Neurochemical Research

, Volume 35, Issue 12, pp 1867–1874

In Search of a Solution to the Sphinx-Like Riddle of GM1



Among the many glycoconjugates contributing to the sugar code, gangliosides have drawn special attention owing to their predominance as the major sialoglycoconjugate category within the nervous system. However, their occurrence, albeit at lower levels, appears ubiquitous in vertebrate cells and even some invertebrate tissues. Now that over 100 gangliosides have been structurally characterized, their diverse physiological functions constitute a remaining enigma. This has been especially true of GM1, for which a surprising array of functions has already been revealed. Our current research has focused on two areas of GM1 function: (a) signaling induced in neural and immune cells by cross-linking of GM1 in the plasma membrane that leads to activation of TRPC5 (transient receptor potiential, canonical form 5) channels, a process important in neuritogenesis and autoimmune suppression; (b) activation by GM1 of a sodium-calcium exchanger (NCX) in the inner membrane of the nuclear envelope (NE) with resulting modulation of nuclear and cellular calcium. The latter has a role in maintaining neuronal viability, loss of which renders neurons vulnerable to Ca2+ overload. Pathological manifestations in mutant mice and their cultured neurons lacking GM1 have shown dramatic rescue with a membrane permeable derivative of GM1 that enters the nucleus and restores NCX activity. Nuclear function of GM1 is related to the presence of neuraminidase in the NE, an enzyme that generates GM1 through hydrolysis of GD1a. A different isoform of this enzyme was found in each of the two membranes of the NE.


GM1 Ganglioside Neuraminidase Calcium regulation Cross-linking of GM1 TRPC5 channels GM1 in the nuclear envelope Sodium-calcium exchanger 



B subunit of cholera toxin


Endoplasmic reticulum








Sodium-calcium exchanger


Nuclear envelope


Effector T cell


Regulatory T cell


Transient receptor potential, isoform 5 of canonical subgroup


  1. 1.
    Svennerholm L (1963) Chromatographic separation of human brain gangliosides. J Neurochem 10:613–623CrossRefPubMedGoogle Scholar
  2. 2.
    Kuhn R, Wiegandt H (1963) Die Konstitution der Ganglio-N-tetraose und des Gangliosids G1. Chemische Berichte 96:866–880CrossRefGoogle Scholar
  3. 3.
    Ledeen R, Salsman K, Gonatas J, Taghavy A (1965) Structure comparison of the major monosialogangliosides from brains of normal human, gargoylism, and late infantile systemic lipidosis. J Neuropath Exp Neurol 24:341–351CrossRefPubMedGoogle Scholar
  4. 4.
    Forman DS, Ledeen RW (1972) Axonal transport of gangliosides in the goldfish optic nerve. Science 177:630–633CrossRefPubMedGoogle Scholar
  5. 5.
    Ledeen RW (1978) Ganglioside structures and distribution: are they localized at the nerve ending? J Supramolec Struct 8:1–17CrossRefGoogle Scholar
  6. 6.
    Yu RK, Yanagisawa M, Ariga T (2007) Glycosphingolipid structures. In: Kamerling JP (ed) Comprehensive glycoscience. Elsevier, Oxford, UK, pp 73–122CrossRefGoogle Scholar
  7. 7.
    Simons K, van Meer G (1988) Lipid sorting in epithelial cells. Biochemistry 27:6197–6202CrossRefPubMedGoogle Scholar
  8. 8.
    Hakomori S-I, Handa K, Iwabuchi K, Yamamura S, Prinetti A (1998) New insights in glycosphingolipid function: “glycosignaling domain”, a cell surface assembly of glycosphingolipids with signal transducer molecules, involved in cell adhesion coupled with signaling. Glycobiology 8:xi–xixPubMedGoogle Scholar
  9. 9.
    Wu G, Ledeen RW (1994) Gangliosides as modulators of neuronal calcium. Prog Brain Res 101:101–112CrossRefPubMedGoogle Scholar
  10. 10.
    Ledeen RW, Wu G (2002) Ganglioside function in calcium homeostasis and signaling. Neurochem Res 27:637–647CrossRefPubMedGoogle Scholar
  11. 11.
    Byrne MC, Ledeen RW, Roisen FJ, Yorke G, Sclafani J (1983) Ganglioside-induced neuritogenesis: verification that gangliosides are the active agents, and comparison of molecular species. J Neurochem 41:1214–1222CrossRefPubMedGoogle Scholar
  12. 12.
    Wu G, Ledeen RW (1991) Stimulation of neurite outgrowth in neuroblastoma cells by neuraminidase: putative role of GM1 ganglioside in differentiation. J Neurochem 56:95–104CrossRefPubMedGoogle Scholar
  13. 13.
    Hasegawa T, Yamaguchi K, Wada T, Takeda A, Itoyama Y, Miyagi T (2000) Molecular cloning of mouse ganglioside sialidase and its increased expression in Neuro2a cell differentiation. J Biol Chem 275:8007–8015CrossRefPubMedGoogle Scholar
  14. 14.
    Dixon SJ, Stewart D, Grinstein S, Spiegel S (1987) Transmembrane signaling by the B subunit of cholera toxin: increased cytoplasmic free calcium in rat lymphocytes. J Cell Biol 105:1153–1161CrossRefPubMedGoogle Scholar
  15. 15.
    Fang Y, Xie X, Ledeen RW, Wu G (2002) Characterization of cholera toxin B subunit induced Ca2+ influx in neuroblastoma cells: evidence for a voltage independent GM1 ganglioside-associated Ca2+ channel. J Neurosci Res 69:669–680CrossRefPubMedGoogle Scholar
  16. 16.
    Wu G, Lu Z-H, Obukhov AG, Nowycky MC, Ledeen RW (2007) Induction of calcium influx through TRPC5 channels by cross-linking of GM1 ganglioside associated with alpha5beta1 integrin initiates neurite outgrowth. J Neurosci 27:7447–7458CrossRefPubMedGoogle Scholar
  17. 17.
    Clapham DE, Runnels LW, Strubing C (2001) The TRP ion channel family. Nature Rev Neurosci 2:387–396CrossRefGoogle Scholar
  18. 18.
    Montell C (2004) Exciting trips for TRPs. Nat Cell Biol 6:690–692CrossRefPubMedGoogle Scholar
  19. 19.
    Wu G, Ledeen RW (2010) In PreparationGoogle Scholar
  20. 20.
    Kopitz J, von Reitzenstein C, Burchert M, Cantz M, Gabius H-J (1998) Galectin-1 is a major receptor for ganglioside GM1, a product of the growth-controlling activity of a cell surface ganglioside sialidase, on human neuroblastoma cells in culture. J Biol Chem 273:11205–11211CrossRefPubMedGoogle Scholar
  21. 21.
    Wang J, Lu Z-H, Gabius H-J, Rohowsky-Kochan C, Ledeen RW, Wu G (2009) Cross-Linking of GM1 ganglioside by galectin-1 mediates regulatory T cell activity involving TRPC5 channel activation: possible role in suppressing experimental autoimmune encephalomyelitis. J Immunol 182:4036–4045CrossRefPubMedGoogle Scholar
  22. 22.
    Sakaguchi S, Sakaguchi N, Asano M, Itoh M, Toda M (1995) Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25): breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J Immunol 155:1151–1164PubMedGoogle Scholar
  23. 23.
    Jiang H, Chess L (2006) Regulation of immune responses by T cells. New Eng J Med 354:1166–1176CrossRefPubMedGoogle Scholar
  24. 24.
    Garin MI et al (2007) Galectin-1: a key effector of regulation mediated by CD4+CD25+ T cells. Blood 109:2058–2065CrossRefPubMedGoogle Scholar
  25. 25.
    Brumeanu TD, Preda-Pais A, Stoica C, Bona C, Casares S (2007) Differential partitioning and trafficking of GM gangliosides and cholesterol-rich lipid rafts in thymic and spenic CD4 T cells. Mol Immunol 44:530–540CrossRefPubMedGoogle Scholar
  26. 26.
    Rabinovich GA, Toscano MA (2009) Turning ‘sweet’ on immunity: galectin-glycan interactions in immune tolerance and inflammation. Nature Rev Immunol 9:338–352CrossRefGoogle Scholar
  27. 27.
    André S, Sanchez-Ruderisch H, Nakagawa H, Bucholz M et al (2007) Tumor suppressor p16INK4a: modulator of glycomic profile and galectin-1 expression to increase susceptibility to carbohydrate-dependent induction of anoikis in pancreatic carcinoma cells. FEBS J 274:3233–3256CrossRefPubMedGoogle Scholar
  28. 28.
    Toscano MA, Bianco GA, Ilarregui JM, Croci DO, Correale J, Hernandez JD, Zwirner NW, Poirer F, Riley EM, Baum LG, Rabinovich GA (2007) Differential glycosylation of TH1, TH2 and TH-17 effector cells selectively regulates susceptibility to cell death. Nat Immunol 8:825–834CrossRefPubMedGoogle Scholar
  29. 29.
    Offner H, Celnik B, Bringman TS, Casentini-Borocz D, Nedwin GE, Vandenbark AA (1990) Recombinant human β-galactoside binding lectin suppresses clinical and histological signs of experimental autoimmune encephalomyelitis. J Neuroimmunol 28:177–184CrossRefPubMedGoogle Scholar
  30. 30.
    Perone MJ, Bertera S, Shufesky WJ, Divito SJ, Montecalvo A, Mathers AR, Larregina AT, Pang M, Seth N, Wucherpfennig KW, Trucco M, Baum LG, Morelli AE (2009) Suppression of autoimmune diabetes by soluble galectin-1. J Immunol 182:2641–2653CrossRefPubMedGoogle Scholar
  31. 31.
    Sobel DO, Yankelevich B, Goyal D, Nelson D, Mazumder A (1998) The B-subunit of cholera toxin induces immunoregulatory cells and prevents diabetes in the NOD mouse. Diabetes 47:186–191CrossRefPubMedGoogle Scholar
  32. 32.
    Salmond RJ, Luross JA, Williams NA (2002) Immune modulation by the cholera-like enterotoxins. Exp Rev Mol Med 4:1–16CrossRefGoogle Scholar
  33. 33.
    Keenan TW, Morré DJ, Huang CM (1972) Distribution of gangliosides among subcellular fractions from rat liver and bovine mammary gland. FEBS Lett 24:204–208CrossRefPubMedGoogle Scholar
  34. 34.
    Matyas GR, Morre DJ (1987) Subcellular distribution and biosynthesis of rat liver gangliosides. Biochim Biophys Acta 921:599–614PubMedGoogle Scholar
  35. 35.
    Katoh N, Kira T, Yuasa A (1993) Protein kinase C substrates and ganglioside inhibitors in bovine mammary nuclei. J Dairy Sci 76:3400–3409CrossRefPubMedGoogle Scholar
  36. 36.
    Wu G, Lu Z-H, Ledeen RW (1995) Induced and spontaneous neuritogenesis are associated with enhanced expression of ganglioside GM1 in the nuclear membrane. J Neurosci 15:3739–3746PubMedGoogle Scholar
  37. 37.
    Saito M, Sugiyama K (2002) Characterization of nuclear gangliosides in rat brain: concentration, composition, and developmental changes. Arch Biochem Biophys 398:153–159CrossRefPubMedGoogle Scholar
  38. 38.
    Gilchrist JSC, Pierce GN (1993) Identification and purification of a calcium-binding protein in hepatic nuclear membranes. J Biol Chem 268:4291–4299PubMedGoogle Scholar
  39. 39.
    Xie X, Wu G, Lu Z-H, Ledeen RW (2002) Potentiation of a sodium-calcium exchanger in the nuclear envelope by nuclear GM1 ganglioside. J Neurochem 81:1185–1195CrossRefPubMedGoogle Scholar
  40. 40.
    Garner MH (2002) Na, K-ATPase in the nuclear envelope regulates Na+:K+gradients in hepatocyte nuclei. J Membr Biol 187:97–115CrossRefPubMedGoogle Scholar
  41. 41.
    Palmer AE, Jin C, Reed JC, Tsien RY (2004) Bcl-2-mediated alterations in endoplasmic reticulum Ca2+ analyzed with an improved genetically encoded fluorescent sensor. Proc Natl Acad Sci USA 101:17404–17409CrossRefPubMedGoogle Scholar
  42. 42.
    Miyawaki A, Griesbeck O, Heim R, Tsien RY (1999) Dynamic and quantitative Ca2+ measurements using improved cameleons. Proc Natl Acad Sci USA 96:2135–2140CrossRefPubMedGoogle Scholar
  43. 43.
    Wu G, Xie X, Lu Z-H, Ledeen RW (2009) Sodium-calcium exchanger complexed with GM1 ganglioside in nuclear membrane transfers calcium from nucleoplasm to endoplasmic reticulum. Proc Natl Acad Sci USA 106:10829–10834CrossRefPubMedGoogle Scholar
  44. 44.
    Kofuji P, Lederer WJ, Schulze DH (1994) Mutually exclusive and cassette exons underlie alternatively spliced isoforms of the Na+/Ca2+ exchanger. J Biol Chem 269:5145–5149PubMedGoogle Scholar
  45. 45.
    He S, Ruknudin A, Bambrick LL, Lederer WJ, Schulze DH (1998) Isoform-specific regulation of the Na+/Ca2+ exchanger in rat astrocytes and neurons by PKA. J Neurosci 18:4833–4841PubMedGoogle Scholar
  46. 46.
    Ledeen RW, Wu G (2006) Gangliosides of the nuclear membrane: a crucial locus of cytoprotective modulation. J Cellular Biochem 97:893–903CrossRefGoogle Scholar
  47. 47.
    Saito M, Fronda LL, Yu RK (1996) Sialidase activity in nuclear membranes of rat brain. J Neurochem 66:2205–2208CrossRefPubMedGoogle Scholar
  48. 48.
    Wang J, Wu G, Miyagi T, Lu Z-H, Ledeen RW (2009) Sialidase occurs in both membranes of the nuclear envelope and hydrolyzes endogenous GD1a. J Neurochem 111:547–554CrossRefPubMedGoogle Scholar
  49. 49.
    Mattson MP, Chan SL (2003) Calcium orchestrates apoptosis. Nat Cell Biol 5:1041–1043CrossRefPubMedGoogle Scholar
  50. 50.
    Liu Y, Wada R, Kawai H, Sango K, Deng C, Tai T, McDonald MP, Araujo K, Crawley JN, Bierfreund U et al (1999) A genetic model of substrate deprivation therapy for a glycosphingolipid storage disorder. J Clin Invest 103:497–505CrossRefPubMedGoogle Scholar
  51. 51.
    Wu G, Lu Z-H, Wang J, Wang Y, Xie X, Meyenhofer MF, Ledeen RW (2005) Enhanced susceptibility to kainate-induced seizures, neuronal apoptosis, and death in mice lacking gangliotetraose gangliosides: protection with LIGA 20, a membrane-permeant analog of GM1. J Neurosci 23:11014–11022CrossRefGoogle Scholar
  52. 52.
    Manev H, Favaron M, Vicini S, Guidotti A, Costa E (1990) Glutamate-induced neuronal death in primary cultures of cerebellar granule cells: protection by synthetic derivatives of endogenous sphingolipids. J Pharmacol Exp Ther 252:419–427PubMedGoogle Scholar
  53. 53.
    Wu G, Lu Z-H, Xie X, Ledeen RW (2004) Susceptibility of cerebellar granule neurons from GM2/GD2 synthase-null mice to apoptosis induced by glutamate excitotoxicity and elevated KCl: rescue by GM1 and LIGA20. Glycoconj J 21:305–313CrossRefPubMedGoogle Scholar
  54. 54.
    Gabius H-J (ed) (2009) The sugar code, fundamentals of glycosciences. Wiley-VCH, Weinheim, GermanyGoogle Scholar
  55. 55.
    Mutoh T, Tokuda A, Miyadai T, Hamaguchi M, Fujiki N (1995) Ganglioside GM1 binds to the Trk protein and regulates receptor function. Proc Natl Acad Sci USA 92:5087–5091CrossRefPubMedGoogle Scholar
  56. 56.
    Wu G, Lu Z-H, Ledeen RW (1997) Interaction of the δ-opioid receptor with GM1 ganglioside: conversion from inhibitory to excitatory mode. Mol Brain Res 44:341–346CrossRefPubMedGoogle Scholar
  57. 57.
    Martinez Z, Zhu M, Hans S, Fink AL (2007) GM1 specifically interacts with alpha-synuclein and inhibits fibrillation. Biochemistry 46:1868–1877CrossRefPubMedGoogle Scholar
  58. 58.
    Sano R, Ida Annunziata, Patterson A, Moshiach S, Gomero E, Opferman J, Forte M, d’Azzo A (2009) GM1-ganglioside accumulation at the mitochondria-associated ER membranes links ER stress to Ca2+-dependent mitochondrial apoptosis. Molecular Cell 36:500–511CrossRefPubMedGoogle Scholar
  59. 59.
    Wang Y, Tsui Z, Yang F (1999) Antagonistic effects of ganglioside GM1 and GM3 on the activity and conformation of sarcoplasmic reticulum Ca2+-ATPase. FEBS Lett 457:144–148CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  1. 1.Department of Neurology and NeurosciencesNew Jersey Medical School, UMDNJNewarkUSA

Personalised recommendations