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TRPM2 Cation Channels and Oxidative Stress-Induced Neuronal Cell Death

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Studies on Veterinary Medicine

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Abstract

Of all the organs in the body, the central nervous system is especially sensitive to free radical damage. Its high consumption of oxygen, rich content of easily oxidizable fatty acids, relatively low content of antioxidant enzymes and antioxidants, and the presence of high levels of iron make it a prime substrate for damage by ROS. The Na+ and Ca2+-permeable melastatin-related transient receptor potential 2 (TRPM2) cation channels can be gated either by ADP-ribose (ADPR) in concert with Ca2+ or by hydrogen peroxide (H2O2), an experimental model for oxidative stress, binding to the channel’s enzymatic Nudix domain. Because the mechanisms that lead to TRPM2 inhibiting in response to ADPR and H2O2 are not understood in neuronal cells, we reviewed the effects of ADPR and oxidative stress in neurological cells such as microglia, hippocampus, and brain as well as neurological diseases such as bipolar diseases. It was observed that TRPM2cation channels in microglia and hippocampal cells were gated both by ADPR and H2O2. In addition, H2O2 seems to be responsible for activation of TRPM2 in neurological diseases. Genetic defects may have an important role in the etiology of bipolar diseases. Experimental studies with respect to patch-clamp and Ca2+ imaging, inhibitor roles of antioxidants are also summarized in the review.

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Abbreviations

ADPR:

Adenosine diphosphatase ribose

CHO:

Chinese hamster ovary

CNS:

Central nervous system

DRG:

Dorsal rood ganglion

GSH:

Glutathione

GSH-Px:

Glutathione peroxidase

HEK:

Human embryonic kidney

NO:

Nitric oxide

NOS:

Nitric oxide synthase

PARG:

Poly(ADP-ribose) glycohydrolase

PARP-1:

Poly(ADP-ribose) polymerase

ROS:

Reactive oxygen species

TRP:

Transient receptor potential

References

  1. Bähler M, Rhoads A. 2002. Calmodulin signaling via the IQ motif. FEBS Lett 513:107–113.

    Article  PubMed  Google Scholar 

  2. Bond CE, Greenfield SA. 2007. Multiple cascade effects of oxidative stress on astroglia. Glia 55:1348–1361.

    Article  PubMed  Google Scholar 

  3. Butterfield DA. 2003. Amyloid beta-peptide [1–42]-associated free radical-induced oxidative stress and neurodegeneration in Alzheimer’s disease brain: mechanisms and consequences. Curr Med Chem 10:2651–2659.

    Article  CAS  PubMed  Google Scholar 

  4. Chanock SJ, Roesler J, Zhan S, Hopkins P, Lee P, Barrett DT, Christensen BL, Curnutte JT, Görlach A. 2000. Genomic structure of the human p47-phox (NCF1) gene. Blood Cells Mol Dis 26:37–46.

    Article  CAS  PubMed  Google Scholar 

  5. Clapham DE. 2003. TRP channels as cellular sensors. Nature 426:517–524.

    Article  CAS  PubMed  Google Scholar 

  6. Clapham DE. 2007. Snapshot: mammalian TRP channels. Cell 129:220.

    Article  PubMed  Google Scholar 

  7. Dreses-Werringloer U, Lambert JC, Vingtdeux V, Zhao H, Vais H, Siebert A, Jain A, Koppel J, Rovelet-Lecrux A, Hannequin D, Pasquier F, Galimberti D, Scarpini E, Mann D, Lendon C, Campion D, Amouyel P, Davies P, Foskett JK, Campagne F, Marambaud P. 2008. A polymorphism in CALHM1 influences Ca2+ homeostasis, Abeta levels, and Alzheimer’s disease risk. Cell 133:1149–1161.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  8. Fonfria E, Marshall IC, Boyfield I, Skaper SD, Hughes JP, Owen DE, Zhang W, Miller BA, Benham CD, McNulty S. 2005. Amyloid beta-peptide(1–42) and hydrogen peroxide-induced toxicity are mediated by TRPM2 in rat primary striatal cultures. J Neurochem 95:715–723.

    Article  CAS  PubMed  Google Scholar 

  9. Fonfria E, Mattei C, Hill K, Brown JT, Randall A, Benham CD, Skaper SD, Campbell CA, Crook B, Murdock PR, Wilson JM, Maurio FP, Owen DE, Tilling PL, McNulty S. 2006. TRPM2 is elevated in the tMCAO stroke model, transcriptionally regulated and functionally expressed in C13 microglia. J Recept Signal Transduct Res 26:179–198.

    Article  CAS  PubMed  Google Scholar 

  10. Gasser A, Glassmeier G, Fliegert R, Langhorst MF, Meinke S, Hein D, Kruger S, Weber K, Heiner I, Oppenheimer N, Schwarz JR, Guse AH. 2006. Activation of T cell calcium influx by the second messenger ADP-ribose. J Biol Chem 281:2489–2496.

    Article  CAS  PubMed  Google Scholar 

  11. Guse AH. 2005. Second messenger function and the structure-activity relationship of cyclic adenosine diphosphoribose (cADPR). FEBS J 272:4590–4597.

    Article  CAS  PubMed  Google Scholar 

  12. Halliwell B. 2006. Oxidative stress and neurodegeneration: where are we now? J Neurochem 97:1634–1658.

    Article  CAS  PubMed  Google Scholar 

  13. Hara Y, Wakamori M, Ishii M, Maeno E, Nishida M, Yoshida T, Yamada H, Shimizu S, Mori E, Kudoh J, Shimizu N, Kurose H, Okada Y, Imoto K, Mori Y. 2002. LTRPC2 Ca2+-permeable channel activated by changes in redox status confers susceptibility to cell death. Mol Cell 9:163–173.

    Article  CAS  PubMed  Google Scholar 

  14. Heiner I, Eisfeld J, Luckhoff A. 2003. Role and regulation of TRP channels in neutrophil granulocytes. Cell Calcium 33:533–540.

    Article  CAS  PubMed  Google Scholar 

  15. Heiner I, Eisfeld J, Warnstedt M, Radukina N, Jungling E, Luckhoff A. 2006. Endogenous ADP-ribose enables calcium-regulated cation currents through TRPM2 channels in neutrophil granulocytes. Biochem J 398:225–232.

    Article  CAS  PubMed  Google Scholar 

  16. Hermosura MC, Cui AM, Go RC, Davenport B, Shetler CM, Heizer JW, Schmitz C, Mocz G, Garruto RM, Perraud AL. 2008. Altered functional properties of a TRPM2 variant in Guamanian ALS and PD. Proc Natl Acad Sci U S A 105:18029–18034.

    Article  CAS  PubMed  Google Scholar 

  17. Hill K, Tigue NJ, Kelsell RE, Benham CD, McNulty S, Schaefer M, Randall AD. 2006. Characterization of recombinant rat TRPM2 and a TRPM2-like conductance in cultured rat striatal neurons. Neuropharmacology 50:89–97.

    Article  CAS  PubMed  Google Scholar 

  18. Inamura K, Sano Y, Mochizuki S, Yokoi H, Miyake A, Nozawa K, Kitada C, Matsushime H, Furuichi K. 2003. Response to ADP-ribose by activation of TRPM2 in the CRI-G1 insulinoma cell line. J Membr Biol 191:201–207.

    Article  CAS  PubMed  Google Scholar 

  19. Kaneko S, Kawakami S, Hara Y, Wakamori M, Itoh E, Minami T, Takada Y, Kume T, Katsuki H, Mori Y, Akaike A. 2006. A critical role of TRPM2 in neuronal cell death by hydrogen peroxide. J Pharmacol Sci 101:66–76.

    Article  CAS  PubMed  Google Scholar 

  20. Kolisek M, Beck A, Fleig A, Penner R. 2005. Cyclic ADP-ribose and hydrogen peroxide synergize with ADP-ribose in the activation of TRPM2 channels. Mol Cell 18:61–69.

    Article  CAS  PubMed  Google Scholar 

  21. Kraft R, Grimm C, Grosse K, Hoffmann A, Sauerbruch S, Kettenmann H, Schultz G, Harteneck C. 2004. Hydrogen peroxide and ADP-ribose induce TRPM2-mediated calcium influx and cation currents in microglia. Am J Physiol Cell Physiol 286:C129–C137.

    Article  CAS  PubMed  Google Scholar 

  22. Kraft R, Harteneck C. 2005. The mammalian melastatin-related transient receptor potential cation channels: an overview. Pflugers Arch 451:204–211.

    Article  CAS  PubMed  Google Scholar 

  23. Kühn FJ, Heiner I, Luckhoff A. 2005. TRPM2: a calcium influx pathway regulated by oxidative stress and the novel second messenger ADP-ribose. Pflugers Arch 451:212–219.

    Article  PubMed  Google Scholar 

  24. Kühn FJP, Kühn C, Nazıroğlu M, Lückhoff A. 2009. Role of an N-terminal splice segment in the activation of the cation channel TRPM2 by ADP-Ribose and hydrogen peroxide. Neurochem Res 34:227–233.

    Article  PubMed  Google Scholar 

  25. Kühn FJ, Lückhoff A. 2004. Sites of the NUDT9-H domain critical for ADP-ribose activation of the cation channel TRPM2. J Biol Chem 279:46431–46437.

    Article  PubMed  Google Scholar 

  26. Li SS. 2005. Specificity and versatility of SH3 and other proline-recognition domains: structural basis and implications for cellular signal transduction. Biochem J 390:641–653.

    Article  CAS  PubMed  Google Scholar 

  27. Massullo P, Sumoza-Toledo A, Bhagat H, Partida-Sánchez S. 2006. TRPM channels, calcium and redox sensors during innate immune responses. Semin Cell Dev Biol 17:654–666.

    Article  CAS  PubMed  Google Scholar 

  28. McQuillin A, Bass NJ, Kalsi G, Lawrence J, Puri V, Choudhury K, Detera-Wadleigh SD, Curtis D, Gurling HM. 2006. Fine mapping of a susceptibility locus for bipolar and genetically related unipolar affective disorders, to a region containing the C21ORF29 and TRPM2 genes on chromosome 21q22.3. Mol Psychiatry 11:134–142.

    Article  CAS  PubMed  Google Scholar 

  29. Morale MC, Serra PA, L’episcopo F, Tirolo C, Caniglia S, Testa N, Gennuso F, Giaquinta G, Rocchitta G, Desole MS, Miele E, Marchetti B.1998. Molecular cloning of a novel putative Ca2+ channel protein (TRPC7) highly expressed in brain. Genomics 54:124–131.

    Article  Google Scholar 

  30. Morale MC, Serra PA, L’episcopo F, Tirolo C, Caniglia S, Testa N, Gennuso F, Giaquinta G, Rocchitta G, Desole MS, Miele E, Marchetti B. 2006. Estrogen, neuroinflammation and neuroprotection in Parkinson’s disease: glia dictates resistance versus vulnerability to neurodegeneration. Neuroscience 138:869–878.

    Article  CAS  PubMed  Google Scholar 

  31. Nazıroğlu M. 2007c. New molecular mechanisms on the activation of TRPM2 channels by oxidative stress and ADP-ribose. Neurochem Res 32:1990–2001.

    Article  CAS  PubMed  Google Scholar 

  32. Nazıroğlu M. 2007b. Molecular Mechanisms of vitamin E on intracellular signaling pathways in brain. In Reactive Oxygen Species and Diseases. Ed. Laszlo Goth, Research Signpost Press: Kerala, India. pp. 239–256.

    Google Scholar 

  33. Nazıroğlu M. 2009. Role of selenium on calcium signaling and oxidative stress-induced molecular pathways in epilepsy. Neurochem Res 34:2181–2191.

    Article  PubMed  Google Scholar 

  34. Nazıroğlu, M. 2010. Effects of vitamin C on oxidative stress-induced molecular pathways in epilepsy. In Vitamin C: Nutrition, Side Effects and Supplements. Ed. Christina M. Jackson, Nova Science Publishers, Inc. ISBN: 978-1-61728-754-1.

    Google Scholar 

  35. Nazıroğlu M, Lückhoff A. 2008a. A calcium influx pathway regulated separately by oxidative stress and ADP-ribose in TRPM2 channels: single channel events. Neurochem Res 33:1256–1262.

    Article  PubMed  Google Scholar 

  36. Nazıroğlu M, Lückhoff A. 2008b. Effects of antioxidants on calcium influx through TRPM2 channels in transfected cells activated by hydrogen peroxide. J Neurol Sci 270:152–158.

    Article  PubMed  Google Scholar 

  37. Nazıroğlu M, Lückhoff A, Jungling E. 2007a. Antagonist effect of flufenamic acid on TRPM2 cation channels activated by hydrogen peroxide. Cell Biochem Funct 25:383–387.

    Article  CAS  PubMed  Google Scholar 

  38. Nilius B. 2007. TRP channels in disease. Biochem Biophys Acta 1772:805–812.

    CAS  PubMed  Google Scholar 

  39. Nilius B, Owsianik G, Voets T, Peters JA. 2007. Transient Receptor Potential cation channels in disease. Physiol Rev 87:165–217.

    Article  CAS  PubMed  Google Scholar 

  40. Ohana L, Newell EW, Stanley EF, Schlichter LC. 2009. The Ca2+ release-activated Ca2+ current (ICRAC) mediates store-operated Ca2+ entry in rat microglia. Channels 3:129–139.

    Article  CAS  PubMed  Google Scholar 

  41. Olah ME, Jackson MF, Li H, Perez Y, Sun HS, Kiyonaka S, Mori Y, Tymianski M, MacDonald JF. 2009. Ca2+-dependent induction of TRPM2 currents in hippocampal neurons. J Physiol 587(Pt 5):965–979.

    Article  CAS  PubMed  Google Scholar 

  42. Özmen I, Nazıroğlu M, Alicı HA, Sahin F, Cengiz M, Eren İ. 2007. Spinal morphine administration reduces the fatty acid contents in spinal cord and brain in rabbits due to oxidative stress. Neurochem Res 32:19–25.

    Article  PubMed  Google Scholar 

  43. Peier AM, Moqrich A, Hergarden AC, Reeve AJ, Andersson DA, Story GM, Earley TJ, Dragoni I, McIntyre P, Bevan S, Patapoutian A. 2002. A TRP channel that senses cold stimuli and menthol. Cell 108:705–715.

    Article  CAS  PubMed  Google Scholar 

  44. Perraud AL, Fleig A, Dunn CA, Bagley LA, Launay P, Schmitz C, Stokes AJ, Zhu Q, Bessman MJ, Penner R, Kinet JP, Scharenberg AM. 2001. ADP-ribose gating of the calcium-permeable LTRPC2 channel revealed by Nudix motif homology. Nature 411:595–599.

    Article  CAS  PubMed  Google Scholar 

  45. Perraud AL, Schmitz C, Scharenberg AM. 2003. TRPM2 Ca2+ permeable cation channels: from gene to biological function. Cell Calcium 33:519–531.

    Article  CAS  PubMed  Google Scholar 

  46. Perraud AL, Takanishi CL, Shen B, Kang S, Smith MK, Schmitz C, Knowles HM, Ferraris D, Li W, Zhang J, Stoddard BL, Scharenberg AM. 2005. Accumulation of free ADP-ribose from mitochondria mediates oxidative stress-induced gating of TRPM2 cation channels.J Biol Chem 280:6138–6148.

    Article  CAS  PubMed  Google Scholar 

  47. Rayman MP. 2009. Selenoproteins and human health: insights from epidemiological data. Biochim Biophys Acta 1790:1533–1540.

    Article  CAS  PubMed  Google Scholar 

  48. Smith MA, Herson PS, Lee K, Pinnock RD, Ashford ML. 2003. Hydrogen-peroxide-induced toxicity of rat striatal neurons involves activation of a nonselective cation channel. J Physiol 547:417–425.

    Article  CAS  PubMed  Google Scholar 

  49. Spencer PS, Nunn PB, Hugon J, Ludolph AC, Ross SM, Roy DN, Robertson RC. 1987. Guam amyotrophic lateral sclerosis-parkinsonism-dementia linked to a plant excitant neurotoxin. Science 237:517–522.

    Article  CAS  PubMed  Google Scholar 

  50. Staaf S, Franck MC, Marmigère F, Mattsson JP, Ernfors P. 2010. Dynamic expression of the TRPM subgroup of ion channels in developing mouse sensory neurons. Gene Expr Patterns 10:65–74.

    Article  CAS  PubMed  Google Scholar 

  51. Tafti M, Ghyselinck NB. 2007. Functional implication of the vitamin A signaling pathway in the brain. Arch Neurol 64:1706–7611.

    Article  PubMed  Google Scholar 

  52. Togashi K, Hara Y, Tominaga T, Higashi T, Konishi Y, Mori Y, Tominaga M. 2006. TRPM2 activation by cyclic ADP-ribose at body temperature is involved in insulin secretion. EMBO J 25:1804–1815.

    Article  CAS  PubMed  Google Scholar 

  53. Watanabe H, Murakami M, Ohba T, Takahashi Y, Ito H. 2008. TRP Channel and cardio-vascular disease. Pharmacol Therap 118:337–351.

    Article  CAS  Google Scholar 

  54. Wehage E, Eisfeld J, Heiner I, Jüngling E, Zitt C, Lückhoff A. 2002. Activation of the cation channel long transient receptor potential channel 2 (LTRPC2) by hydrogen peroxide. A splice variant reveals a mode of activation independent of ADP-ribose. J Biol Chem 277:23150–23156.

    Article  CAS  PubMed  Google Scholar 

  55. Xu C, Macciardi F, Li PP, Yoon IS, Cooke RG, Hughes B, Parikh SV, McIntyre RS, Kennedy JL, Warsh JJ. 2006. Association of the putative susceptibility gene, transient receptor potential protein melastatin type 2, with bipolar disorder. Am J Med Genet B Neuropsychiatr Genet 141:36–43.

    Article  Google Scholar 

  56. Yamamoto S, Shimizu S, Kiyonaka S, Takahashi N, Wajima T, Hara Y, Negoro T, Hiroi T, Kiuchi Y, Okada T, Kaneko S, Lange I, Fleig A, Penner R, Nishi M, Takeshima H, Mori Y. 2008. TRPM2-mediated Ca2+ influx induces chemokine production in monocytes that aggravates inflammatory neutrophil infiltration. Nat Med 14:738–747.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  57. Yanagihara R, Garruto RM, Gajdusek DC, Tomita A, Uchikawa T, Konagaya Y, Chen KM, Sobue I, Plato CC, Gibbs CJ Jr. 1984. Calcium and vitamin D metabolism in Guamanian Chamorros with amyotrophic lateral sclerosis and parkinsonism-dementia. Ann Neurol 15:42–48.

    Article  CAS  PubMed  Google Scholar 

  58. Yase Y. 1972. The pathogenesis of amyotrophic lateral sclerosis. Lancet 2:292–296.

    Article  CAS  PubMed  Google Scholar 

  59. Yuan JP, Kiselyov K, Shin DM, Chen J, Shcheynikov N, Kang SH, Dehoff MH, Schwarz MK, Seeburg PH, Muallem S, Worley PF. 2003. Homer binds TRPC family channels and is required for gating of TRPC1 by IP3 receptors. Cell 114:777–789.

    Article  CAS  PubMed  Google Scholar 

  60. Nazıroğlu M. 2010. TRPM2 cation channels, oxidative stress and neurological diseases: Where are we now? Neurochem Res. [Epub ahead of print] DOI: 10.1007/s11064-010-0347-4.

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Biophysics, Süleyman Demirel University, Morfoloji Binasi, TR-32260, Isparta, Turkey

    Mustafa Naziroğlu

  2. Neuroscience Research Center, Suleyman Demirel University, Isparta, Turkey

    Mustafa Naziroğlu

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  1. Mustafa Naziroğlu
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Correspondence to Mustafa Naziroğlu .

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Editors and Affiliations

  1. , Pharmacology and Therapeutics, Community Veterinary Hospital, Largo, 33770, Florida, USA

    Lester Mandelker

  2. Faculty of Veterinary Sciences, Department of Internal Medicine and Clin, Szent Istvan University, Istvan u. 2, Budapest, 1143, Hungary

    Peter Vajdovich

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Naziroğlu, M. (2011). TRPM2 Cation Channels and Oxidative Stress-Induced Neuronal Cell Death. In: Mandelker, L., Vajdovich, P. (eds) Studies on Veterinary Medicine. Oxidative Stress in Applied Basic Research and Clinical Practice. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-61779-071-3_4

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