Skip to main content
SpringerLink
Log in

Nuclear GAPDH: changing the fate of Müller cells in diabetes

  • Published:
Journal of Ocular Biology, Diseases, and Informatics

Abstract

Müller cells, the primary glial cells are a crucial component of the retinal tissue performing a wide range of functions including maintaining the blood-retinal barrier. Several studies suggest that diabetes leads to Müller cell dysfunction and loss. The pathophysiology of hyperglycemia-induced cellular injury of Müller cells remains only poorly understood. Recently, the concept that translocation of the predominantly cytosolic glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH) to the nucleus and its accumulation in this cellular compartment alters transcriptional events associated with cell death induction has gained major interest. High glucose conditions induce nuclear translocation and accumulation of GAPDH in the nucleus of Müller cells in vivo and in vitro. With regards to Müller cell dysfunction, the effects of nuclear accumulation of GAPDH are multifaceted. Considering the functional versatility of GAPDH including gene regulation, DNA repair, telomere protection, etc., it is of immense importance to explore possible GAPDH actions to unravel the mysteries around the role of GAPDH in hyperglycemia-induced cellular changes in order to develop novel therapeutic strategies. Therefore, this review focuses on the molecular events associated with the nuclear translocation of GAPDH and how it affects the fate of Müller cells in diabetes.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Centers for Disease Control and Prevention. National Diabetes Fact Sheet: national estimates and general information on diabetes and prediabetes in the United States, 2011. Atlanta, GA: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention; 2011.

    Google Scholar 

  2. Yau J, Rogers S, Kawasaki R, Lamoureux E, Kowalski J, Bek T, et al. Global prevalence and major risk factors of diabetic retinopathy. Diabetes Care. 2012;35(3):556–64. doi:10.2337/dc11-1909.

    Article  PubMed  Google Scholar 

  3. Cheung N, Mitchell P, Wong TY. Diabetic retinopathy. Lancet. 2010;376(9735):124–36. doi:10.1016/S0140-6736(09)62124-3.

    Article  PubMed  Google Scholar 

  4. Distler C, Dreher Z. Glia cells of the monkey retina–II. Müller cells. Vis Res. 1996;36(16):2381–94.

    Article  PubMed  CAS  Google Scholar 

  5. Kannan R, Bao Y, Wang Y, Sarthy V, Kaplowitz N. Protection from oxidant injury by sodium-dependent GSH uptake in retinal Müller cells. Exp Eye Res. 1999;68(5):609–16. doi:10.1006/exer.1998.0639.

    Article  PubMed  CAS  Google Scholar 

  6. Miller R, Dowling J. Intracellular responses of the Müller (glial) cells of mudpuppy retina: their relation to b-wave of the electroretinogram. J Neurophysiol. 1970;33(3):323–41.

    PubMed  CAS  Google Scholar 

  7. Newman E, Frambach D, Odette L. Control of extracellular potassium levels by retinal glial cell K+ siphoning. Science. 1984;225(4667):1174–5.

    Article  PubMed  CAS  Google Scholar 

  8. Reichenbach A, Stolzenburg J, Eberhardt W, Chao T, Dettmer D, Hertz L. What do retinal Müller (glial) cells do for their neuronal ‘small siblings’? J Chem Neuroanat. 1993;66(4):201–13.

    Article  Google Scholar 

  9. Sarthy V. Müller cells in retinal health and disease. Arch Soc Esp Oftalmol. 2000;75(6):367–8.

    PubMed  CAS  Google Scholar 

  10. Schütte M, Werner P. Redistribution of glutathione in the ischemic rat retina. Neurosci Lett. 1998;246(1):53–6.

    Article  PubMed  Google Scholar 

  11. Tout S, Chan-Ling T, Holländer H, Stone J. The role of Müller cells in the formation of the blood–retinal barrier. Neuroscience. 1993;55(1):291–301.

    Article  PubMed  CAS  Google Scholar 

  12. Poitry-Yamate C, Poitry S, Tsacopoulos M. Lactate released by Müller glial cells is metabolized by photoreceptors from mammalian retina. J Neurosci Off J Soc Neurosci. 1995;15(7):5179–91.

    CAS  Google Scholar 

  13. Tsacopoulos M, Magistretti P. Metabolic coupling between glia and neurons. J Neurosci Off J Soc Neurosci. 1996;16:877–85.

    CAS  Google Scholar 

  14. Matsui K, Hosoi N, Tachibana M. Active role of glutamate uptake in the synaptic transmission from retinal nonspiking neurons. J Neurosci Off J Soc Neurosci. 1999;19(16):6755–66.

    CAS  Google Scholar 

  15. Riepe R, Norenburg M. Müller cell localisation of glutamine synthetase in rat retina. Nature. 1977;268:654–5.

    Article  PubMed  CAS  Google Scholar 

  16. White R, Neal M. The uptake of l-glutamate by the retina. Brain Res. 1976;111(1):79–93.

    Article  PubMed  CAS  Google Scholar 

  17. Newman E, Reichenbach A. The Müller cell: a functional element of the retina. Trends Neurosci. 1996;19(8):307–12.

    Article  PubMed  CAS  Google Scholar 

  18. Dubois-Dauphin M, Poitry-Yamate C, de Bilbao F, Julliard A, Jourdan F, Donati G. Early postnatal Müller cell death leads to retinal but not optic nerve degeneration in NSE-Hu-Bcl-2 transgenic mice. Neuroscience. 2000;95(1):9–21.

    Article  PubMed  CAS  Google Scholar 

  19. Puro D, Mano T. Modulation of calcium channels in human retinal glial cells by basic fibroblast growth factor: a possible role in retinal pathobiology. J Neurosci Off J Soc Neurosci. 1991;11(6):1873–80.

    CAS  Google Scholar 

  20. Ward M, Jobling A, Kalloniatis M, Fletcher E. Glutamate uptake in retinal glial cells during diabetes. Diabetologia. 2005;48(2):351–60. doi:10.1007/s00125-004-1639-5.

    Article  PubMed  CAS  Google Scholar 

  21. Abu el Asrar A, Maimone D, Morse P, Gregory S, Reder A. Cytokines in the vitreous of patients with proliferative diabetic retinopathy. Am J Ophthalmol. 1992;114(6):731–6.

    PubMed  CAS  Google Scholar 

  22. Busik J, Mohr S, Grant M. Hyperglycemia-induced reactive oxygen species toxicity to endothelial cells is dependent on paracrine mediators. Diabetes. 2008;57(7):1952–65. doi:10.2337/db07-1520.

    Article  PubMed  CAS  Google Scholar 

  23. Joussen A, Poulaki V, Le M, Koizumi K, Esser C, Janicki H, et al. A central role for inflammation in the pathogenesis of diabetic retinopathy. FASEB J Off Publ Fed Am Soc Exp Biol. 2004;18(12):1450–2. doi:10.1096/fj.03-1476fje.

    CAS  Google Scholar 

  24. Mohr S, Xi X, Tang J, Kern T. Caspase activation in retinas of diabetic and galactosemic mice and diabetic patients. Diabetes. 2002;51(4):1172–9.

    Article  PubMed  CAS  Google Scholar 

  25. Vincent J, Mohr S. Inhibition of caspase-1/interleukin-1beta signaling prevents degeneration of retinal capillaries in diabetes and galactosemia. Diabetes. 2007;56(1):224–30. doi:10.2337/db06-0427.

    Article  PubMed  CAS  Google Scholar 

  26. Yego E, Vincent J, Sarthy V, Busik J, Mohr S. Differential regulation of high glucose-induced glyceraldehyde-3-phosphate dehydrogenase nuclear accumulation in Müller cells by IL-1beta and IL-6. Invest Ophthalmol Vis Sci. 2009;50(4):1920–8. doi:10.1167/iovs.08-2082.

    Article  PubMed  Google Scholar 

  27. Kusner L, Sarthy V, Mohr S. Nuclear translocation of glyceraldehyde-3-phosphate dehydrogenase: a role in high glucose-induced apoptosis in retinal Müller cells. Invest Ophthalmol Vis Sci. 2004;45(5):1553–61.

    PubMed  Google Scholar 

  28. Barber R, Harmer D, Coleman R, Clark B. GAPDH as a housekeeping gene: analysis of GAPDH mRNA expression in a panel of 72 human tissues. Physiol Genomics. 2005;21:389–95. doi:10.1152/physiolgenomics.00025.2005.

    Article  PubMed  CAS  Google Scholar 

  29. Tisdale E. Glyceraldehyde-3-phosphate dehydrogenase is phosphorylated by protein kinase Ciota/lambda and plays a role in microtubule dynamics in the early secretory pathway. J Biol Chem. 2002;277(5):3334–41. doi:10.1074/jbc.M109744200.

    Article  PubMed  CAS  Google Scholar 

  30. Tisdale E, Azizi F, Artalejo C. Rab2 utilizes glyceraldehyde-3-phosphate dehydrogenase and protein kinase C{iota} to associate with microtubules and to recruit dynein. J Biol Chem. 2009;284(9):5876–84. doi:10.1074/jbc.M807756200.

    Article  PubMed  CAS  Google Scholar 

  31. Andrade J, Pearce S, Zhao H, Barroso M. Interactions among p22, glyceraldehyde-3-phosphate dehydrogenase and microtubules. Biochem J. 2004;384(Pt 2):327–36. doi:10.1042/bj20040622.

    PubMed  CAS  Google Scholar 

  32. Tisdale E, Kelly C, Artalejo C. Glyceraldehyde-3-phosphate dehydrogenase interacts with Rab2 and plays an essential role in endoplasmic reticulum to Golgi transport exclusive of its glycolytic activity. J Biol Chem. 2004;279(52):54046–52. doi:10.1074/jbc.M409472200.

    Article  PubMed  CAS  Google Scholar 

  33. Harada N, Yasunaga R, Higashimura Y, Yamaji R, Fujimoto K, Moss J, et al. Glyceraldehyde-3-phosphate dehydrogenase enhances transcriptional activity of androgen receptor in prostate cancer cells. J Biol Chem. 2007;282(31):22651–61. doi:10.1074/jbc.M610724200.

    Article  PubMed  CAS  Google Scholar 

  34. Singh R, Green M. Sequence-specific binding of transfer RNA by glyceraldehyde-3-phosphate dehydrogenase. Science. 1993;259(5093):365–8.

    Article  PubMed  CAS  Google Scholar 

  35. Rodríguez-Pascual F, Redondo-Horcajo M, Magán-Marchal N, Lagares D, Martínez-Ruiz A, Kleinert H, et al. Glyceraldehyde-3-phosphate dehydrogenase regulates endothelin-1 expression by a novel, redox-sensitive mechanism involving mRNA stability. Mol Cell Biol. 2008;28(23):7139–55. doi:10.1128/mcb.01145-08.

    Article  PubMed  Google Scholar 

  36. Bonafé N, Gilmore-Hebert M, Folk N, Azodi M, Zhou Y, Chambers S. Glyceraldehyde-3-phosphate dehydrogenase binds to the AU-Rich 3′ untranslated region of colony-stimulating factor-1 (CSF-1) messenger RNA in human ovarian cancer cells: possible role in CSF-1 posttranscriptional regulation and tumor phenotype. Cancer Res. 2005;65(9):3762–71. doi:10.1158/0008-5472.can-04-3954.

    Article  PubMed  Google Scholar 

  37. Zhou Y, Yi X, Jn S, Bonafe N, Gilmore-Hebert M, McAlpine J, et al. The multifunctional protein glyceraldehyde-3-phosphate dehydrogenase is both regulated and controls colony-stimulating factor-1 messenger RNA stability in ovarian cancer. Mol Cancer Res: MCR. 2008;6(8):1375–84. doi:10.1158/1541-7786.mcr-07-2170.

    Article  PubMed  CAS  Google Scholar 

  38. Backlund M, Paukku K, Daviet L, De Boer R, Valo E, Hautaniemi S, et al. Posttranscriptional regulation of angiotensin II type 1 receptor expression by glyceraldehyde 3-phosphate dehydrogenase. Nucleic Acids Res. 2009;37(7):2346–58. doi:10.1093/nar/gkp098.

    Article  PubMed  CAS  Google Scholar 

  39. Carujo S, Estanyol J, Ejarque A, Agell N, Bachs O, Pujol M. Glyceraldehyde 3-phosphate dehydrogenase is a SET-binding protein and regulates cyclin B-cdk1 activity. Oncogene. 2006;25:4033–42. doi:10.1038/sj.onc.1209433.

    Article  PubMed  CAS  Google Scholar 

  40. Zheng L, Roeder R, Luo Y. S phase activation of the histone H2B promoter by OCA-S, a coactivator complex that contains GAPDH as a key component. Cell. 2003;114(2):255–66.

    Article  PubMed  CAS  Google Scholar 

  41. Mansur N, Meyer-Siegler K, Wurzer J, Sirover M. Cell cycle regulation of the glyceraldehyde-3-phosphate dehydrogenase/uracil DNA glycosylase gene in normal human cells. Nucleic Acids Res. 1993;21(4):993–8.

    Article  PubMed  CAS  Google Scholar 

  42. Ronai Z. Glycolytic enzymes as DNA binding proteins. Int J Biochem. 1993;25(7):1073–6.

    Article  PubMed  CAS  Google Scholar 

  43. Azam S, Jouvet N, Jilani A, Vongsamphanh R, Yang X, Yang S, et al. Human glyceraldehyde-3-phosphate dehydrogenase plays a direct role in reactivating oxidized forms of the DNA repair enzyme APE1. J Biol Chem. 2008;283(45):30632–41. doi:10.1074/jbc.M801401200.

    Article  PubMed  CAS  Google Scholar 

  44. Sundararaj K, Wood R, Ponnusamy S, Salas A, Szulc Z, Bielawska A, et al. Rapid shortening of telomere length in response to ceramide involves the inhibition of telomere binding activity of nuclear glyceraldehyde-3-phosphate dehydrogenase. J Biol Chem. 2004;279(7):6152–62. doi:10.1074/jbc.M310549200.

    Article  PubMed  CAS  Google Scholar 

  45. Demarse N, Ponnusamy S, Spicer E, Apohan E, Baatz J, Ogretmen B, et al. Direct binding of glyceraldehyde 3-phosphate dehydrogenase to telomeric DNA protects telomeres against chemotherapy-induced rapid degradation. J Mol Biol. 2009;394(4):789–803. doi:10.1016/j.jmb.2009.09.062.

    Article  PubMed  CAS  Google Scholar 

  46. Patterson R, van Rossum D, Kaplin A, Barrow R, Snyder S. Inositol 1,4,5-trisphosphate receptor/GAPDH complex augments Ca2+ release via locally derived NADH. Proc Natl Acad Sci USA. 2005;102(5):1357–9. doi:10.1073/pnas.0409657102.

    Article  PubMed  CAS  Google Scholar 

  47. Ravichandran V, Seres T, Moriguchi T, Thomas J, Johnston R. S-thiolation of glyceraldehyde-3-phosphate dehydrogenase induced by the phagocytosis-associated respiratory burst in blood monocytes. J Biol Chem. 1994;269(40):25010–5.

    PubMed  CAS  Google Scholar 

  48. Du X, Matsumura T, Edelstein D, Rossetti L, Zsengellér Z, Szabó C, et al. Inhibition of GAPDH activity by poly(ADP-ribose) polymerase activates three major pathways of hyperglycemic damage in endothelial cells. J Clin Invest. 2003;112(7):1049–57. doi:10.1172/jci18127.

    PubMed  CAS  Google Scholar 

  49. Devalaraja-Narashimha K, Padanilam B. PARP-1 inhibits glycolysis in ischemic kidneys. J Am Soc Nephrol: JASN. 2009;20(1):95–103. doi:10.1681/asn.2008030325.

    Article  PubMed  Google Scholar 

  50. Tarze A, Deniaud A, Le Bras M, Maillier E, Molle D, Larochette N, et al. GAPDH, a novel regulator of the pro-apoptotic mitochondrial membrane permeabilization. Oncogene. 2007;26(18):2606–20. doi:10.1038/sj.onc.1210074.

    Article  PubMed  CAS  Google Scholar 

  51. Colell A, Ricci J-E, Tait S, Milasta S, Maurer U, Bouchier-Hayes L, et al. GAPDH and autophagy preserve survival after apoptotic cytochrome c release in the absence of caspase activation. Cell. 2007;129(5):983–97. doi:10.1016/j.cell.2007.03.045.

    Article  PubMed  CAS  Google Scholar 

  52. Saunders P, Chalecka-Franaszek E, Chuang D. Subcellular distribution of glyceraldehyde-3-phosphate dehydrogenase in cerebellar granule cells undergoing cytosine arabinoside-induced apoptosis. J Neurochem. 1997;69(5):1820–8.

    Article  PubMed  CAS  Google Scholar 

  53. Sawa A, Khan A, Hester L, Snyder S. Glyceraldehyde-3-phosphate dehydrogenase: nuclear translocation participates in neuronal and nonneuronal cell death. Proc Natl Acad Sci USA. 1997;94(21):11669–74.

    Article  PubMed  CAS  Google Scholar 

  54. Ishitani R, Tanaka M, Sunaga K, Katsube N, Chuang D. Nuclear localization of overexpressed glyceraldehyde-3-phosphate dehydrogenase in cultured cerebellar neurons undergoing apoptosis. Mol Pharmacol. 1998;53(4):701–7.

    PubMed  CAS  Google Scholar 

  55. Kragten E, Lalande I, Zimmermann K, Roggo S, Schindler P, Muller D, et al. Glyceraldehyde-3-phosphate dehydrogenase, the putative target of the antiapoptotic compounds CGP 3466 and R-(−)-deprenyl. J Biol Chem. 1998;273(10):5821–8.

    Article  PubMed  CAS  Google Scholar 

  56. Carlile G, Chalmers-Redman R, Tatton N, Pong A, Borden K, Tatton W. Reduced apoptosis after nerve growth factor and serum withdrawal: conversion of tetrameric glyceraldehyde-3-phosphate dehydrogenase to a dimer. Mol Pharmacol. 2000;57(2):2–12.

    PubMed  CAS  Google Scholar 

  57. Dastoor Z, Dreyer J. Potential role of nuclear translocation of glyceraldehyde-3-phosphate dehydrogenase in apoptosis and oxidative stress. J Cell Sci. 2001;114:1643–53.

    PubMed  CAS  Google Scholar 

  58. Hara M, Agrawal N, Kim S, Cascio M, Fujimuro M, Ozeki Y, et al. S-nitrosylated GAPDH initiates apoptotic cell death by nuclear translocation following SIAH1 binding. Nat Cell Biol. 2005;7:665–74. doi:10.1038/ncb1268.

    Article  PubMed  CAS  Google Scholar 

  59. Sen N, Hara M, Ahmad A, Cascio M, Kamiya A, Ehmsen J, et al. GOSPEL: a neuroprotective protein that binds to GAPDH upon S-nitrosylation. Neuron. 2009;63(1):81–91. doi:10.1016/j.neuron.2009.05.024.

    Article  PubMed  CAS  Google Scholar 

  60. Sourisseau T, Desbois C, Debure L, Bowtell D, Cato A, Schneikert J, et al. Alteration of the stability of Bag-1 protein in the control of olfactory neuronal apoptosis. J Cell Sci. 2001;114(Pt 7):1409–16.

    PubMed  CAS  Google Scholar 

  61. Fiucci G, Beaucourt S, Duflaut D, Lespagnol A, Stumptner-Cuvelette P, Géant A, et al. SIAH-1b is a direct transcriptional target of p53: identification of the functional p53 responsive element in the siah-1b promoter. Proc Natl Acad Sci USA. 2004;101(10):3510–5. doi:10.1073/pnas.0400177101.

    Article  PubMed  CAS  Google Scholar 

  62. Polekhina G, House C, Traficante N, Mackay J, Relaix F, Sassoon D, et al. SIAH ubiquitin ligase is structurally related to TRAF and modulates TNF-alpha signaling. Nat Struct Biol. 2002;9(1):68–75. doi:10.1038/nsb743.

    Article  PubMed  CAS  Google Scholar 

  63. House C, Frew I, Huang H-L, Wiche G, Traficante N, Nice E, et al. A binding motif for SIAH ubiquitin ligase. Proc Natl Acad Sci USA. 2003;100(6):3101–6. doi:10.1073/pnas.0534783100.

    Article  PubMed  CAS  Google Scholar 

  64. House C, Hancock N, Möller A, Cromer B, Fedorov V, Bowtell D, et al. Elucidation of the substrate binding site of SIAH ubiquitin ligase. Structure (London, England: 1993). 2006;14(4):695–701. doi:10.1016/j.str.2005.12.013.

    Article  CAS  Google Scholar 

  65. Sen N, Hara M, Kornberg M, Cascio M, Bae B-I, Shahani N, et al. Nitric oxide-induced nuclear GAPDH activates p300/CBP and mediates apoptosis. Nat Cell Biol. 2008;10:866–73. doi:10.1038/ncb1747.

    Article  PubMed  CAS  Google Scholar 

  66. Kornberg M, Sen N, Hara M, Juluri K, Nguyen J, Snowman A, et al. GAPDH mediates nitrosylation of nuclear proteins. Nat Cell Biol. 2010;12(11):1094–100. doi:10.1038/ncb2114.

    Article  PubMed  CAS  Google Scholar 

  67. Yego E, Mohr S. SIAH-1 protein is necessary for high glucose-induced glyceraldehyde-3-phosphate dehydrogenase nuclear accumulation and cell death in Müller cells. J Biol Chem. 2010;285:3181–90. doi:10.1074/jbc.M109.083907.

    Article  PubMed  CAS  Google Scholar 

  68. Creagh E, Conroy H, Martin S. Caspase-activation pathways in apoptosis and immunity. Immunol Rev. 2003;193:10–21.

    Article  PubMed  CAS  Google Scholar 

  69. Madsen-Bouterse S, Mohammad G, Kowluru R. Glyceraldehyde-3-phosphate dehydrogenase in retinal microvasculature: implications for the development and progression of diabetic retinopathy. Invest Ophthalmol Vis Sci. 2010;51(3):1765–72. doi:10.1167/iovs.09-4171.

    Article  PubMed  Google Scholar 

  70. Krady J, Basu A, Allen C, Xu Y, LaNoue K, Gardner T, et al. Minocycline reduces proinflammatory cytokine expression, microglial activation, and caspase-3 activation in a rodent model of diabetic retinopathy. Diabetes. 2005;54(5):1559–65.

    Article  PubMed  CAS  Google Scholar 

  71. Jeanclos E, Krolewski A, Skurnick J, Kimura M, Aviv H, Warram J, et al. Shortened telomere length in white blood cells of patients with IDDM. Diabetes. 1998;47(3):482–6.

    Article  PubMed  CAS  Google Scholar 

  72. González M, Sanz I, Silva V, Asenjo S, Gleisner A, Bustamante M. Differential modulation by native and glycated low density lipoproteins of peripheral blood mononuclear cells proliferation induced by phytohemagglutinin in insulin-dependent diabetes mellitus patients. Clin Chim Acta Int J Clin Chem. 2000;293(1–2):223–8.

    Article  Google Scholar 

  73. Uziel O, Singer J, Danicek V, Sahar G, Berkov E, Luchansky M, et al. Telomere dynamics in arteries and mononuclear cells of diabetic patients: effect of diabetes and of glycemic control. Exp Gerontol. 2007;42(10):971–8. doi:10.1016/j.exger.2007.07.005.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This manuscript was supported by NIH/NEI EY-017268 (SM).

Author information

Authors and Affiliations

  1. Department of Physiology, Michigan State University, 3175 Biomedical Physical Sciences, East Lansing, MI, 48824, USA

    Prathiba Jayaguru & Susanne Mohr

Authors
  1. Prathiba Jayaguru
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Susanne Mohr
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Susanne Mohr.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Jayaguru, P., Mohr, S. Nuclear GAPDH: changing the fate of Müller cells in diabetes. j ocul biol dis inform 4, 34–41 (2011). https://doi.org/10.1007/s12177-012-9085-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12177-012-9085-y

Keywords

Search

Navigation