RAPGEF3

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Rap guanine nucleotide exchange factor 3 also known as exchange factor directly activated by cAMP 1 (EPAC1) or cAMP-regulated guanine nucleotide exchange factor I (cAMP-GEFI) is a protein that in humans is encoded by the RAPGEF3 gene.[1][2][3]

As the name suggests, EPAC proteins (EPAC1 and EPAC2) are a family of intracellular sensors for cAMP, and function as nucleotide exchange factors for the Rap subfamily of RAS-like small GTPases.

History and discovery

Since the landmark discovery of the prototypic second messenger cAMP in 1957, three families of eukaryotic cAMP receptors have been identified to mediate the intracellular functions of cAMP. While protein kinase A (PKA) or cAMP-dependent protein kinase and cyclic nucleotide regulated ion channel (CNG and HCN) were initially unveiled in 1968 and 1985 respectively; EPAC genes were discovered in 1998 independently by two research groups. Kawasaki et al. identified cAMP-GEFI and cAMP-GEFII as novel genes enriched in brain using a differential display protocol and by screening clones with cAMP-binding motif.[3] De Rooij and colleagues performed a database search for proteins with sequence homology to both GEFs for Ras and Rap1 and to cAMP-binding sites, which led to the identification and subsequent cloning of RAPGEF3 gene.[2] The discovery of EPAC family cAMP sensors suggests that the complexity and possible readouts of cAMP signaling are much more elaborate than previously envisioned. This is due to the fact that the net physiological effects of cAMP entail the integration of EPAC- and PKA-dependent pathways, which may act independently, converge synergistically, or oppose each other in regulating a specific cellular function.[4][5][6]

Gene

Human RAPGEF3 gene is present on chromosome 12 (12q13.11: 47,734,367-47,771,041).[7] Out of the many predicted transcript variants, three that are validated in the NCBI database include transcript variant 1 (6,239 bp), 2 (5,773 bp) and 3 (6,003 bp). While variant 1 encodes for EPAC1a (923 amino acids), both variant 2 and 3 encode EPAC1b (881 amino acids).[1]

Protein family

In mammals, the EPAC protein family contains two members: EPAC1 (this protein) and EPAC2 (RAPGEF4). They further belong to a more extended family of Rap/Ras-specific GEF proteins that also include C3G (RAPGEF1), PDZ-GEF1 (RAPGEF2), PDZ-GEF2 (RAPGEF6), Repac (RAPGEF5), CalDAG-GEF1 (ARHGEF1), CalDAG-GEF3 (ARHGEF3), PLCε1 (PLCE1) and RasGEF1A, B, C.

Protein structure and mechanism of activation

EPAC proteins consist of two structural lobes/halves connected by the so-called central “switchboard” region.[8] The N terminal regulatory lobe is responsible for cAMP binding while the C-terminal lobe contains the nucleotide exchange factor activity. At the basal cAMP-free state, EPAC is kept in an auto-inhibitory conformation, in which the N-terminal lobe folds on top of the C-terminal lobe, blocking the active site.[9][10] Binding of cAMP to EPAC induces a hinge motion between the regulatory and catalytic halves. As a consequence, the regulatory lobe moves away from catalytic lobe, freeing the active site.[11][12] In addition, cAMP also prompts conformational changes within the regulatory lobe that lead to the exposure of a lipid binding motif, allowing the proper targeting of EPAC1 to the plasma membrane.[13][14] Entropically favorable changes in protein dynamics have also been implicated in cAMP mediated EPAC activation.[15][16]

Tissue distribution and cellular localization

Human and mice EPAC1 mRNA expression is rather ubiquitous. As per Human Protein Atlas documentation, EPAC1 mRNA is detectable in all normal human tissues. Further, medium to high levels of corresponding protein are also measureable in more than 50% of the 80 tissue samples analyzed.[17] In mice, high levels of EPAC1 mRNA are detected in kidney, ovary, skeletal muscle, thyroid and certain areas of the brain.[3]

EPAC1 is a multifunctional protein whose cellular functions are tightly regulated in spatial and temporal manners. EPAC1 is localized to various subcellular locations during different stages of the cell cycle.[18] Through interactions with an array of cellular partners, EPAC1 has been shown to form discrete signalsomes at plasma membrane,[14][19][20][21] nuclear-envelope,[22][23][24] and cytoskeleton,[25][26][27] where EPAC1 regulates numerous cellular functions.

Clinical relevance

Studies based on genetically engineered mouse models of EPAC1 have provided valuable insights into understanding the in vivo functions of EPAC1 under both physiological and pathophysiological conditions. Overall, mice deficient of EPAC1 or both EPAC1 and EPAC2 appear relatively normal without major phenotypic defects. These observations are consistent with the fact that cAMP is a major stress response signal not essential for survival. This makes EPAC1 an attractive target for therapeutic intervention as the on-target toxicity of EPAC-based therapeutics will likely be low. Up to data, genetic and pharmacological analyses of EPAC1 in mice have revealed that EPAC1 plays important roles in cardiac stresses and heart failure,[28][29] leptin resistance and energy homeostasis,[30][31][32] chronic pain,[33][34] infection,[35][36] cancer metastasis[37] and metabolism.[38]

Pharmacological agonists and antagonists

There have been significant interests in discovering and developing small modulators specific for EPAC proteins for better understanding the functions of EPAC mediated cAMP signaling, as well as for exploring the therapeutic potential of targeting EPAC proteins. Structure-based design targeting the key difference between the cAMP binding sites of EPAC and PKA led to the identification of a cAMP analogue, 8-pCPT-2’-O-Me-cAMP that is capable of selectively activate EPAC1.[39][40] Further modifications allowed the development of more membrane permeable and metabolically stable EPAC-specific agonists.[41][42][43][44]

A high throughput screening effort resulted in the discovery of several novel EPAC specific inhibitors (ESIs),[45][46][47] among which two ESIs act as EPAC2 selective antagonists with negligible activity towards EPAC1.[48] Another ESI, CE3F4, with modest selectivity for EPAC1 over EPAC2, has also been reported.[49] The discovery of EPAC specific antagonists represents a research milestone that allows the pharmacological manipulation of EPAC activity. In particular, one EPAC antagonist, ESI-09, with excellent activity and minimal toxicity in vivo, has been shown to be a useful pharmacological tool for probing physiological functions of EPAC proteins and for testing therapeutic potential of targeting EPAC in animal disease models.[35][37][50]

Notes


References

  1. ↑ 1.0 1.1 "Entrez". Entrez gene. Retrieved 19 June 2015.
  2. ↑ 2.0 2.1 de Rooij J, Zwartkruis FJ, Verheijen MH, Cool RH, Nijman SM, Wittinghofer A, Bos JL (Dec 1998). "Epac is a Rap1 guanine-nucleotide-exchange factor directly activated by cyclic AMP". Nature. 396 (6710): 474–7. doi:10.1038/24884. PMID 9853756.
  3. ↑ 3.0 3.1 3.2 Kawasaki H, Springett GM, Mochizuki N, Toki S, Nakaya M, Matsuda M, Housman DE, Graybiel AM (Dec 1998). "A family of cAMP-binding proteins that directly activate Rap1". Science. 282 (5397): 2275–9. doi:10.1126/science.282.5397.2275. PMID 9856955.
  4. ↑ Mei FC, Qiao J, Tsygankova OM, Meinkoth JL, Quilliam LA, Cheng X (Mar 2002). "Differential signaling of cyclic AMP: opposing effects of exchange protein directly activated by cyclic AMP and cAMP-dependent protein kinase on protein kinase B activation". The Journal of Biological Chemistry. 277 (13): 11497–504. doi:10.1074/jbc.M110856200. PMID 11801596.
  5. ↑ Cheng X, Ji Z, Tsalkova T, Mei F (Jul 2008). "Epac and PKA: a tale of two intracellular cAMP receptors". Acta Biochimica et Biophysica Sinica. 40 (7): 651–62. doi:10.1111/j.1745-7270.2008.00438.x. PMC 2630796. PMID 18604457.
  6. ↑ Huston E, Lynch MJ, Mohamed A, Collins DM, Hill EV, MacLeod R, Krause E, Baillie GS, Houslay MD (Sep 2008). "EPAC and PKA allow cAMP dual control over DNA-PK nuclear translocation". Proceedings of the National Academy of Sciences of the United States of America. 105 (35): 12791–6. doi:10.1073/pnas.0805167105. PMC 2529053. PMID 18728186.
  7. ↑ "Ensembl". H. Human RAPGEF3 gene. Retrieved 19 June 2015.
  8. ↑ Rehmann H, Das J, Knipscheer P, Wittinghofer A, Bos JL (Feb 2006). "Structure of the cyclic-AMP-responsive exchange factor Epac2 in its auto-inhibited state". Nature. 439 (7076): 625–8. doi:10.1038/nature04468. PMID 16452984.
  9. ↑ de Rooij J, Rehmann H, van Triest M, Cool RH, Wittinghofer A, Bos JL (Jul 2000). "Mechanism of regulation of the Epac family of cAMP-dependent RapGEFs". The Journal of Biological Chemistry. 275 (27): 20829–36. doi:10.1074/jbc.M001113200. PMID 10777494.
  10. ↑ Rehmann H, Rueppel A, Bos JL, Wittinghofer A (Jun 2003). "Communication between the regulatory and the catalytic region of the cAMP-responsive guanine nucleotide exchange factor Epac". The Journal of Biological Chemistry. 278 (26): 23508–14. doi:10.1074/jbc.M301680200. PMID 12707263.
  11. ↑ Rehmann H, Arias-Palomo E, Hadders MA, Schwede F, Llorca O, Bos JL (Sep 2008). "Structure of Epac2 in complex with a cyclic AMP analogue and RAP1B". Nature. 455 (7209): 124–7. doi:10.1038/nature07187. PMID 18660803.
  12. ↑ Tsalkova T, Blumenthal DK, Mei FC, White MA, Cheng X (Aug 2009). "Mechanism of Epac activation: structural and functional analyses of Epac2 hinge mutants with constitutive and reduced activities". The Journal of Biological Chemistry. 284 (35): 23644–51. doi:10.1074/jbc.M109.024950. PMC 2749139. PMID 19553663.
  13. ↑ Li S, Tsalkova T, White MA, Mei FC, Liu T, Wang D, Woods VL, Cheng X (May 2011). "Mechanism of intracellular cAMP sensor Epac2 activation: cAMP-induced conformational changes identified by amide hydrogen/deuterium exchange mass spectrometry (DXMS)". The Journal of Biological Chemistry. 286 (20): 17889–97. doi:10.1074/jbc.M111.224535. PMC 3093864. PMID 21454623.
  14. ↑ 14.0 14.1 Consonni SV, Gloerich M, Spanjaard E, Bos JL (Mar 2012). "cAMP regulates DEP domain-mediated binding of the guanine nucleotide exchange factor Epac1 to phosphatidic acid at the plasma membrane". Proceedings of the National Academy of Sciences of the United States of America. 109 (10): 3814–9. doi:10.1073/pnas.1117599109. PMC 3309772. PMID 22343288.
  15. ↑ Das R, Chowdhury S, Mazhab-Jafari MT, Sildas S, Selvaratnam R, Melacini G (Aug 2009). "Dynamically driven ligand selectivity in cyclic nucleotide binding domains". The Journal of Biological Chemistry. 284 (35): 23682–96. doi:10.1074/jbc.M109.011700. PMC 2749143. PMID 19403523.
  16. ↑ VanSchouwen B, Selvaratnam R, Fogolari F, Melacini G (Dec 2011). "Role of dynamics in the autoinhibition and activation of the exchange protein directly activated by cyclic AMP (EPAC)". The Journal of Biological Chemistry. 286 (49): 42655–69. doi:10.1074/jbc.M111.277723. PMC 3234915. PMID 21873431.
  17. ↑ "Human Protein Altas". RAPGEF3. Retrieved 19 June 2015.
  18. ↑ Qiao J, Mei FC, Popov VL, Vergara LA, Cheng X (Jul 2002). "Cell cycle-dependent subcellular localization of exchange factor directly activated by cAMP". The Journal of Biological Chemistry. 277 (29): 26581–6. doi:10.1074/jbc.M203571200. PMID 12000763.
  19. ↑ Ponsioen B, Gloerich M, Ritsma L, Rehmann H, Bos JL, Jalink K (May 2009). "Direct spatial control of Epac1 by cyclic AMP". Molecular and Cellular Biology. 29 (10): 2521–31. doi:10.1128/MCB.01630-08. PMC 2682048. PMID 19273589.
  20. ↑ Gloerich M, Ponsioen B, Vliem MJ, Zhang Z, Zhao J, Kooistra MR, Price LS, Ritsma L, Zwartkruis FJ, Rehmann H, Jalink K, Bos JL (Nov 2010). "Spatial regulation of cyclic AMP-Epac1 signaling in cell adhesion by ERM proteins". Molecular and Cellular Biology. 30 (22): 5421–31. doi:10.1128/MCB.00463-10. PMC 2976368. PMID 20855527.
  21. ↑ Hochbaum D, Barila G, Ribeiro-Neto F, Altschuler DL (Jan 2011). "Radixin assembles cAMP effectors Epac and PKA into a functional cAMP compartment: role in cAMP-dependent cell proliferation". The Journal of Biological Chemistry. 286 (1): 859–66. doi:10.1074/jbc.M110.163816. PMC 3013045. PMID 21047789.
  22. ↑ Dodge-Kafka KL, Soughayer J, Pare GC, Carlisle Michel JJ, Langeberg LK, Kapiloff MS, Scott JD (Sep 2005). "The protein kinase A anchoring protein mAKAP coordinates two integrated cAMP effector pathways". Nature. 437 (7058): 574–8. doi:10.1038/nature03966. PMC 1636584. PMID 16177794.
  23. ↑ Gloerich M, Bos JL (Oct 2011). "Regulating Rap small G-proteins in time and space". Trends in Cell Biology. 21 (10): 615–23. doi:10.1016/j.tcb.2011.07.001. PMID 21820312.
  24. ↑ Liu C, Takahashi M, Li Y, Dillon TJ, Kaech S, Stork PJ (Aug 2010). "The interaction of Epac1 and Ran promotes Rap1 activation at the nuclear envelope". Molecular and Cellular Biology. 30 (16): 3956–69. doi:10.1128/MCB.00242-10. PMC 2916442. PMID 20547757.
  25. ↑ Mei FC, Cheng X (Oct 2005). "Interplay between exchange protein directly activated by cAMP (Epac) and microtubule cytoskeleton". Molecular bioSystems. 1 (4): 325–31. doi:10.1039/b511267b. PMID 16880999.
  26. ↑ Sehrawat S, Cullere X, Patel S, Italiano J, Mayadas TN (Mar 2008). "Role of Epac1, an exchange factor for Rap GTPases, in endothelial microtubule dynamics and barrier function". Molecular Biology of the Cell. 19 (3): 1261–70. doi:10.1091/mbc.E06-10-0972. PMC 2262967. PMID 18172027.
  27. ↑ Sehrawat S, Ernandez T, Cullere X, Takahashi M, Ono Y, Komarova Y, Mayadas TN (Jan 2011). "AKAP9 regulation of microtubule dynamics promotes Epac1-induced endothelial barrier properties". Blood. 117 (2): 708–18. doi:10.1182/blood-2010-02-268870. PMC 3031489. PMID 20952690.
  28. ↑ Métrich M, Lucas A, Gastineau M, Samuel JL, Heymes C, Morel E, Lezoualc'h F (Apr 2008). "Epac mediates beta-adrenergic receptor-induced cardiomyocyte hypertrophy". Circulation Research. 102 (8): 959–65. doi:10.1161/CIRCRESAHA.107.164947. PMID 18323524.
  29. ↑ Okumura S, Fujita T, Cai W, Jin M, Namekata I, Mototani Y, Jin H, Ohnuki Y, Tsuneoka Y, Kurotani R, Suita K, Kawakami Y, Hamaguchi S, Abe T, Kiyonari H, Tsunematsu T, Bai Y, Suzuki S, Hidaka Y, Umemura M, Ichikawa Y, Yokoyama U, Sato M, Ishikawa F, Izumi-Nakaseko H, Adachi-Akahane S, Tanaka H, Ishikawa Y (Jun 2014). "Epac1-dependent phospholamban phosphorylation mediates the cardiac response to stresses". The Journal of Clinical Investigation. 124 (6): 2785–801. doi:10.1172/JCI64784. PMC 4038559. PMID 24892712.
  30. ↑ Fukuda M, Williams KW, Gautron L, Elmquist JK (Mar 2011). "Induction of leptin resistance by activation of cAMP-Epac signaling". Cell Metabolism. 13 (3): 331–9. doi:10.1016/j.cmet.2011.01.016. PMC 3747952. PMID 21356522.
  31. ↑ Yan J, Mei FC, Cheng H, Lao DH, Hu Y, Wei J, Patrikeev I, Hao D, Stutz SJ, Dineley KT, Motamedi M, Hommel JD, Cunningham KA, Chen J, Cheng X (Mar 2013). "Enhanced leptin sensitivity, reduced adiposity, and improved glucose homeostasis in mice lacking exchange protein directly activated by cyclic AMP isoform 1". Molecular and Cellular Biology. 33 (5): 918–26. doi:10.1128/MCB.01227-12. PMC 3623083. PMID 23263987.
  32. ↑ Almahariq M, Mei FC, Cheng X (Feb 2014). "Cyclic AMP sensor EPAC proteins and energy homeostasis". Trends in Endocrinology and Metabolism. 25 (2): 60–71. doi:10.1016/j.tem.2013.10.004. PMC 3946731. PMID 24231725.
  33. ↑ Eijkelkamp N, Linley JE, Torres JM, Bee L, Dickenson AH, Gringhuis M, Minett MS, Hong GS, Lee E, Oh U, Ishikawa Y, Zwartkuis FJ, Cox JJ, Wood JN (2013). "A role for Piezo2 in EPAC1-dependent mechanical allodynia". Nature Communications. 4: 1682. doi:10.1038/ncomms2673. PMC 3644070. PMID 23575686.
  34. ↑ Wang H, Heijnen CJ, van Velthoven CT, Willemen HL, Ishikawa Y, Zhang X, Sood AK, Vroon A, Eijkelkamp N, Kavelaars A (Dec 2013). "Balancing GRK2 and EPAC1 levels prevents and relieves chronic pain". The Journal of Clinical Investigation. 123 (12): 5023–34. doi:10.1172/JCI66241. PMC 3859388. PMID 24231349.
  35. ↑ 35.0 35.1 Gong B, Shelite T, Mei FC, Ha T, Hu Y, Xu G, Chang Q, Wakamiya M, Ksiazek TG, Boor PJ, Bouyer DH, Popov VL, Chen J, Walker DH, Cheng X (Nov 2013). "Exchange protein directly activated by cAMP plays a critical role in bacterial invasion during fatal rickettsioses". Proceedings of the National Academy of Sciences of the United States of America. 110 (48): 19615–20. doi:10.1073/pnas.1314400110. PMC 3845138. PMID 24218580.
  36. ↑ Tao X, Mei F, Agrawal A, Peters CJ, Ksiazek TG, Cheng X, Tseng CT (Apr 2014). "Blocking of exchange proteins directly activated by cAMP leads to reduced replication of Middle East respiratory syndrome coronavirus". Journal of Virology. 88 (7): 3902–10. doi:10.1128/JVI.03001-13. PMC 3993534. PMID 24453361.
  37. ↑ 37.0 37.1 Almahariq M, Chao C, Mei FC, Hellmich MR, Patrikeev I, Motamedi M, Cheng X (Feb 2015). "Pharmacological inhibition and genetic knockdown of exchange protein directly activated by cAMP 1 reduce pancreatic cancer metastasis in vivo". Molecular Pharmacology. 87 (2): 142–9. doi:10.1124/mol.114.095158. PMC 4293446. PMID 25385424.
  38. ↑ Onodera Y, Nam JM, Bissell MJ (Jan 2014). "Increased sugar uptake promotes oncogenesis via EPAC/RAP1 and O-GlcNAc pathways". The Journal of Clinical Investigation. 124 (1): 367–84. doi:10.1172/JCI63146. PMC 3871217. PMID 24316969.
  39. ↑ Enserink JM, Christensen AE, de Rooij J, van Triest M, Schwede F, Genieser HG, Døskeland SO, Blank JL, Bos JL (Nov 2002). "A novel Epac-specific cAMP analogue demonstrates independent regulation of Rap1 and ERK". Nature Cell Biology. 4 (11): 901–6. doi:10.1038/ncb874. PMID 12402047.
  40. ↑ Christensen AE, Selheim F, de Rooij J, Dremier S, Schwede F, Dao KK, Martinez A, Maenhaut C, Bos JL, Genieser HG, Døskeland SO (Sep 2003). "cAMP analog mapping of Epac1 and cAMP kinase. Discriminating analogs demonstrate that Epac and cAMP kinase act synergistically to promote PC-12 cell neurite extension". The Journal of Biological Chemistry. 278 (37): 35394–402. doi:10.1074/jbc.M302179200. PMID 12819211.
  41. ↑ Poppe H, Rybalkin SD, Rehmann H, Hinds TR, Tang XB, Christensen AE, Schwede F, Genieser HG, Bos JL, Doskeland SO, Beavo JA, Butt E (Apr 2008). "Cyclic nucleotide analogs as probes of signaling pathways". Nature Methods. 5 (4): 277–8. doi:10.1038/nmeth0408-277. PMID 18376388.
  42. ↑ Vliem MJ, Ponsioen B, Schwede F, Pannekoek WJ, Riedl J, Kooistra MR, Jalink K, Genieser HG, Bos JL, Rehmann H (Sep 2008). "8-pCPT-2'-O-Me-cAMP-AM: an improved Epac-selective cAMP analogue". Chembiochem. 9 (13): 2052–4. doi:10.1002/cbic.200800216. PMID 18633951.
  43. ↑ Holz GG, Chepurny OG, Schwede F (Jan 2008). "Epac-selective cAMP analogs: new tools with which to evaluate the signal transduction properties of cAMP-regulated guanine nucleotide exchange factors". Cellular Signalling. 20 (1): 10–20. doi:10.1016/j.cellsig.2007.07.009. PMC 2215344. PMID 17716863.
  44. ↑ Schwede F, Bertinetti D, Langerijs CN, Hadders MA, Wienk H, Ellenbroek JH, de Koning EJ, Bos JL, Herberg FW, Genieser HG, Janssen RA, Rehmann H (Jan 2015). "Structure-guided design of selective Epac1 and Epac2 agonists". PLoS Biology. 13 (1): e1002038. doi:10.1371/journal.pbio.1002038. PMC 4300089. PMID 25603503.
  45. ↑ Tsalkova T, Mei FC, Cheng X (2012). "A fluorescence-based high-throughput assay for the discovery of exchange protein directly activated by cyclic AMP (EPAC) antagonists". PLOS ONE. 7 (1): e30441. doi:10.1371/journal.pone.0030441. PMC 3262007. PMID 22276201.
  46. ↑ Tsalkova T, Mei FC, Li S, Chepurny OG, Leech CA, Liu T, Holz GG, Woods VL, Cheng X (Nov 2012). "Isoform-specific antagonists of exchange proteins directly activated by cAMP". Proceedings of the National Academy of Sciences of the United States of America. 109 (45): 18613–8. doi:10.1073/pnas.1210209109. PMC 3494926. PMID 23091014.
  47. ↑ Almahariq M, Tsalkova T, Mei FC, Chen H, Zhou J, Sastry SK, Schwede F, Cheng X (Jan 2013). "A novel EPAC-specific inhibitor suppresses pancreatic cancer cell migration and invasion". Molecular Pharmacology. 83 (1): 122–8. doi:10.1124/mol.112.080689. PMC 3533471. PMID 23066090.
  48. ↑ Tsalkova T, Mei FC, Li S, Chepurny OG, Leech CA, Liu T, Holz GG, Woods VL, Cheng X (Nov 2012). "Isoform-specific antagonists of exchange proteins directly activated by cAMP". Proceedings of the National Academy of Sciences of the United States of America. 109 (45): 18613–8. doi:10.1073/pnas.1210209109. PMC 3494926. PMID 23091014.
  49. ↑ Courilleau D, Bisserier M, Jullian JC, Lucas A, Bouyssou P, Fischmeister R, Blondeau JP, Lezoualc'h F (Dec 2012). "Identification of a tetrahydroquinoline analog as a pharmacological inhibitor of the cAMP-binding protein Epac". The Journal of Biological Chemistry. 287 (53): 44192–202. doi:10.1074/jbc.M112.422956. PMC 3531735. PMID 23139415.
  50. ↑ Zhu Y, Chen H, Boulton S, Mei F, Ye N, Melacini G, Zhou J, Cheng X (20 March 2015). "Biochemical and pharmacological characterizations of ESI-09 based EPAC inhibitors: defining the ESI-09 "therapeutic window"". Scientific Reports. 5: 9344. doi:10.1038/srep09344. PMC 4366844. PMID 25791905.

Further reading

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