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TRPM2 mediates the lysophosphatidic acid-induced neurite retraction in the develo** brain

  • Signaling and cell physiology
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Abstract

Intracellular Ca2+ signal is a key regulator of axonal growth during brain development. As transient receptor potential (TRP) channels are permeable to Ca2+ and mediate numerous brain functions, it is conceivable that many TRP channels would regulate neuronal differentiation. We therefore screened TRP channels that are involved in the regulation of neurite growth. Among the TRP channels, the Trpm2 level was inversely associated with neurite growth. TRPM2 was highly expressed in embryonic brain. Pharmacological perturbation or knockdown of TRPM2 markedly increased the axonal growth, whereas its overexpression inhibited the axonal growth. Addition of ADP ribose, an endogenous activator of TRPM2, to PC12 cells significantly repressed the axonal growth. TRPM2 was actively involved in the neuronal retraction induced by cerebrospinal fluid-rich lysophosphatidic acid (LPA). More importantly, neurons isolated from the brain of Trpm2-deficient mice have significantly longer neurites with a greater number of spines than those obtained from the brain of wild-type mice. Therefore, we conclude that TRPM2 mediates the LPA-induced suppression of axonal growth, which provides a long-sought mechanism underlying the effect of LPA on neuronal development.

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References

  1. Amaral MD, Pozzo-Miller L (2007) TRPC3 channels are necessary for brain-derived neurotrophic factor to activate a nonselective cationic current and to induce dendritic spine formation. J Neurosci 27(19):5179–5189

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  2. Bito H, Furuyashiki T, Ishihara H, Shibasaki Y, Ohashi K, Mizuno K, Maekawa M, Ishizaki T, Narumiya S (2000) A critical role for a Rho-associated kinase, p160ROCK, in determining axon outgrowth in mammalian CNS neurons. Neuron 26(2):431–441

    Article  PubMed  CAS  Google Scholar 

  3. Buelow B, Song Y, Scharenberg AM (2008) The poly(ADP-ribose) polymerase PARP-1 is required for oxidative stress-induced TRPM2 activation in lymphocytes. J Biol Chem 283(36):24571–24583

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  4. Csanady L, Torocsik B (2009) Four Ca2+ ions activate TRPM2 channels by binding in deep crevices near the pore but intracellularly of the gate. J Gen Physiol 133(2):189–203

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  5. da Silva JS, Dotti CG (2002) Breaking the neuronal sphere: regulation of the actin cytoskeleton in neuritogenesis. Nat Rev Neurosci 3(9):694–704

    Article  PubMed  Google Scholar 

  6. Dehay C, Kennedy H (2007) Cell-cycle control and cortical development. Nat Rev Neurosci 8(6):438–450

    Article  PubMed  CAS  Google Scholar 

  7. Fukushima N, Ishii I, Contos JJ, Weiner JA, Chun J (2001) Lysophospholipid receptors. Annu Rev Pharmacol Toxicol 41:507–534

    Article  PubMed  CAS  Google Scholar 

  8. Fukushima N, Weiner JA, Kaushal D, Contos JJ, Rehen SK, Kingsbury MA, Kim KY, Chun J (2002) Lysophosphatidic acid influences the morphology and motility of young, postmitotic cortical neurons. Mol Cell Neurosci 20(2):271–282

    Article  PubMed  CAS  Google Scholar 

  9. Gomez TM, Zheng JQ (2006) The molecular basis for calcium-dependent axon pathfinding. Nat Rev Neurosci 7(2):115–125

    Article  PubMed  CAS  Google Scholar 

  10. Greka A, Navarro B, Oancea E, Duggan A, Clapham DE (2003) TRPC5 is a regulator of hippocampal neurite length and growth cone morphology. Nat Neurosci 6(8):837–845

    Article  PubMed  CAS  Google Scholar 

  11. Harrison SM, Reavill C, Brown G, Brown JT, Cluderay JE, Crook B, Davies CH, Dawson LA, Grau E, Heidbreder C, Hemmati P, Hervieu G, Howarth A, Hughes ZA, Hunter AJ, Latcham J, Pickering S, Pugh P, Rogers DC, Shilliam CS, Maycox PR (2003) LPA1 receptor-deficient mice have phenotypic changes observed in psychiatric disease. Mol Cell Neurosci 24(4):1170–1179

    Article  PubMed  CAS  Google Scholar 

  12. Hecht JH, Weiner JA, Post SR, Chun J (1996) Ventricular zone gene-1 (vzg-1) encodes a lysophosphatidic acid receptor expressed in neurogenic regions of the develo** cerebral cortex. J Cell Biol 135(4):1071–1083

    Article  PubMed  CAS  Google Scholar 

  13. Hill K, Benham CD, McNulty S, Randall AD (2004) Flufenamic acid is a pH-dependent antagonist of TRPM2 channels. Neuropharmacology 47(3):450–460

    Article  PubMed  CAS  Google Scholar 

  14. Hill K, McNulty S, Randall AD (2004) Inhibition of TRPM2 channels by the antifungal agents clotrimazole and econazole. Naunyn Schmiedebergs Arch Pharmacol 370(4):227–237

    Article  PubMed  CAS  Google Scholar 

  15. Hottiger MO, Boothby M, Koch-Nolte F, Luscher B, Martin NM, Plummer R, Wang ZQ, Ziegler M (2011) Progress in the function and regulation of ADP-ribosylation. Sci Signal 4(174):mr5

    PubMed  Google Scholar 

  16. Hui H, McHugh D, Hannan M, Zeng F, Xu SZ, Khan SU, Levenson R, Beech DJ, Weiss JL (2006) Calcium-sensing mechanism in TRPC5 channels contributing to retardation of neurite outgrowth. J Physiol 572(Pt 1):165–172

    PubMed  CAS  PubMed Central  Google Scholar 

  17. Itagaki K, Kannan KB, Hauser CJ (2005) Lysophosphatidic acid triggers calcium entry through a non-store-operated pathway in human neutrophils. J Leukoc Biol 77(2):181–189

    Article  PubMed  CAS  Google Scholar 

  18. Jang Y, Jung J, Kim H, Oh J, Jeon JH, Jung S, Kim KT, Cho H, Yang DJ, Kim SM, Kim IB, Song MR, Oh U (2012) Axonal neuropathy-associated TRPV4 regulates neurotrophic factor-derived axonal growth. J Biol Chem 287(8):6014–6024

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  19. Jang Y, Lee Y, Kim SM, Yang YD, Jung J, Oh U (2012) Quantitative analysis of TRP channel genes in mouse organs. Arch Pharm Res 35(10):1823–1830

    Article  PubMed  CAS  Google Scholar 

  20. Kaczmarek JS, Riccio A, Clapham DE (2012) Calpain cleaves and activates the TRPC5 channel to participate in semaphorin 3A-induced neuronal growth cone collapse. Proc Natl Acad Sci U S A 109(20):7888–7892

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  21. Kingsbury MA, Rehen SK, Contos JJ, Higgins CM, Chun J (2003) Non-proliferative effects of lysophosphatidic acid enhance cortical growth and folding. Nat Neurosci 6(12):1292–1299

    Article  PubMed  CAS  Google Scholar 

  22. Koo JY, Jang Y, Cho H, Lee CH, Jang KH, Chang YH, Shin J, Oh U (2007) Hydroxy-alpha-sanshool activates TRPV1 and TRPA1 in sensory neurons. Eur J Neurosci 26(5):1139–1147

    Article  PubMed  Google Scholar 

  23. Ledesma MD, Dotti CG (2003) Membrane and cytoskeleton dynamics during axonal elongation and stabilization. Int Rev Cytol 227:183–219

    Article  PubMed  CAS  Google Scholar 

  24. Lendahl U, Zimmerman LB, McKay RD (1990) CNS stem cells express a new class of intermediate filament protein. Cell 60(4):585–595

    Article  PubMed  CAS  Google Scholar 

  25. Levi A, Biocca S, Cattaneo A, Calissano P (1988) The mode of action of nerve growth factor in PC12 cells. Mol Neurobiol 2(3):201–226

    Article  PubMed  CAS  Google Scholar 

  26. Li Y, Mu Y, Gage FH (2009) Development of neural circuits in the adult hippocampus. Curr Top Dev Biol 87:149–174

    Article  PubMed  CAS  Google Scholar 

  27. Li Z, Van Aelst L, Cline HT (2000) Rho GTPases regulate distinct aspects of dendritic arbor growth in Xenopus central neurons in vivo. Nat Neurosci 3(3):217–225

    Article  PubMed  CAS  Google Scholar 

  28. Luo L, O’Leary DD (2005) Axon retraction and degeneration in development and disease. Annu Rev Neurosci 28:127–156

    Article  PubMed  CAS  Google Scholar 

  29. Michaelsen K, Lohmann C (2010) Calcium dynamics at develo** synapses: mechanisms and functions. Eur J Neurosci 32(2):218–223

    Article  PubMed  Google Scholar 

  30. Moughal NA, Waters CM, Valentine WJ, Connell M, Richardson JC, Tigyi G, Pyne S, Pyne NJ (2006) Protean agonism of the lysophosphatidic acid receptor-1 with Ki16425 reduces nerve growth factor-induced neurite outgrowth in pheochromocytoma 12 cells. J Neurochem 98(6):1920–1929

    Article  PubMed  CAS  Google Scholar 

  31. Nagamine K, Kudoh J, Minoshima S, Kawasaki K, Asakawa S, Ito F, Shimizu N (1998) Molecular cloning of a novel putative Ca2+ channel protein (TRPC7) highly expressed in brain. Genomics 54(1):124–131

    Article  PubMed  CAS  Google Scholar 

  32. Naziroglu M (2011) TRPM2 cation channels, oxidative stress and neurological diseases: where are we now? Neurochem Res 36(3):355–366

    Article  PubMed  CAS  Google Scholar 

  33. Nieto-Posadas A, Picazo-Juarez G, Llorente I, Jara-Oseguera A, Morales-Lazaro S, Escalante-Alcalde D, Islas LD, Rosenbaum T (2012) Lysophosphatidic acid directly activates TRPV1 through a C-terminal binding site. Nat Chem Biol 8(1):78–85

    Article  CAS  Google Scholar 

  34. Nilius B, Voets T (2005) TRP channels: a TR(I)P through a world of multifunctional cation channels. Pflugers Arch 451(1):1–10

    Article  PubMed  CAS  Google Scholar 

  35. Nilius B, Voets T (2013) The puzzle of TRPV4 channelopathies. EMBO Rep 14(9):845

    Article  CAS  Google Scholar 

  36. 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(6837):595–599

    Article  PubMed  CAS  Google Scholar 

  37. 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(7):6138–6148

    Article  PubMed  CAS  Google Scholar 

  38. Pool M, Thiemann J, Bar-Or A, Fournier AE (2008) NeuriteTracer: a novel ImageJ plugin for automated quantification of neurite outgrowth. J Neurosci Methods 168(1):134–139

    Article  PubMed  Google Scholar 

  39. Price RD, Yamaji T, Matsuoka N (2003) FK506 potentiates NGF-induced neurite outgrowth via the Ras/Raf/MAP kinase pathway. Br J Pharmacol 140(5):825–829

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  40. Roberts C, Winter P, Shilliam CS, Hughes ZA, Langmead C, Maycox PR, Dawson LA (2005) Neurochemical changes in LPA1 receptor deficient mice—a putative model of schizophrenia. Neurochem Res 30(3):371–377

    Article  PubMed  CAS  Google Scholar 

  41. Sano Y, Inamura K, Miyake A, Mochizuki S, Yokoi H, Matsushime H, Furuichi K (2001) Immunocyte Ca2+ influx system mediated by LTRPC2. Science 293(5533):1327–1330

    Article  PubMed  CAS  Google Scholar 

  42. Sato K, Malchinkhuu E, Muraki T, Ishikawa K, Hayashi K, Tosaka M, Mochiduki A, Inoue K, Tomura H, Mogi C, Nochi H, Tamoto K, Okajima F (2005) Identification of autotaxin as a neurite retraction-inducing factor of PC12 cells in cerebrospinal fluid and its possible sources. J Neurochem 92(4):904–914

    Article  PubMed  CAS  Google Scholar 

  43. Shim S, Goh EL, Ge S, Sailor K, Yuan JP, Roderick HL, Bootman MD, Worley PF, Song H, Ming GL (2005) XTRPC1-dependent chemotropic guidance of neuronal growth cones. Nat Neurosci 8(6):730–735

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  44. Shim S, Yuan JP, Kim JY, Zeng W, Huang G, Milshteyn A, Kern D, Muallem S, Ming GL, Worley PF (2009) Peptidyl-prolyl isomerase FKBP52 controls chemotropic guidance of neuronal growth cones via regulation of TRPC1 channel opening. Neuron 64(4):471–483

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  45. Tigyi G, Miledi R (1992) Lysophosphatidates bound to serum albumin activate membrane currents in Xenopus oocytes and neurite retraction in PC12 pheochromocytoma cells. J Biol Chem 267(30):21360–21367

    PubMed  CAS  Google Scholar 

  46. 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(9):1804–1815

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  47. Wen Z, Zheng JQ (2006) Directional guidance of nerve growth cones. Curr Opin Neurobiol 16(1):52–58

    Article  PubMed  CAS  Google Scholar 

  48. **ang SY, Dusaban SS, Brown JH (2013) Lysophospholipid receptor activation of RhoA and lipid signaling pathways. Biochim Biophys Acta 1831(1):213–222

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  49. **e Y, Gibbs TC, Meier KE (2002) Lysophosphatidic acid as an autocrine and paracrine mediator. Biochim Biophys Acta 1582(1–3):270–281

    Article  PubMed  CAS  Google Scholar 

  50. 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(7):738–747

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  51. Yung YC, Mutoh T, Lin ME, Noguchi K, Rivera RR, Choi JW, Kingsbury MA, Chun J (2011) Lysophosphatidic acid signaling may initiate fetal hydrocephalus. Sci Transl Med 3(99):99ra87

    Article  PubMed  PubMed Central  Google Scholar 

  52. Zhang Z, Zhang W, Jung DY, Ko HJ, Lee Y, Friedline RH, Lee E, Jun J, Ma Z, Kim F, Tsitsilianos N, Chapman K, Morrison A, Cooper MP, Miller BA, Kim JK (2012) TRPM2 Ca2+ channel regulates energy balance and glucose metabolism. Am J Physiol Endocrinol Metab 302(7):E807–E816

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  53. Zhong Z, Zhai Y, Liang S, Mori Y, Han R, Sutterwala FS, Qiao L (2013) TRPM2 links oxidative stress to NLRP3 inflammasome activation. Nat Commun 4:1611

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgments

This study was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIP; no. 2011-0018358 and NRF-2013R1A1A2063015) and Brain Korea 21 plus of NRF.

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Authors and Affiliations

  1. Channel Research Center, CRI, College of Pharmacy, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul, 151-742, Republic of Korea

    Yongwoo Jang, Mi Hyun Lee, Jesun Lee, Jooyoung Jung, Sung Hoon Lee & Uhtaek Oh

  2. Department of Molecular Medicine and Biopharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea

    Dong-** Yang & Uhtaek Oh

  3. Institut Pasteur Korea, Sampyeong-dong, Bundang-gu, Sungnam-si, Gyeonggi-do, 463-400, Republic of Korea

    Uhtaek Oh

  4. College of Medicine and Institute of Mental Health, Hanyang University, Seoul, 133-791, Republic of Korea

    Byung Woo Kim & Hyeon Son

  5. Department of Physiology and Biomedical Sciences, College of Medicine, Seoul National University, Seoul, 110-799, Republic of Korea

    Boyoon Lee & Sunghoe Chang

  6. Graduate School of Engineering, Kyoto University, Kyoto, Japan

    Yasuo Mori

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  1. Yongwoo Jang
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Correspondence to Uhtaek Oh.

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Jang, Y., Lee, M.H., Lee, J. et al. TRPM2 mediates the lysophosphatidic acid-induced neurite retraction in the develo** brain. Pflugers Arch - Eur J Physiol 466, 1987–1998 (2014). https://doi.org/10.1007/s00424-013-1436-4

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