The Korean Journal of Physiology and Pharmacology

  • 제22권3호
  • /
  • Pages.277-289
  • /
  • 2018
  • /
  • 1226-4512(pISSN)
  • /
  • 2093-3827(eISSN)
대한약리학회 (The Korean Society of Pharmacology)
권호 표지
DOI QR코드

DOI QR Code

Exposure to 835 MHz RF-EMF decreases the expression of calcium channels, inhibits apoptosis, but induces autophagy in the mouse hippocampus

  • Kim, Ju Hwan (Department of Pharmacology, College of Medicine, Dankook University) ;
  • Sohn, Uy Dong (Department of Pharmacology, College of Pharmacy, Chung-Ang University) ;
  • Kim, Hyung-Gun (Department of Pharmacology, College of Medicine, Dankook University) ;
  • Kim, Hak Rim (Department of Pharmacology, College of Medicine, Dankook University)
  • 투고 : 2017.08.07
  • 심사 : 2018.01.27
  • 발행 : 2018.05.01
PDF 다운로드
⟨ 이전 논문 다음 논문 ⟩

초록

The exponential increase in the use of mobile communication has triggered public concerns about the potential adverse effects of radiofrequency electromagnetic fields (RF-EMF) emitted by mobile phones on the central nervous system (CNS). In this study, we explored the relationship between calcium channels and apoptosis or autophagy in the hippocampus of C57BL/6 mice after RF-EMF exposure with a specific absorption rate (SAR) of 4.0 W/kg for 4 weeks. Firstly, the expression level of voltage-gated calcium channels (VGCCs), a key regulator of the entry of calcium ions into the cell, was confirmed by immunoblots. We investigated and confirmed that pan-calcium channel expression in hippocampal neurons were significantly decreased after exposure to RF-EMF. With the observed accumulation of autolysosomes in hippocampal neurons via TEM, the expressions of autophagy-related genes and proteins (e.g., LC3B-II) had significantly increased. However, down-regulation of the apoptotic pathway may contribute to the decrease in calcium channel expression, and thus lower levels of calcium in hippocampal neurons. These results suggested that exposure of RF-EMF could alter intracellular calcium homeostasis by decreasing calcium channel expression in the hippocampus; presumably by activating the autophagy pathway, while inhibiting apoptotic regulation as an adaptation process for 835 MHz RF-EMF exposure.

키워드

참고문헌

  1. Baan R, Grosse Y, Lauby-Secretan B, El Ghissassi F, Bouvard V, Benbrahim-Tallaa L, Guha N, Islami F, Galichet L, Straif K; WHO International Agency for Research on Cancer Monograph Working Group. Carcinogenicity of radiofrequency electromagnetic fields. Lancet Oncol. 2011;12:624-626. https://doi.org/10.1016/S1470-2045(11)70147-4
  2. Aldad TS, Gan G, Gao XB, Taylor HS. Fetal radiofrequency radiation exposure from 800-1900 mhz-rated cellular telephones affects neurodevelopment and behavior in mice. Sci Rep. 2012;2:312. https://doi.org/10.1038/srep00312
  3. Hao D, Yang L, Chen S, Tong J, Tian Y, Su B, Wu S, Zeng Y. Effects of long-term electromagnetic field exposure on spatial learning and memory in rats. Neurol Sci. 2013;34:157-164.
  4. Chen C, Ma Q, Liu C, Deng P, Zhu G, Zhang L, He M, Lu Y, Duan W, Pei L, Li M, Yu Z, Zhou Z. Exposure to 1800 MHz radiofrequency radiation impairs neurite outgrowth of embryonic neural stem cells. Sci Rep. 2014;4:5103.
  5. Tang J, Zhang Y, Yang L, Chen Q, Tan L, Zuo S, Feng H, Chen Z, Zhu G. Exposure to 900 MHz electromagnetic fields activates the mkp-1/ERK pathway and causes blood-brain barrier damage and cognitive impairment in rats. Brain Res. 2015;1601:92-101. https://doi.org/10.1016/j.brainres.2015.01.019
  6. Kim JH, Kim HJ, Yu DH, Kweon HS, Huh YH, Kim HR. Changes in numbers and size of synaptic vesicles of cortical neurons induced by exposure to 835 MHz radiofrequency-electromagnetic field. PLoS One. 2017;12:e0186416. https://doi.org/10.1371/journal.pone.0186416
  7. Buttiglione M, Roca L, Montemurno E, Vitiello F, Capozzi V, Cibelli G. Radiofrequency radiation (900 MHz) induces Egr-1 gene expression and affects cell-cycle control in human neuroblastoma cells. J Cell Physiol. 2007;213:759-767. https://doi.org/10.1002/jcp.21146
  8. Liu YX, Tai JL, Li GQ, Zhang ZW, Xue JH, Liu HS, Zhu H, Cheng JD, Liu YL, Li AM, Zhang Y. Exposure to 1950-MHz TD-SCDMA electromagnetic fields affects the apoptosis of astrocytes via caspase-3-dependent pathway. PLoS One. 2012;7:e42332. https://doi.org/10.1371/journal.pone.0042332
  9. Gherardini L, Ciuti G, Tognarelli S, Cinti C. Searching for the perfect wave: the effect of radiofrequency electromagnetic fields on cells. Int J Mol Sci. 2014;15:5366-5387. https://doi.org/10.3390/ijms15045366
  10. Liu K, Zhang G, Wang Z, Liu Y, Dong J, Dong X, Liu J, Cao J, Ao L, Zhang S. The protective effect of autophagy on mouse spermatocyte derived cells exposure to 1800 MHz radiofrequency electromagnetic radiation. Toxicol Lett. 2014;228:216-224. https://doi.org/10.1016/j.toxlet.2014.05.004
  11. Kim JH, Huh YH, Kim HR. Induction of autophagy in the striatum and hypothalamus of mice after 835 MHz radiofrequency exposure. PLoS One. 2016;11:e0153308. https://doi.org/10.1371/journal.pone.0153308
  12. Cuervo AM. Autophagy: in sickness and in health. Trends Cell Biol. 2004;14:70-77. https://doi.org/10.1016/j.tcb.2003.12.002
  13. Mizushima N, Levine B, Cuervo AM, Klionsky DJ. Autophagy fights disease through cellular self-digestion. Nature. 2008;451:1069-1075. https://doi.org/10.1038/nature06639
  14. Konkel A, Cohen NJ. Relational memory and the hippocampus: representations and methods. Front Neurosci. 2009;3:166-174. https://doi.org/10.3389/neuro.01.023.2009
  15. Deng W, Aimone JB, Gage FH. New neurons and new memories: how does adult hippocampal neurogenesis affect learning and memory? Nat Rev Neurosci. 2010;11:339-350. https://doi.org/10.1038/nrn2822
  16. Eichenbaum H, Cohen NJ. Can we reconcile the declarative memory and spatial navigation views on hippocampal function? Neuron. 2014;83:764-770. https://doi.org/10.1016/j.neuron.2014.07.032
  17. Wang L, Zang Y, He Y, Liang M, Zhang X, Tian L, Wu T, Jiang T, Li K. Changes in hippocampal connectivity in the early stages of Alzheimer's disease: evidence from resting state fMRI. Neuroimage. 2006;31:496-504. https://doi.org/10.1016/j.neuroimage.2005.12.033
  18. Del Campo M, Hoozemans JJ, Dekkers LL, Rozemuller AJ, Korth C, Muller-Schiffmann A, Scheltens P, Blankenstein MA, Jimenez CR, Veerhuis R, Teunissen CE. BRI2-BRICHOS is increased in human amyloid plaques in early stages of Alzheimer's disease. Neurobiol Aging. 2014;35:1596-1604. https://doi.org/10.1016/j.neurobiolaging.2014.01.007
  19. Campbell S, Marriott M, Nahmias C, MacQueen GM. Lower hippocampal volume in patients suffering from depression: a metaanalysis. Am J Psychiatry. 2004;161:598-607. https://doi.org/10.1176/appi.ajp.161.4.598
  20. Videbech P, Ravnkilde B. Hippocampal volume and depression: a meta-analysis of MRI studies. Am J Psychiatry. 2004;161:1957-1966. https://doi.org/10.1176/appi.ajp.161.11.1957
  21. Maskey D, Kim M, Aryal B, Pradhan J, Choi IY, Park KS, Son T, Hong SY, Kim SB, Kim HG, Kim MJ. Effect of 835 MHz radiofrequency radiation exposure on calcium binding proteins in the hippocampus of the mouse brain. Brain Res. 2010;1313:232-241. https://doi.org/10.1016/j.brainres.2009.11.079
  22. Rizzuto R, Pinton P, Ferrari D, Chami M, Szabadkai G, Magalhaes PJ, Di Virgilio F, Pozzan T. Calcium and apoptosis: facts and hypotheses. Oncogene. 2003;22:8619-8627. https://doi.org/10.1038/sj.onc.1207105
  23. Sendrowski K, Rusak M, Sobaniec P, Ilendo E, Dabrowska M, Bockowski L, Koput A, Sobaniec W. Study of the protective effect of calcium channel blockers against neuronal damage induced by glutamate in cultured hippocampal neurons. Pharmacol Rep. 2013;65:730-736. https://doi.org/10.1016/S1734-1140(13)71052-1
  24. Mattson MP, Chan SL. Calcium orchestrates apoptosis. Nat Cell Biol. 2003;5:1041-1043. https://doi.org/10.1038/ncb1203-1041
  25. Kim JH, Yu DH, Huh YH, Lee EH, Kim HG, Kim HR. Long-term exposure to 835 MHz RF-EMF induces hyperactivity, autophagy and demyelination in the cortical neurons of mice. Sci Rep. 2017;7:41129. https://doi.org/10.1038/srep41129
  26. Moreno Davila H. Molecular and functional diversity of voltagegated calcium channels. Ann N Y Acad Sci. 1999;868:102-117. https://doi.org/10.1111/j.1749-6632.1999.tb11281.x
  27. Tanida I, Ueno T, Kominami E. LC3 conjugation system in mammalian autophagy. Int J Biochem Cell Biol. 2004;36:2503-2518. https://doi.org/10.1016/j.biocel.2004.05.009
  28. Yang C, Kaushal V, Shah SV, Kaushal GP. Autophagy is associated with apoptosis in cisplatin injury to renal tubular epithelial cells. Am J Physiol Renal Physiol. 2008;294:F777-787. https://doi.org/10.1152/ajprenal.00590.2007
  29. Klionsky DJ, Abdelmohsen K, Abe A, Abedin MJ, Abeliovich H, et al. Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition). Autophagy. 2016;12:1-222. https://doi.org/10.1080/15548627.2015.1100356
  30. Berridge MJ. Neuronal calcium signaling. Neuron. 1998;21:13-26. https://doi.org/10.1016/S0896-6273(00)80510-3
  31. Berliocchi L, Bano D, Nicotera P. $Ca^{2+}$ signals and death programmes in neurons. Philos Trans R Soc Lond B Biol Sci. 2005;360:2255-2258. https://doi.org/10.1098/rstb.2005.1765
  32. Bootman MD, Collins TJ, Peppiatt CM, Prothero LS, MacKenzie L, De Smet P, Travers M, Tovey SC, Seo JT, Berridge MJ, Ciccolini F, Lipp P. Calcium signalling--an overview. Semin Cell Dev Biol. 2001;12:3-10. https://doi.org/10.1006/scdb.2000.0211
  33. Graham SH, Chen J. Programmed cell death in cerebral ischemia. J Cereb Blood Flow Metab. 2001;21:99-109. https://doi.org/10.1097/00004647-200102000-00001
  34. Hoyer-Hansen M, Bastholm L, Szyniarowski P, Campanella M, Szabadkai G, Farkas T, Bianchi K, Fehrenbacher N, Elling F, Rizzuto R, Mathiasen IS, Jaattela M. Control of macroautophagy by calcium, calmodulin-dependent kinase kinase-beta, and Bcl-2. Mol Cell. 2007;25:193-205. https://doi.org/10.1016/j.molcel.2006.12.009
  35. Harr MW, Distelhorst CW. Apoptosis and autophagy: decoding calcium signals that mediate life or death. Cold Spring Harb Perspect Biol. 2010;2:a005579.
  36. Park HW, Park H, Semple IA, Jang I, Ro SH, Kim M, Cazares VA, Stuenkel EL, Kim JJ, Kim JS, Lee JH. Pharmacological correction of obesity-induced autophagy arrest using calcium channel blockers. Nat Commun. 2014;5:4834. https://doi.org/10.1038/ncomms5834
  37. Kokturk S, Yardimoglu M, Celikozlu SD, Dolanbay EG, Cimbiz A. Effect of Lycopersicon esculentum extract on apoptosis in the rat cerebellum, following prenatal and postnatal exposure to an electromagnetic field. Exp Ther Med. 2013;6:52-56. https://doi.org/10.3892/etm.2013.1123
  38. Marino G, Niso-Santano M, Baehrecke EH, Kroemer G. Self-consumption: the interplay of autophagy and apoptosis. Nat Rev Mol Cell Biol. 2014;15:81-94. https://doi.org/10.1038/nrm3735
  39. Salminen A, Kaarniranta K, Kauppinen A. Beclin 1 interactome controls the crosstalk between apoptosis, autophagy and inflammasome activation: impact on the aging process. Ageing Res Rev. 2013;12:520-534. https://doi.org/10.1016/j.arr.2012.11.004
  40. Pyo JO, Nah J, Jung YK. Molecules and their functions in autophagy. Exp Mol Med. 2012;44:73-80. https://doi.org/10.3858/emm.2012.44.2.029
  41. Nixon RA. The role of autophagy in neurodegenerative disease. Nat Med. 2013;19:983-997. https://doi.org/10.1038/nm.3232
  42. Nassif M, Valenzuela V, Rojas-Rivera D, Vidal R, Matus S, Castillo K, Fuentealba Y, Kroemer G, Levine B, Hetz C. Pathogenic role of BECN1/Beclin 1 in the development of amyotrophic lateral sclerosis. Autophagy. 2014;10:1256-1271. https://doi.org/10.4161/auto.28784
  43. Shintani T, Klionsky DJ. Autophagy in health and disease: a doubleedged sword. Science. 2004;306:990-995. https://doi.org/10.1126/science.1099993
  44. Tooze SA, Yoshimori T. The origin of the autophagosomal membrane. Nat Cell Biol. 2010;12:831-835. https://doi.org/10.1038/ncb0910-831
  45. He C, Wei Y, Sun K, Li B, Dong X, Zou Z, Liu Y, Kinch LN, Khan S, Sinha S, Xavier RJ, Grishin NV, Xiao G, Eskelinen EL, Scherer PE, Whistler JL, Levine B. Beclin 2 functions in autophagy, degradation of G protein-coupled receptors, and metabolism. Cell. 2013;154:1085-1099. https://doi.org/10.1016/j.cell.2013.07.035
  46. Kabeya Y, Mizushima N, Yamamoto A, Oshitani-Okamoto S, Ohsumi Y, Yoshimori T. LC, GABARAP and GATE16 localize to autophagosomal membrane depending on form-II formation. J Cell Sci. 2004;117:2805-2812. https://doi.org/10.1242/jcs.01131
  47. Chen Y, Klionsky DJ. The regulation of autophagy - unanswered questions. J Cell Sci. 2011;124:161-170. https://doi.org/10.1242/jcs.064576
  48. Maskey D, Yousefi S, Schmid I, Zlobec I, Perren A, Friis R, Simon HU. ATG5 is induced by DNA-damaging agents and promotes mitotic catastrophe independent of autophagy. Nat Commun. 2013;4:2130.
  49. Murphy MP, LeVine H 3rd. Alzheimer's disease and the amyloidbeta peptide. J Alzheimers Dis. 2010;19:311-323. https://doi.org/10.3233/JAD-2010-1221
  50. Cho MH, Cho K, Kang HJ, Jeon EY, Kim HS, Kwon HJ, Kim HM, Kim DH, Yoon SY. Autophagy in microglia degrades extracellular ${\beta}$-amyloid fibrils and regulates the NLRP3 inflammasome. Autophagy. 2014;10:1761-1775. https://doi.org/10.4161/auto.29647
  51. Neher E, Sakaba T. Multiple roles of calcium ions in the regulation of neurotransmitter release. Neuron. 2008;59:861-872. https://doi.org/10.1016/j.neuron.2008.08.019
  52. Augustine GJ. How does calcium trigger neurotransmitter release? Curr Opin Neurobiol. 2001;11:320-326. https://doi.org/10.1016/S0959-4388(00)00214-2
  53. Rubin RD, Watson PD, Duff MC, Cohen NJ. The role of the hippocampus in flexible cognition and social behavior. Front Hum Neurosci. 2014;8:742.
  54. Mineur YS, Obayemi A, Wigestrand MB, Fote GM, Calarco CA, Li AM, Picciotto MR. Cholinergic signaling in the hippocampus regulates social stress resilience and anxiety- and depression-like behavior. Proc Natl Acad Sci U S A. 2013;110:3573-3578. https://doi.org/10.1073/pnas.1219731110

피인용 문헌

  1. Alternating Electric Fields (TTFields) Activate Ca v 1.2 Channels in Human Glioblastoma Cells vol.11, pp.1, 2019, https://doi.org/10.3390/cancers11010110
  2. Possible Effects of Radiofrequency Electromagnetic Field Exposure on Central Nerve System vol.27, pp.3, 2018, https://doi.org/10.4062/biomolther.2018.152
  3. Possible effects of different doses of 2.1 GHz electromagnetic radiation on learning, and hippocampal levels of cholinergic biomarkers in Wistar rats vol.40, pp.1, 2018, https://doi.org/10.1080/15368378.2020.1851251
  4. Exposure to RF-EMF Alters Postsynaptic Structure and Hinders Neurite Outgrowth in Developing Hippocampal Neurons of Early Postnatal Mice vol.22, pp.10, 2018, https://doi.org/10.3390/ijms22105340
  5. Effects of electromagnetic fields on neuronal ion channels: a systematic review vol.1499, pp.1, 2018, https://doi.org/10.1111/nyas.14597
  6. Exposure to long-term evolution radiofrequency electromagnetic fields decreases neuroblastoma cell proliferation via Akt/mTOR-mediated cellular senescence vol.84, pp.20, 2021, https://doi.org/10.1080/15287394.2021.1944944
  7. Modulation of magnetoencephalography alpha band activity by radiofrequency electromagnetic field depicted in sensor and source space vol.11, pp.1, 2021, https://doi.org/10.1038/s41598-021-02560-0