RAPGEF4

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Rap guanine nucleotide exchange factor (GEF) 4 (RAPGEF4), also known as exchange protein directly activated by cAMP 2 (EPAC2) is a protein that in humans is encoded by the RAPGEF4 gene.[1][2][3]

Epac2 is a target of cAMP, a major second messenger in various cells. Epac2 is coded by the RAPGEF4 gene, and is expressed mainly in brain, neuroendocrine, and endocrine tissues.[4] Epac2 functions as a guanine nucleotide exchange factor for the Ras-like small GTPase Rap upon cAMP stimulation.[4][5] Epac2 is involved in a variety of cAMP-mediated cellular functions in endocrine and neuroendocrine cells and neurons.[6][7]

Gene and transcripts

Human Epac2 is coded by RAPGEF4 located at chromosome 2q31-q32, and three isoforms (Epac2A, Epac2B, and Epac2C) are generated by alternate promoter usage and differential splicing.[4][8][9] Epac2A (called Epac2 originally) is a multi-domain protein with 1,011 amino acids, and is expressed mainly in brain and neuroendocrine and endocrine tissues such as pancreatic islets and neuroendocrine cells.[4] Epac2A is composed of two regions, an amino-terminal regulatory region and a carboxy-terminal catalytic region. The regulatory region contains two cyclic nucleotide-binding domains (cNBD-A and cNBD-B) and a DEP (Dishevelled, Egl-10, and Pleckstrin) domain. The catalytic region, which is responsible for the activation of Rap, consists of a CDC25 homology domain (CDC25-HD), a Ras exchange motif (REM) domain, and a Ras association (RA) domain.[10] Epac2B is devoid of the first cNBD-A domain and Epac2C is devoid of a cNBD-A and a DEP domain. Epac2B and Epac2C are expressed specifically in adrenal gland[8] and liver,[9] respectively.

Mechanism of action

The crystal structure reveals that the catalytic region of Epac2 interacts with cNBD-B intramolecularly, and in the absence of cAMP is sterically masked by a regulatory region, which thereby inhibits interaction between the catalytic region and Rap1.[11] The crystal structure of the cAMP analog-bound active form of Epac2 in a complex with Rap1B indicates that the binding of cAMP to the cNBD-B domain induces the dynamic conformational changes that allow the regulatory region to rotate away. This conformational change enables access of Rap1 to the catalytic region and allows activation.[11][12]

Specific agonists

Several Epac-selective cAMP analogs have been developed to clarify the functional roles of Epacs as well those of the Epac-dependent signaling pathway distinct from the PKA-dependent signaling pathway.[13] The modifications of 8-position in the purine structure and 2’-position in ribose is considered to be crucial to the specificity for Epacs. So far, 8-pCPT-2’-O-Me-cAMP (8-pCPT) and its membrane permeable form 8-pCPT-AM are used for their great specificity toward Epacs. Sulfonylurea drugs (SUs), widely used for the treatment of type 2 diabetes through stimulation of insulin secretion from pancreatic β-cells, have also been shown to specifically activate Epac2.[14]

Function

In pancreatic β-cells, cAMP signaling, which can be activated by various extracellular stimuli including hormonal and neural inputs primarily through Gs-coupled receptors, is of importance for normal regulation of insulin secretion to maintain glucose homeostasis. Activation of cAMP signaling amplifies insulin secretion by Epac2-dependent as well as PKA-dependent pathways.[6] Epac2-Rap1 signaling is critical to promote exocytosis of insulin-containing vesicles from the readily releasable pool.[15] In Epac2-mediated exocytosis of insulin granules, Epac2 interacts with Rim2,[16][17] which is a scaffold protein localized in both plasma membrane and insulin granules, and determines the docking and priming states of exocytosis.[18][19] In addition, piccolo, a possible Ca2+ sensor protein,[20] interacts with the Epac2-Rim2 complex to regulate cAMP-induced insulin secretion.[18] It is suggested that phospholipase C-ε (PLC-ε), one of the effector proteins of Rap, regulates intracellular Ca2+ dynamics by altering the activities of ion channels such as ATP-sensitive potassium channel, ryanodine receptor, and IP3 receptor.[7][21] In neurons, Epac is involved in neurotransmitter release in glutamatergic synapses from calyx of Held and in crayfish neuromuscular junction.[22][23][24] Epac also has roles in the development of brain by regulation of neurite growth and neuronal differentiation as well as axon regeneration in mammalian tissue.[25][26] Furthermore, Epac2 may regulate synaptic plasticity, and thus control higher brain functions such as memory and learning.[27][28] In heart, Epac1 is expressed predominantly, and is involved in the development of hypertrophic events by chronic cAMP stimulation through β-adrenergic receptors.[29] In contrast, chronic stimulation of Epac2 may be a cause of cardiac arrhythmia through CaMKII-dependent diastolic sarcoplasmic reticulum (SR) Ca2+ release in mice.[30][31] Epac2 also is involved in GLP-1-stimulated atrial natriuretic peptide (ANP) secretion from heart.[32]

Clinical implications

As Epac2 is involved in many physiological functions in various cells, defects in the Epac2/Rap1 signaling mechanism could contribute to the development of various pathological states. Studies of Epac2 knockout mice indicate that Epac-mediated signaling is required for potentiation of insulin secretion by incretins (gut hormones released from enteroendocrine cells following meal ingestion) such as glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide,[33][34] suggesting that Epac2 is a promising target for treatment of diabetes. In fact, incretin-based diabetes therapies are currently used in clinical practice worldwide; development of Epac2-selective agonists might well lead to the discovery of further novel anti-diabetic drugs. An analog of GLP-1 has been shown to exert a blood pressure-lowering effect by stimulation of atrial natriuretic peptide (ANP) secretion through Epac2.[32] In heart, chronic stimulation of β-adrenergic receptor is known to progress to arrhythmia through an Epac2-dependent mechanism.[30][31] In brain, up-regulation of Epac1 and down-regulation of Epac2 mRNA are observed in patients with Alzheimer’s disease, suggesting roles of Epacs in the disease.[35] An Epac2 rare coding variant is found in patients with autism and could be responsible for the dendritic morphological abnormalities.[36][37] Thus, Epac2 is involved in the pathogenesis and pathophysiology of various diseases, and represents a promising therapeutic target.

References

  1. ↑ "Entrez Gene: RAPGEF4 Rap guanine nucleotide exchange factor (GEF) 4".
  2. ↑ Kawasaki H, Springett GM, Mochizuki N, Toki S, Nakaya M, Matsuda M, Housman DE, Graybiel AM (December 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.
  3. ↑ de Rooij J, Rehmann H, van Triest M, Cool RH, Wittinghofer A, Bos JL (July 2000). "Mechanism of regulation of the Epac family of cAMP-dependent RapGEFs". J. Biol. Chem. 275 (27): 20829–36. doi:10.1074/jbc.M001113200. PMID 10777494.
  4. ↑ 4.0 4.1 4.2 4.3 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.
  5. ↑ 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.
  6. ↑ 6.0 6.1 Seino S, Shibasaki T (Oct 2005). "PKA-dependent and PKA-independent pathways for cAMP-regulated exocytosis". Physiological Reviews. 85 (4): 1303–42. doi:10.1152/physrev.00001.2005. PMID 16183914.
  7. ↑ 7.0 7.1 Schmidt M, Dekker FJ, Maarsingh H (Apr 2013). "Exchange protein directly activated by cAMP (epac): a multidomain cAMP mediator in the regulation of diverse biological functions". Pharmacological Reviews. 65 (2): 670–709. doi:10.1124/pr.110.003707. PMID 23447132.
  8. ↑ 8.0 8.1 Niimura M, Miki T, Shibasaki T, Fujimoto W, Iwanaga T, Seino S (Jun 2009). "Critical role of the N-terminal cyclic AMP-binding domain of Epac2 in its subcellular localization and function". Journal of Cellular Physiology. 219 (3): 652–8. doi:10.1002/jcp.21709. PMID 19170062.
  9. ↑ 9.0 9.1 Ueno H, Shibasaki T, Iwanaga T, Takahashi K, Yokoyama Y, Liu LM, Yokoi N, Ozaki N, Matsukura S, Yano H, Seino S (Nov 2001). "Characterization of the gene EPAC2: structure, chromosomal localization, tissue expression, and identification of the liver-specific isoform". Genomics. 78 (1–2): 91–8. doi:10.1006/geno.2001.6641. PMID 11707077.
  10. ↑ Bos JL (Dec 2006). "Epac proteins: multi-purpose cAMP targets". Trends in Biochemical Sciences. 31 (12): 680–6. doi:10.1016/j.tibs.2006.10.002. PMID 17084085.
  11. ↑ 11.0 11.1 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.
  12. ↑ 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.
  13. ↑ Chen H, Wild C, Zhou X, Ye N, Cheng X, Zhou J (May 2014). "Recent advances in the discovery of small molecules targeting exchange proteins directly activated by cAMP (EPAC)". Journal of Medicinal Chemistry. 57 (9): 3651–65. doi:10.1021/jm401425e. PMC 4016168. PMID 24256330.
  14. ↑ Zhang CL, Katoh M, Shibasaki T, Minami K, Sunaga Y, Takahashi H, Yokoi N, Iwasaki M, Miki T, Seino S (Jul 2009). "The cAMP sensor Epac2 is a direct target of antidiabetic sulfonylurea drugs". Science. 325 (5940): 607–10. doi:10.1126/science.1172256. PMID 19644119.
  15. ↑ Shibasaki T, Takahashi H, Miki T, Sunaga Y, Matsumura K, Yamanaka M, Zhang C, Tamamoto A, Satoh T, Miyazaki J, Seino S (Dec 2007). "Essential role of Epac2/Rap1 signaling in regulation of insulin granule dynamics by cAMP". Proceedings of the National Academy of Sciences of the United States of America. 104 (49): 19333–8. doi:10.1073/pnas.0707054104. PMC 2148290. PMID 18040047.
  16. ↑ Kashima Y, Miki T, Shibasaki T, Ozaki N, Miyazaki M, Yano H, Seino S (Dec 2001). "Critical role of cAMP-GEFII--Rim2 complex in incretin-potentiated insulin secretion". The Journal of Biological Chemistry. 276 (49): 46046–53. doi:10.1074/jbc.M108378200. PMID 11598134.
  17. ↑ Ozaki N, Shibasaki T, Kashima Y, Miki T, Takahashi K, Ueno H, Sunaga Y, Yano H, Matsuura Y, Iwanaga T, Takai Y, Seino S (Nov 2000). "cAMP-GEFII is a direct target of cAMP in regulated exocytosis". Nature Cell Biology. 2 (11): 805–11. doi:10.1038/35041046. PMID 11056535.
  18. ↑ 18.0 18.1 Shibasaki T, Sunaga Y, Fujimoto K, Kashima Y, Seino S (Feb 2004). "Interaction of ATP sensor, cAMP sensor, Ca2+ sensor, and voltage-dependent Ca2+ channel in insulin granule exocytosis". The Journal of Biological Chemistry. 279 (9): 7956–61. doi:10.1074/jbc.M309068200. PMID 14660679.
  19. ↑ Yasuda T, Shibasaki T, Minami K, Takahashi H, Mizoguchi A, Uriu Y, Numata T, Mori Y, Miyazaki J, Miki T, Seino S (Aug 2010). "Rim2alpha determines docking and priming states in insulin granule exocytosis". Cell Metabolism. 12 (2): 117–29. doi:10.1016/j.cmet.2010.05.017. PMID 20674857.
  20. ↑ Fujimoto K, Shibasaki T, Yokoi N, Kashima Y, Matsumoto M, Sasaki T, Tajima N, Iwanaga T, Seino S (Dec 2002). "Piccolo, a Ca2+ sensor in pancreatic beta-cells. Involvement of cAMP-GEFII.Rim2. Piccolo complex in cAMP-dependent exocytosis". The Journal of Biological Chemistry. 277 (52): 50497–502. doi:10.1074/jbc.M210146200. PMID 12401793.
  21. ↑ Gloerich M, Bos JL (2010). "Epac: defining a new mechanism for cAMP action". Annual Review of Pharmacology and Toxicology. 50: 355–75. doi:10.1146/annurev.pharmtox.010909.105714. PMID 20055708.
  22. ↑ Gekel I, Neher E (Aug 2008). "Application of an Epac activator enhances neurotransmitter release at excitatory central synapses". The Journal of Neuroscience. 28 (32): 7991–8002. doi:10.1523/JNEUROSCI.0268-08.2008. PMID 18685024.
  23. ↑ Sakaba T, Neher E (Jan 2001). "Preferential potentiation of fast-releasing synaptic vesicles by cAMP at the calyx of Held". Proceedings of the National Academy of Sciences of the United States of America. 98 (1): 331–6. doi:10.1073/pnas.021541098. PMC 14590. PMID 11134533.
  24. ↑ Zhong N, Zucker RS (Jan 2005). "cAMP acts on exchange protein activated by cAMP/cAMP-regulated guanine nucleotide exchange protein to regulate transmitter release at the crayfish neuromuscular junction". The Journal of Neuroscience. 25 (1): 208–14. doi:10.1523/JNEUROSCI.3703-04.2005. PMID 15634783.
  25. ↑ 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.
  26. ↑ Murray AJ, Shewan DA (Aug 2008). "Epac mediates cyclic AMP-dependent axon growth, guidance and regeneration". Molecular and Cellular Neurosciences. 38 (4): 578–88. doi:10.1016/j.mcn.2008.05.006. PMID 18583150.
  27. ↑ Gelinas JN, Banko JL, Peters MM, Klann E, Weeber EJ, Nguyen PV (Jun 2008). "Activation of exchange protein activated by cyclic-AMP enhances long-lasting synaptic potentiation in the hippocampus". Learning & Memory. 15 (6): 403–11. doi:10.1101/lm.830008. PMC 2414251. PMID 18509114.
  28. ↑ Ster J, de Bock F, Bertaso F, Abitbol K, Daniel H, Bockaert J, Fagni L (Jan 2009). "Epac mediates PACAP-dependent long-term depression in the hippocampus". The Journal of Physiology. 587 (Pt 1): 101–13. doi:10.1113/jphysiol.2008.157461. PMC 2670026. PMID 19001039.
  29. ↑ 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.
  30. ↑ 30.0 30.1 Hothi SS, Gurung IS, Heathcote JC, Zhang Y, Booth SW, Skepper JN, Grace AA, Huang CL (Nov 2008). "Epac activation, altered calcium homeostasis and ventricular arrhythmogenesis in the murine heart". Pflügers Archiv. 457 (2): 253–70. doi:10.1007/s00424-008-0508-3. PMC 3714550. PMID 18600344.
  31. ↑ 31.0 31.1 Pereira L, Cheng H, Lao DH, Na L, van Oort RJ, Brown JH, Wehrens XH, Chen J, Bers DM (Feb 2013). "Epac2 mediates cardiac β1-adrenergic-dependent sarcoplasmic reticulum Ca2+ leak and arrhythmia". Circulation. 127 (8): 913–22. doi:10.1161/CIRCULATIONAHA.12.148619. PMC 3690126. PMID 23363625.
  32. ↑ 32.0 32.1 Kim M, Platt MJ, Shibasaki T, Quaggin SE, Backx PH, Seino S, Simpson JA, Drucker DJ (May 2013). "GLP-1 receptor activation and Epac2 link atrial natriuretic peptide secretion to control of blood pressure". Nature Medicine. 19 (5): 567–75. doi:10.1038/nm.3128. PMID 23542788.
  33. ↑ Seino S, Takahashi H, Takahashi T, Shibasaki T (Jan 2012). "Treating diabetes today: a matter of selectivity of sulphonylureas". Diabetes, Obesity & Metabolism. 14 Suppl 1: 9–13. doi:10.1111/j.1463-1326.2011.01507.x. PMID 22118705.
  34. ↑ Takahashi H, Shibasaki T, Park JH, Hidaka S, Takahashi T, Ono A, Song DK, Seino S (Apr 2015). "Role of Epac2A/Rap1 signaling in interplay between incretin and sulfonylurea in insulin secretion". Diabetes. 64 (4): 1262–72. doi:10.2337/db14-0576. PMID 25315008.
  35. ↑ McPhee I, Gibson LC, Kewney J, Darroch C, Stevens PA, Spinks D, Cooreman A, MacKenzie SJ (Dec 2005). "Cyclic nucleotide signalling: a molecular approach to drug discovery for Alzheimer's disease". Biochemical Society Transactions. 33 (Pt 6): 1330–2. doi:10.1042/BST20051330. PMID 16246111.
  36. ↑ Bacchelli E, Blasi F, Biondolillo M, Lamb JA, Bonora E, Barnby G, Parr J, Beyer KS, Klauck SM, Poustka A, Bailey AJ, Monaco AP, Maestrini E (Nov 2003). "Screening of nine candidate genes for autism on chromosome 2q reveals rare nonsynonymous variants in the cAMP-GEFII gene". Molecular Psychiatry. 8 (11): 916–24. doi:10.1038/sj.mp.4001340. PMID 14593429.
  37. ↑ Srivastava DP, Woolfrey KM, Jones KA, Anderson CT, Smith KR, Russell TA, Lee H, Yasvoina MV, Wokosin DL, Ozdinler PH, Shepherd GM, Penzes P (2012). "An autism-associated variant of Epac2 reveals a role for Ras/Epac2 signaling in controlling basal dendrite maintenance in mice". PLoS Biology. 10 (6): e1001350. doi:10.1371/journal.pbio.1001350. PMC 3383751. PMID 22745599.
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