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 [6].

* 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. Reverte-Salisa L, Siddig S, Hildebrand S, Yao X, Zurkovic J, Jaeckstein MY, Heeren J, Lezoualc'h F, Krahmer N, Pfeifer A. (2024) EPAC1 enhances brown fat growth and beige adipogenesis. Nat Cell Biol, 26 (1): 113-123. [PMID:38195707]

6. 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]