PROTEIN KINASE A AND Epac ACTIVATION BY cAMP REGULATES THE EXPRESSION OF GLIAL FIBRILLARY ACIDIC PROTEIN IN GLIAL CELLS

Authors

  • Naotoshi Sugimoto 1. Department of Physiology, Graduate School of Medical Science, Kanazawa University, Kanazawa; 2. Department of Pediatrics, Graduate School of Medical Science, Kanazawa University, Kanazawa
  • Shinji Miwa Department of Orthopedic Surgery, Graduate School of Medical Science, Kanazawa University, Kanazawa,
  • Hiroyuki Nakamura Department of Public Health, Graduate School of Medical Science, Kanazawa University, Kanazawa
  • Hiroyuki Tsuchiya Department of Orthopedic Surgery, Graduate School of Medical Science, Kanazawa University, Kanazawa
  • Akihiro Yachie Department of Pediatrics, Graduate School of Medical Science, Kanazawa University, Kanazawa

Abstract

Cyclic adenosine monophosphate (cAMP) controls differentiation in several types of cells during brain development. However, the molecular mechanism of cAMP-controlled differentiation is not fully understood. We investigated the role of protein kinase A (PKA) and exchange protein directly activated by cAMP (Epac) on cAMP-induced glial fibrillary acidic protein (GFAP), an astrocyte marker, in cultured glial cells. B92 glial cells were treated with cAMP-elevating drugs, an activator of adenylate cyclase, phosphodiesterase inhibitor and a ß adrenal receptor agonist. These cAMP-elevating agents induced dramatic morphological changes and expression of GFAP. A cAMP analog, 8-Br-cAMP, which activates Epac as well as PKA, induced GFAP expression and morphological changes, while another cAMP analog, 8-CPT-cAMP, which activates Epac with greater efficacy when compared to PKA, induced GFAP expression but very weak morphological changes. Most importantly, the treatment with a PKA inhibitor partially reduced cAMP-induced GFAP expression. Taken together, these results indicate that cAMP-elevating drugs lead to the induction of GFAP via PKA and/or Epac activation in B92 glial cells.

DOI: 10.2298/ABS160112067S

Key words: adenylate cyclase; Epac; GFAP; phosphodiesterase; PKA

Received: January 12, 2016; Revised: February 1, 2016; Accepted: February 2, 2016; Published online: August 3, 2016

How to cite this article: Sugimoto N, Miwa S, Nakamura H, Tsuchiya H, Yachie A. Protein kinase A and Epac activation by cAMP regulates the expression of glial fibrillary acidic protein in glial cells. Arch Biol Sci. 2016;68(4):795-801.

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References

Vallejo I, Vallejo M. Pituitary adenylate cyclase-activating polypeptide induces astrocyte differentiation of precursor cells from developing cerebral cortex. Mol Cell Neurosci. 2002;21:671-83.

McManus MF, Chen LC, Vallejo I, Vallejo M. Astroglial differentiation of cortical precursor cells triggered by activation of the cAMP-dependent signaling pathway. J Neurosci. 1999;19:9004-15.

Takanaga H, Yoshitake T, Hara S, Yamasaki C, Kunimoto M. cAMP-induced astrocytic differentiation of C6 glioma cells is mediated by autocrine interleukin-6. J Biol Chem. 2004;279:15441-7.

Segovia J, Lawless GM, Tillakaratne NJ, Brenner M, Tobin AJ. Cyclic AMP decreases the expression of a neuronal marker (GAD67) and increases the expression of an astroglial marker (GFAP) in C6 cells. J Neurochem. 1994;63:1218-25.

Le Prince G, Fages C, Rolland B, Nunez J, Tardy M. DBcAMP effect on the expression of GFAP and of its encoding mRNA in astroglial primary cultures. Glia. 1991;4:322-6.

Goldman JE, Abramson B. Cyclic AMP-induced shape changes of astrocytes are accompanied by rapid depolymerization of actin. Brain Res. 1990;528:189-96.

Moore AR, Willoughby DA. The role of cAMP regulation in controlling inflammation. Clin Exp Immunol. 1995;101:387-9.

Moon EY, Lee JH, Lee JW, Song JH, Pyo S. ROS/Epac1-mediated Rap1/NF-kappaB activation is required for the expression of BAFF in Raw264.7 murine macrophages. Cell Signal. 2011;23:1479-88.

Kim S, Jee K, Kim D, Koh H, Chung J. Cyclic AMP inhibits Akt activity by blocking the membrane localization of PDK1. J Biol Chem.2001;276:12864-70.

Hong K, Lou L, Gupta S, Ribeiro-Neto F, Altschuler DL. A novel Epac-Rap-PP2A signaling module controls cAMP-dependent Akt regulation. J Biol Chem. 2008; 283, 23129-23138.

Kopperud R, Krakstad C, Selheim F, Døskeland SO. cAMP effector mechanisms. Novel twists for an 'old' signaling system. FEBS Lett. 2003;546:121-6.

Seino S, Shibasaki T. PKA-dependent and PKA-independent pathways for cAMP-regulated exocytosis. Physiol Rev. 2005;85:1303-42.

Sugimoto N, Miwa S, Ohno-Shosaku T, Tsuchiya H, Hitomi Y, Nakamura H, Tomita K, Yachie A, Koizumi S. Activation of tumor suppressor protein PTEN and induction of apoptosis are involved in cAMP-mediated inhibition of cell number in B92 glial cells. Neurosci Lett. 2011;497:55-9.

Sugimoto N, Miwa S, Hitomi Y, Nakamura H, Tsuchiya H, Yachie A. Theobromine, the primary methylxanthine found in Theobroma cacao, prevents malignant glioblastoma proliferation by negatively regulating phosphodiesterase-4, extracellular signal-regulated kinase, Akt/mammalian target of rapamycin kinase, and nuclear factor- B. Nutr Cancer. 2014;66:419-23.

Sugimoto N, Toma T, Shimizu M, Kuroda M, Wada T, Yachie A. Shiga toxin-2 enhances heat-shock-induced apoptotic cell death in cultured and primary glial cells. Cell Biol Toxicol. 2014;30:289-99.

Loza MJ, Foster S, Peters SP, Penn RB. Beta-agonists modulate T-cell functions via direct actions on type 1 and type 2 cells. Blood. 2006;107:2052-60.

Comerford KM, Lawrence DW, Synnestvendt K, Levi BP, Colgan SP. Role of vasodilator-stimulated phosphoprotein in PKA-induced changes in endothelial junctional permeability. FASB J. 2002;16:583-5.

Miwa S, Sugimoto N, Shirai T, Hayashi K, Nishida H, Ohnari I, Takeuchi A, Yachie A, Tsuchiya H. Caffeine activates tumor suppressor PTEN in sarcoma cells. Int J Oncol. 2011;39:465-72.

Liu X, Yang JM, Zhang SS, Liu XY, Liu DX. Induction of cell cycle arrest at G1 and S phases and cAMP-dependent differentiation in C6 glioma by low concentration of cycloheximide. BMC Cancer. 2010;10:684.

Cebolla B, Fernández-Pérez A, Perea G, Araque A, Vallejo M. DREAM mediates cAMP-dependent, Ca2+-induced stimulation of GFAP gene expression and regulates cortical astrogliogenesis. J Neurosci. 2008;28:6703-13.

Roymans D, Grobben B, Claes P, Slegers H. Protein tyrosine kinase-dependent regulation of adenylate cyclase and phosphatidylinositol 3-kinase activates the expression of glial fibrillary acidic protein upon induction of differentiation in rat C6 glioma. Cell Biol Int. 2001;25:467-74.

Roymans D, Vissenberg K, De Jonghe C, Grobben B, Claes P, Verbelen JP, Van Broeckhoven C, Slegers H. Phosphatidylinositol 3-kinas activity is required for the expression of glial fibrillary acidic protein upon cAMP-dependent induction of differentiation in rat C6 glioma. J Neurochem. 2001;76:610-8.

Shafit-Zagardo B, Kume-Iwaki A, Goldman JE. Astrocytes regulate GFAP mRNA levels by cyclic AMP and protein kinase C-dependent mechanisms. Glia. 1988;1:346-54

Maehama T, Dixon JE. PTEN: a tumour suppressor that functions as a phospholipid phosphatase. Trends Cell Biol. 1999;9:125-8.

Cantley LC, Neel BG. New insights into tumor suppression: PTEN suppresses tumor formation by restraining the phosphoinositide 3-kinase/Akt pathway. Proc Natl Acad Sci USA. 1999;96:4240-5.

Simpson L, Parsons R. PTEN: life as a tumor suppressor. Exp Cell Res. 2001;264:29-41.

Li L, Liu F, Ross AH. PTEN regulation of neural development and CNS stem cells. J Cell Biochem. 2003;88:24-8.

Stiles B, Groszer M, Wang S, Jiao J, Wu H. PTENless means more. Dev Biol. 2004;273:175-84.

Lachyankar MB, Sultana N, Schonhoff CM, Mitra P, Poliha W, Lambert S, Quesenberry PJ, Litofsky NS, Recht LD, Nabi R, Miller SJ, Ohta S, Neel BG, Ross AH. A role for nuclear PTEN in neuronal differentiation. J Neurosci. 2000;20:1404-13.

Musatov S, Roberts J, Brooks AI, Pena J, Betchen S, Pfaff DW, Kaplitt MG. Inhibition of neuronal phenotype by PTEN in PC12 cells. PNAS. 2004;101:3627-31.

Otaegi G, Yusta-Boyo MJ, Vergano-Vera E, Mendez-Gomez HR, Carrera AC, Abad JL, Gonzalez M, de la Rosa EJ, Vicario-Abejon C, de Pablo F. Modulation of the PI 3-kinase-Akt signaling pathway by IGF-I and PTEN regulates the differentiation of neural stem/precursor cells. J Cell Sci. 2006;119:2739-48.

Canetti C, Serezani CH, Atrasz RG, Whie ES, Aronoff DM, Peters-Golden M. Activation of phosphatase and tensin homolog on chromosome 10mediates the inhibition of FcvR phagocytosis by prostaglandin E2 in alveolar macrophages. J Immunol. 2007;179:8350-6.

Malchinkhuu E, Sato K, Maehama T, Ishiuchi S, Yoshimoto Y, Mogi C, Kimura T, Kurose H, Tomura H, Okajima F. Role of Rap1B and tumor suppressor PTEN in the negative regulation of lysophosphatidic acid-induced migration by isoproterenol in glioma cells. Mol Biol Cell. 2009;20:5156-65.

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. 2002;4:901-6.

Moon EY, Lee GH, Lee MS, Kim HM, Lee JW. Phosphodiesterase inhibitors control A172 human glioblastoma cell death through cAMP-mediated activation of protein kinase A and Epac1/Rap1 pathways. Life Sci. 2012;90:373-80.

Gloerich M, Bos JL. Epac: defining a new mechanism for cAMP action. Annu Rev Pharmacol Toxicol. 2010;50:355-75.

Lee JW, Lee J, Moon EY. HeLa human cervical cancer cell migration is inhibited by treatment with dibutyryl-cAMP. Anticancer Res. 2014;34:3447-55.

Huang H, Wang H, Figueiredo-Pereira ME. Regulating the ubiquitin/proteasome pathway via cAMP-signaling: neuroprotective potential. Cell Biochem Biophys. 2013;67:55-66.

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Published

2016-11-25

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Sugimoto N, Miwa S, Nakamura H, Tsuchiya H, Yachie A. PROTEIN KINASE A AND Epac ACTIVATION BY cAMP REGULATES THE EXPRESSION OF GLIAL FIBRILLARY ACIDIC PROTEIN IN GLIAL CELLS. Arch Biol Sci [Internet]. 2016Nov.25 [cited 2024Nov.13];68(4):795-801. Available from: https://www.serbiosoc.org.rs/arch/index.php/abs/article/view/1252

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