zhou J. (2014) Recent advances in the discovery of small molecules targeting exchange proteins directly activated by cAMP (EPAC). J. Med. Chem., 57 (9): 3651-65. [PMID:24256330]

4. Enserink JM, Christensen AE, de Rooij J, van Triest M, Schwede F, Genieser HG, Døskeland SO, Blank JL, Bos JL. (2002) A novel Epac-specific cAMP analogue demonstrates independent regulation of Rap1 and ERK. Nat. Cell Biol., 4 (11): 901-6. [PMID:12402047]

5. Schmidt M, Evellin S, Weernink PA, von Dorp F, Rehmann H, Lomasney JW, Jakobs KH. (2001) A new phospholipase-C-calcium signalling pathway mediated by cyclic AMP and a Rap GTPase. Nat. Cell Biol., 3 (11): 1020-4. [PMID:11715024]