Biology: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.

Notes

References

  1. ↑ "Entrez Gene: RAPGEF4 Rap guanine nucleotide exchange factor (GEF) 4". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=11069. 
  2. ↑ "A family of cAMP-binding proteins that directly activate Rap1". Science 282 (5397): 2275–9. December 1998. doi:10.1126/science.282.5397.2275. PMID 9856955. Bibcode: 1998Sci...282.2275K. 
  3. ↑ "Mechanism of regulation of the Epac family of cAMP-dependent RapGEFs". J. Biol. Chem. 275 (27): 20829–36. July 2000. doi:10.1074/jbc.M001113200. PMID 10777494. 
  4. ↑ 4.0 4.1 4.2 4.3 "A family of cAMP-binding proteins that directly activate Rap1". Science 282 (5397): 2275–9. Dec 1998. doi:10.1126/science.282.5397.2275. PMID 9856955. Bibcode: 1998Sci...282.2275K. 
  5. ↑ "Epac is a Rap1 guanine-nucleotide-exchange factor directly activated by cyclic AMP". Nature 396 (6710): 474–7. Dec 1998. doi:10.1038/24884. PMID 9853756. Bibcode: 1998Natur.396..474D. 
  6. ↑ 6.0 6.1 "PKA-dependent and PKA-independent pathways for cAMP-regulated exocytosis". Physiological Reviews 85 (4): 1303–42. Oct 2005. doi:10.1152/physrev.00001.2005. PMID 16183914. https://semanticscholar.org/paper/316e2056198722ea7d529fe06914428af3c055e2. 
  7. ↑ 7.0 7.1 "Exchange protein directly activated by cAMP (epac): a multidomain cAMP mediator in the regulation of diverse biological functions". Pharmacological Reviews 65 (2): 670–709. Apr 2013. doi:10.1124/pr.110.003707. PMID 23447132. https://semanticscholar.org/paper/4a5c38242a9d27b7464629427e9bccabb9bd26ae. 
  8. ↑ 8.0 8.1 "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. Jun 2009. doi:10.1002/jcp.21709. PMID 19170062. 
  9. ↑ 9.0 9.1 "Characterization of the gene EPAC2: structure, chromosomal localization, tissue expression, and identification of the liver-specific isoform". Genomics 78 (1–2): 91–8. Nov 2001. doi:10.1006/geno.2001.6641. PMID 11707077. 
  10. ↑ "Epac proteins: multi-purpose cAMP targets". Trends in Biochemical Sciences 31 (12): 680–6. Dec 2006. doi:10.1016/j.tibs.2006.10.002. PMID 17084085. 
  11. ↑ 11.0 11.1 "Structure of the cyclic-AMP-responsive exchange factor Epac2 in its auto-inhibited state". Nature 439 (7076): 625–8. Feb 2006. doi:10.1038/nature04468. PMID 16452984. Bibcode: 2006Natur.439..625R. 
  12. ↑ "Structure of Epac2 in complex with a cyclic AMP analogue and RAP1B". Nature 455 (7209): 124–7. Sep 2008. doi:10.1038/nature07187. PMID 18660803. Bibcode: 2008Natur.455..124R. 
  13. ↑ "Recent advances in the discovery of small molecules targeting exchange proteins directly activated by cAMP (EPAC)". Journal of Medicinal Chemistry 57 (9): 3651–65. May 2014. doi:10.1021/jm401425e. PMID 24256330. 
  14. ↑ "The cAMP sensor Epac2 is a direct target of antidiabetic sulfonylurea drugs". Science 325 (5940): 607–10. Jul 2009. doi:10.1126/science.1172256. PMID 19644119. Bibcode: 2009Sci...325..607Z. https://semanticscholar.org/paper/ca2ac11ce8b920650876b49c2704bb29e5b2569f. 
  15. ↑ "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. Dec 2007. doi:10.1073/pnas.0707054104. PMID 18040047. Bibcode: 2007PNAS..10419333S. 
  16. ↑ "Critical role of cAMP-GEFII--Rim2 complex in incretin-potentiated insulin secretion". The Journal of Biological Chemistry 276 (49): 46046–53. Dec 2001. doi:10.1074/jbc.M108378200. PMID 11598134. 
  17. ↑ "cAMP-GEFII is a direct target of cAMP in regulated exocytosis". Nature Cell Biology 2 (11): 805–11. Nov 2000. doi:10.1038/35041046. PMID 11056535. 
  18. ↑ 18.0 18.1 "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. Feb 2004. doi:10.1074/jbc.M309068200. PMID 14660679. 
  19. ↑ "Rim2alpha determines docking and priming states in insulin granule exocytosis". Cell Metabolism 12 (2): 117–29. Aug 2010. doi:10.1016/j.cmet.2010.05.017. PMID 20674857. 
  20. ↑ "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. Dec 2002. doi:10.1074/jbc.M210146200. PMID 12401793. 
  21. ↑ "Epac: defining a new mechanism for cAMP action". Annual Review of Pharmacology and Toxicology 50: 355–75. 2010. doi:10.1146/annurev.pharmtox.010909.105714. PMID 20055708. https://semanticscholar.org/paper/5ec01ff82e60de18fd2ab8914531ac13d20e5d50. 
  22. ↑ "Application of an Epac activator enhances neurotransmitter release at excitatory central synapses". The Journal of Neuroscience 28 (32): 7991–8002. Aug 2008. doi:10.1523/JNEUROSCI.0268-08.2008. PMID 18685024. 
  23. ↑ "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. Jan 2001. doi:10.1073/pnas.021541098. PMID 11134533. 
  24. ↑ "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. Jan 2005. doi:10.1523/JNEUROSCI.3703-04.2005. PMID 15634783. 
  25. ↑ "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. Sep 2003. doi:10.1074/jbc.M302179200. PMID 12819211. 
  26. ↑ "Epac mediates cyclic AMP-dependent axon growth, guidance and regeneration". Molecular and Cellular Neurosciences 38 (4): 578–88. Aug 2008. doi:10.1016/j.mcn.2008.05.006. PMID 18583150. 
  27. ↑ "Activation of exchange protein activated by cyclic-AMP enhances long-lasting synaptic potentiation in the hippocampus". Learning & Memory 15 (6): 403–11. Jun 2008. doi:10.1101/lm.830008. PMID 18509114. 
  28. ↑ "Epac mediates PACAP-dependent long-term depression in the hippocampus". The Journal of Physiology 587 (Pt 1): 101–13. Jan 2009. doi:10.1113/jphysiol.2008.157461. PMID 19001039. 
  29. ↑ "Epac mediates beta-adrenergic receptor-induced cardiomyocyte hypertrophy". Circulation Research 102 (8): 959–65. Apr 2008. doi:10.1161/CIRCRESAHA.107.164947. PMID 18323524. 
  30. ↑ 30.0 30.1 "Epac activation, altered calcium homeostasis and ventricular arrhythmogenesis in the murine heart". Pflügers Archiv 457 (2): 253–70. Nov 2008. doi:10.1007/s00424-008-0508-3. PMID 18600344. 
  31. ↑ 31.0 31.1 "Epac2 mediates cardiac β1-adrenergic-dependent sarcoplasmic reticulum Ca2+ leak and arrhythmia". Circulation 127 (8): 913–22. Feb 2013. doi:10.1161/CIRCULATIONAHA.12.148619. PMID 23363625. 
  32. ↑ 32.0 32.1 "GLP-1 receptor activation and Epac2 link atrial natriuretic peptide secretion to control of blood pressure". Nature Medicine 19 (5): 567–75. May 2013. doi:10.1038/nm.3128. PMID 23542788. 
  33. ↑ "Treating diabetes today: a matter of selectivity of sulphonylureas". Diabetes, Obesity & Metabolism 14 Suppl 1: 9–13. Jan 2012. doi:10.1111/j.1463-1326.2011.01507.x. PMID 22118705. 
  34. ↑ "Role of Epac2A/Rap1 signaling in interplay between incretin and sulfonylurea in insulin secretion". Diabetes 64 (4): 1262–72. Apr 2015. doi:10.2337/db14-0576. PMID 25315008. 
  35. ↑ "Cyclic nucleotide signalling: a molecular approach to drug discovery for Alzheimer's disease". Biochemical Society Transactions 33 (Pt 6): 1330–2. Dec 2005. doi:10.1042/BST20051330. PMID 16246111. 
  36. ↑ "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. Nov 2003. doi:10.1038/sj.mp.4001340. PMID 14593429. 
  37. ↑ "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. 2012. doi:10.1371/journal.pbio.1001350. PMID 22745599. 

External links

  • Overview of all the structural information available in the PDB for UniProt: Q9EQZ6 (Mouse Rap guanine nucleotide exchange factor 4) at the PDBe-KB.




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