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

* Bouvet M, Blondeau JP, Lezoualc'h F. (2019) The Epac1 Protein: Pharmacological Modulators, Cardiac Signalosome and Pathophysiology. Cells, 8 (12): 1543. DOI: 10.3390/cells8121543 [PMID:31795450]

* 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]

* Luchowska-Stańska U, Morgan D, Yarwood SJ, Barker G. (2019) Selective small-molecule EPAC activators. Biochem Soc Trans, 47 (5): 1415-1427. DOI: 10.1042/BST20190254 [PMID:31671184]

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]