BMB Reports

생화학분자생물학회 (Korean Society for Biochemistry and Molecular Biology)
권호 표지
DOI QR코드

DOI QR Code

Epac: new emerging cAMP-binding protein

  • Lee, Kyungmin (Laboratory for Behavioral Neural Circuitry and Physiology, Department of Anatomy, Brain Science & Engineering Institute, School of Medicine, Kyungpook National University)
  • 투고 : 2020.10.15
  • 심사 : 2020.11.30
  • 발행 : 2021.03.31
PDF 다운로드
⟨ 이전 논문 다음 논문 ⟩

초록

The well-known second messenger cyclic adenosine monophosphate (cAMP) regulates the morphology and physiology of neurons and thus higher cognitive brain functions. The discovery of exchange protein activated by cAMP (Epac) as a guanine nucleotide exchange factor for Rap GTPases has shed light on protein kinase A (PKA)-independent functions of cAMP signaling in neural tissues. Studies of cAMP-Epac-mediated signaling in neurons under normal and disease conditions also revealed its diverse contributions to neurodevelopment, synaptic remodeling, and neurotransmitter release, as well as learning, memory, and emotion. In this mini-review, the various roles of Epac isoforms, including Epac1 and Epac2, highly expressed in neural tissues are summarized, and controversies or issues are highlighted that need to be resolved to uncover the critical functions of Epac in neural tissues and the potential for a new therapeutic target of mental disorders.

키워드

참고문헌

  1. de Rooij J, Rehmann H, van Triest M, Cool RH, Wittinghofer A and Bos JL (2000) Mechanism of regulation of the Epac family of cAMP-dependent RapGEFs. J Biol Chem 275, 20829-20836 https://doi.org/10.1074/jbc.M001113200
  2. Kawasaki H, Springett GM, Mochizuki N et al (1998) A family of cAMP-binding proteins that directly activate Rap1. Science 282, 2275-2279 https://doi.org/10.1126/science.282.5397.2275
  3. Frische EW and Zwartkruis FJ (2010) Rap1, a mercenary among the Ras-like GTPases. Dev Biol 340, 1-9 https://doi.org/10.1016/j.ydbio.2009.12.043
  4. Banerjee U and Cheng X (2015) Exchange protein directly activated by cAMP encoded by the mammalian rapgef3 gene: structure, function and therapeutics. Gene 570, 157-167 https://doi.org/10.1016/j.gene.2015.06.063
  5. Hoivik EA, Witsoe SL, Bergheim IR et al (2013) DNA methylation of alternative promoters directs tissue specific expression of Epac2 isoforms. PLoS One 8, e67925 https://doi.org/10.1371/journal.pone.0067925
  6. Lezoualc'h F, Fazal L, Laudette M and Conte C (2016) Cyclic AMP sensor EPAC proteins and their role in cardiovascular function and disease. Circ Res 118, 881-897 https://doi.org/10.1161/CIRCRESAHA.115.306529
  7. Rehmann H (2013) Epac-inhibitors: facts and artefacts. Sci Rep 3, 3032 https://doi.org/10.1038/srep03032
  8. Schwede F, Bertinetti D, Langerijs CN et al (2015) Structure-guided design of selective Epac1 and Epac2 agonists. PLoS Biol 13, e1002038 https://doi.org/10.1371/journal.pbio.1002038
  9. Munoz-Llancao P, Henriquez DR, Wilson C et al (2015) Exchange protein directly activated by cAMP (EPAC) regulates neuronal polarization through Rap1B. J Neurosci 35, 11315-11329 https://doi.org/10.1523/JNEUROSCI.3645-14.2015
  10. Yang Y, Shu X, Liu D et al (2012) EPAC null mutation impairs learning and social interactions via aberrant regulation of miR-124 and Zif268 translation. Neuron 73, 774-788 https://doi.org/10.1016/j.neuron.2012.02.003
  11. Lee K, Kobayashi Y, Seo H et al (2015) Involvement of cAMP-guanine nucleotide exchange factor II in hippocampal long-term depression and behavioral flexibility. Mol Brain 8, 38 https://doi.org/10.1186/s13041-015-0130-1
  12. Srivastava DP, Jones KA, Woolfrey KM et al (2012) Social, communication, and cortical structural impairments in Epac2-deficient mice. J Neurosci 32, 11864-11878 https://doi.org/10.1523/JNEUROSCI.1349-12.2012
  13. Fernandes HB, Riordan S, Nomura T et al (2015) Epac2 mediates cAMP-dependent potentiation of neurotransmission in the hippocampus. J Neurosci 35, 6544-6553 https://doi.org/10.1523/JNEUROSCI.0314-14.2015
  14. Seo H and Lee K (2016) Epac2 contributes to PACAP-induced astrocytic differentiation through calcium ion influx in neural precursor cells. BMB Rep 49, 128-133 https://doi.org/10.5483/BMBRep.2016.49.2.202
  15. Woolfrey KM, Srivastava DP, Photowala H et al (2009) Epac2 induces synapse remodeling and depression and its disease-associated forms alter spines. Nat Neurosci 12, 1275-1284 https://doi.org/10.1038/nn.2386
  16. Matus A (1999) Postsynaptic actin and neuronal plasticity. Curr Opin Neurobiol 9, 561-565 https://doi.org/10.1016/S0959-4388(99)00018-5
  17. Martin SJ, Grimwood PD and Morris RG (2000) Synaptic plasticity and memory: an evaluation of the hypothesis. Annu Rev Neurosci 23, 649-711 https://doi.org/10.1146/annurev.neuro.23.1.649
  18. Murphy DD and Segal M (1997) Morphological plasticity of dendritic spines in central neurons is mediated by activation of cAMP response element binding protein. Proc Natl Acad Sci U S A 94, 1482-1487 https://doi.org/10.1073/pnas.94.4.1482
  19. Deisseroth K, Bito H and Tsien RW (1996) Signaling from synapse to nucleus: postsynaptic CREB phosphorylation during multiple forms of hippocampal synaptic plasticity. Neuron 16, 89-101 https://doi.org/10.1016/S0896-6273(00)80026-4
  20. Impey S, Mark M, Villacres EC, Poser S, Chavkin C and Storm DR (1996) Induction of CRE-mediated gene expression by stimuli that generate long-lasting LTP in area CA1 of the hippocampus. Neuron 16, 973-982 https://doi.org/10.1016/S0896-6273(00)80120-8
  21. Nguyen PV and Kandel ER (1996) A macromolecular synthesis-dependent late phase of long-term potentiation requiring cAMP in the medial perforant pathway of rat hippocampal slices. J Neurosci 16, 3189-3198 https://doi.org/10.1523/jneurosci.16-10-03189.1996
  22. Jones KA, Sumiya M, Woolfrey KM, Srivastava DP and Penzes P (2019) Loss of EPAC2 alters dendritic spine morphology and inhibitory synapse density. Mol Cell Neurosci 98, 19-31 https://doi.org/10.1016/j.mcn.2019.05.001
  23. Bacchelli E, Blasi F, Biondolillo M et al (2003) Screening of nine candidate genes for autism on chromosome 2q reveals rare nonsynonymous variants in the cAMP-GEFII gene. Mol Psychiatry 8, 916-924 https://doi.org/10.1038/sj.mp.4001340
  24. Gutierrez-Castellanos N, Da Silva-Matos CM, Zhou K et al (2017) Motor learning requires purkinje cell synaptic potentiation through activation of AMPA-receptor subunit GluA3. Neuron 93, 409-424 https://doi.org/10.1016/j.neuron.2016.11.046
  25. Gekel I and Neher E (2008) Application of an Epac activator enhances neurotransmitter release at excitatory central synapses. J Neurosci 28, 7991-8002 https://doi.org/10.1523/JNEUROSCI.0268-08.2008
  26. Ferrero JJ, Alvarez AM, Ramirez-Franco J et al (2013) beta-Adrenergic receptors activate exchange protein directly activated by cAMP (Epac), translocate Munc13-1, and enhance the Rab3A-RIM1alpha interaction to potentiate glutamate release at cerebrocortical nerve terminals. J Biol Chem 288, 31370-31385 https://doi.org/10.1074/jbc.M113.463877
  27. Gelinas JN, Banko JL, Peters MM, Klann E, Weeber EJ and Nguyen PV (2008) Activation of exchange protein activated by cyclic-AMP enhances long-lasting synaptic potentiation in the hippocampus. Learn Mem 15, 403-411 https://doi.org/10.1101/lm.830008
  28. Ster J, de Bock F, Bertaso F et al (2009) Epac mediates PACAP-dependent long-term depression in the hippocampus. J Physiol 587, 101-113 https://doi.org/10.1113/jphysiol.2008.157461
  29. Murray AJ and Shewan DA (2008) Epac mediates cyclic AMP-dependent axon growth, guidance and regeneration. Mol Cell Neurosci 38, 578-588 https://doi.org/10.1016/j.mcn.2008.05.006
  30. Li WP, Ma K, Jiang XY et al (2018) Molecular mechanism of panaxydol on promoting axonal growth in PC12 cells. Neural Regen Res 13, 1927-1936 https://doi.org/10.4103/1673-5374.239439
  31. Shi GX, Rehmann H and Andres DA (2006) A novel cyclic AMP-dependent Epac-Rit signaling pathway contributes to PACAP38-mediated neuronal differentiation. Mol Cell Biol 26, 9136-9147 https://doi.org/10.1128/MCB.00332-06
  32. Baameur F, Singhmar P, Zhou Y et al (2016) Epac1 interacts with importin beta1 and controls neurite outgrowth independently of cAMP and Rap1. Sci Rep 6, 36370 https://doi.org/10.1038/srep36370
  33. Srivastava DP, Woolfrey KM, Jones KA et al (2012) An autism-associated variant of Epac2 reveals a role for Ras/Epac2 signaling in controlling basal dendrite maintenance in mice. PLoS Biol 10, e1001350 https://doi.org/10.1371/journal.pbio.1001350
  34. Guijarro-Belmar A, Viskontas M, Wei Y, Bo X, Shewan D and Huang W (2019) Epac2 elevation reverses inhibition by chondroitin sulfate proteoglycans in vitro and transforms postlesion inhibitory environment to promote axonal outgrowth in an ex vivo model of spinal cord injury. J Neurosci 39, 8330-8346 https://doi.org/10.1523/jneurosci.0374-19.2019
  35. Murray AJ, Tucker SJ and Shewan DA (2009) cAMP-dependent axon guidance is distinctly regulated by Epac and protein kinase A. J Neurosci 29, 15434-15444 https://doi.org/10.1523/JNEUROSCI.3071-09.2009
  36. Boomkamp SD, McGrath MA, Houslay MD and Barnett SC (2014) Epac and the high affinity rolipram binding conformer of PDE4 modulate neurite outgrowth and myelination using an in vitro spinal cord injury model. Br J Pharmacol 171, 2385-2398 https://doi.org/10.1111/bph.12588
  37. Kiermayer S, Biondi RM, Imig J et al (2005) Epac activation converts cAMP from a proliferative into a differentiation signal in PC12 cells. Mol Biol Cell 16, 5639-5648 https://doi.org/10.1091/mbc.E05-05-0432
  38. Xu N, Engbers J, Khaja S, Xu L, Clark JJ and Hansen MR (2012) Influence of cAMP and protein kinase A on neurite length from spiral ganglion neurons. Hear Res 283, 33-44 https://doi.org/10.1016/j.heares.2011.11.010
  39. Seo H and Lee K (2019) Cell-specific expression of Epac2 in the subventricular and subgranular zones. Mol Brain 12, 113 https://doi.org/10.1186/s13041-019-0537-1
  40. Zhou L, Ma SL, Yeung PK et al (2016) Anxiety and depression with neurogenesis defects in exchange protein directly activated by cAMP 2-deficient mice are ameliorated by a selective serotonin reuptake inhibitor, Prozac. Transl Psychiatry 6, e881 https://doi.org/10.1038/tp.2016.129
  41. Simon K, Hennen S, Merten N et al (2016) The orphan G protein-coupled receptor GPR17 negatively regulates oligodendrocyte differentiation via Galphai/o and Its downstream effector molecules. J Biol Chem 291, 705-718 https://doi.org/10.1074/jbc.M115.683953
  42. Bacallao K and Monje PV (2013) Opposing roles of PKA and EPAC in the cAMP-dependent regulation of schwann cell proliferation and differentiation [corrected]. PLoS One 8, e82354 https://doi.org/10.1371/journal.pone.0082354
  43. Nikoletopoulou V, Markaki M, Palikaras K and Tavernarakis N (2013) Crosstalk between apoptosis, necrosis and autophagy. Biochim Biophys Acta 1833, 3448-3459 https://doi.org/10.1016/j.bbamcr.2013.06.001
  44. Almahariq M, Mei FC and Cheng X (2016) The pleiotropic role of exchange protein directly activated by cAMP 1 (EPAC1) in cancer: implications for therapeutic intervention. Acta Biochim Biophys Sin (Shanghai) 48, 75-81 https://doi.org/10.1093/abbs/gmv115
  45. Suzuki S, Yokoyama U, Abe T et al (2010) Differential roles of Epac in regulating cell death in neuronal and myocardial cells. J Biol Chem 285, 24248-24259 https://doi.org/10.1074/jbc.M109.094581
  46. Zhang L, Zhang L, Liu H et al (2018) Inhibition of Epac2 attenuates neural cell apoptosis and improves neurological deficits in a rat model of traumatic brain injury. Front Neurosci 12, 263 https://doi.org/10.3389/fnins.2018.00263
  47. Zhuang Y, Xu H, Richard SA et al (2019) Inhibition of EPAC2 attenuates intracerebral hemorrhage-induced secondary brain injury via the p38/BIM/Caspase-3 pathway. J Mol Neurosci 67, 353-363 https://doi.org/10.1007/s12031-018-1215-y
  48. Tiwari S, Felekkis K, Moon EY, Flies A, Sherr DH and Lerner A (2004) Among circulating hematopoietic cells, B-CLL uniquely expresses functional EPAC1, but EPAC1-mediated Rap1 activation does not account for PDE4 inhibitor-induced apoptosis. Blood 103, 2661-2667 https://doi.org/10.1182/blood-2003-06-2154
  49. Misra UK and Pizzo SV (2005) Coordinate regulation of forskolin-induced cellular proliferation in macrophages by protein kinase A/cAMP-response element-binding protein (CREB) and Epac1-Rap1 signaling: effects of silencing CREB gene expression on Akt activation. J Biol Chem 280, 38276-38289 https://doi.org/10.1074/jbc.M507332200
  50. Kwak HJ, Park KM, Choi HE, Chung KS, Lim HJ and Park HY (2008) PDE4 inhibitor, roflumilast protects cardiomyocytes against NO-induced apoptosis via activation of PKA and Epac dual pathways. Cell Signal 20, 803-814 https://doi.org/10.1016/j.cellsig.2007.12.011
  51. Dodge-Kafka KL, Soughayer J, Pare GC et al (2005) The protein kinase A anchoring protein mAKAP coordinates two integrated cAMP effector pathways. Nature 437, 574-578 https://doi.org/10.1038/nature03966
  52. Li Y, Asuri S, Rebhun JF, Castro AF, Paranavitana NC and Quilliam LA (2006) The RAP1 guanine nucleotide exchange factor Epac2 couples cyclic AMP and Ras signals at the plasma membrane. J Biol Chem 281, 2506-2514 https://doi.org/10.1074/jbc.M508165200
  53. Galluzzi L, Baehrecke EH, Ballabio A et al (2017) Molecular definitions of autophagy and related processes. EMBO J 36, 1811-1836 https://doi.org/10.15252/embj.201796697
  54. Sarkar S (2013) Regulation of autophagy by mTOR-dependent and mTOR-independent pathways: autophagy dysfunction in neurodegenerative diseases and therapeutic application of autophagy enhancers. Biochem Soc Trans 41, 1103-1130 https://doi.org/10.1042/BST20130134
  55. Ugland H, Naderi S, Brech A, Collas P and Blomhoff HK (2011) cAMP induces autophagy via a novel pathway involving ERK, cyclin E and Beclin 1. Autophagy 7, 1199-1211 https://doi.org/10.4161/auto.7.10.16649
  56. Sarkar S, Ravikumar B, Floto RA and Rubinsztein DC (2009) Rapamycin and mTOR-independent autophagy inducers ameliorate toxicity of polyglutamine-expanded huntingtin and related proteinopathies. Cell Death Differ 16, 46-56 https://doi.org/10.1038/cdd.2008.110
  57. Ostroveanu A, van der Zee EA, Eisel UL, Schmidt M and Nijholt IM (2010) Exchange protein activated by cyclic AMP 2 (Epac2) plays a specific and time-limited role in memory retrieval. Hippocampus 20, 1018-1026 https://doi.org/10.1002/hipo.20700
  58. Roh M, Lee H, Seo H et al (2020) Perseverative stereotypic behavior of Epac2 KO mice in a reward-based decision making task. Neurosci Res 161, 8-17 https://doi.org/10.1016/j.neures.2020.08.010
  59. Dwivedi Y, Mondal AC, Rizavi HS et al (2006) Differential and brain region-specific regulation of Rap-1 and Epac in depressed suicide victims. Arch Gen Psychiatry 63, 639-648 https://doi.org/10.1001/archpsyc.63.6.639
  60. Aesoy R, Muwonge H, Asrud KS et al (2018) Deletion of exchange proteins directly activated by cAMP (Epac) causes defects in hippocampal signaling in female mice. PLoS One 13, e0200935 https://doi.org/10.1371/journal.pone.0200935