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PubMed1991

Murine peritoneal macrophage gangliosides inhibit lymphocyte proliferation.

Gangliosides have been shown to act as immunoregulatory agents by altering proliferative responses of lymphocytes to both antigens and mitogens. Most early studies have utilized brain gangliosides and have required high concentrations. The role of endogenous gangliosides from macrophages has remained unexplored. In this study, thioglycolate-elicited murine peritoneal macrophage gangliosides were purified and added to cultures of murine lymphocytes. Nanogram amounts caused a profound inhibition of LPS-induced DNA synthesis of splenocytes and of purified B lymphocytes, without demonstrable cellular toxicity. No effect was seen using asialo-GM1. This effect was present across a wide range of lipopolysaccharide (LPS) doses. Nanogram amounts of macrophage gangliosides also inhibited concanavalin A (ConA)-mediated lymphocyte proliferation. Inhibition of LPS-induced mitogenesis was present even if gangliosides were removed from the extracellular environment after 15-60 min of incubation prior to the addition of LPS. This inhibition was reversible with incubation of ganglioside pre-treated lymphocytes in medium containing serum. These inhibitory properties of macrophage gangliosides are distinct from those found in studies using brain gangliosides, and support a potential role for macrophage gangliosides as negative modulators of lymphocyte proliferation.

Animals↗
PubMed1982

Gangliosides associated with microsomal subfractions of brain: comparison with synaptic plasma membranes.

To study ganglioside distribution within subcellular components and test the hypothesis that they are localized at the nerve ending, microsomes and synaptic plasma membranes were isolated from young adult rat brains and compared with respect to ganglioside composition. These were shown to be heterogeneous preparations by fractionation on a discontinuous sucrose gradient into subfractions which had differing ganglioside concentrations. The highest ganglioside concentrations occurred in membranes banding at the 0.8M/1.0M and 1.0M/1.3M interfaces for both microsomes and synaptic plasma membranes. These subfractions had closely similar ganglioside concentrations and pattern distributions. In addition, the kinetics of ganglioside labeling following administration of [3H]-glucosamine were similar for the two preparations. The fact that microsomal subfractions representing heterogeneous mixtures of brain cell membranes showed close similarity to synaptosomal plasma membranes argues against localization of gangliosides at the nerve ending. These results, together with other lines of evidence, support the concept that gangliosides are distributed over large portions of the neuron (and perhaps other brain cells). Data concerning the labeling of gangliosides in different microsomal subfractions indicated a movement of label over time from the more dense to the less dense membranes, as was also noted for the glycoproteins in the same subfractions. Specific radioactivity of the gangliosides increased relative to that of the glycoproteins with time.

Animals↗
PubMed2000

Changes in liver gangliosides in streptozotocin-induced diabetic rats.

Diabetes mellitus is associated with various structural and functional liver abnormalities that affect the glycogen and lipid metabolisms. The effects of streptozotocin-induced diabetes and of insulin supplementation to Sprague-Dawley diabetic rats on ganglioside patterns in liver were determined. Diabetic livers showed a tendency to hepatomegaly 3 weeks after STZ-induction of diabetes. The concentration of total gangliosides in diabetic and non-diabetic livers was similar, but the concentration of total gangliosides in the liver of insulin-stabilized rats was slightly increased. Bidimensional TLC chromatographic analysis of gangliosides isolated from normal diabetic and insulin-stabilized diabetic livers showed quantitative and qualitative changes. In comparison with normal controls, the densitometric analyses of diabetic liver ganglioside patterns had increased amounts of GM3, GM1, GD1b, and GT1b gangliosides, while GM2 could not be detected. The hepatic ganglioside pattern of insulin-stabilized diabetic rats was partially restored, resembling the profile of normal rats. The activity of GalNAcT, GalT-2 and SialT-4 transferases was measured in liver microsomal fractions of the different groups of animals. Diabetic rats showed an increased activity of GalNAcT and a decrease in the activity of GalT-2 and SialT-4 compared with the controls. The enzymatic activities found in insulin-treated rats showed a tendency to return to the values observed in normal control animals. The results evidenced that streptozotocin-induced diabetes affects the liver ganglioside pattern and the ganglioside synthesis enzyme activity. The alterations found in ganglioside metabolism could represent one of the earliest changes associated with the diabetic pathology.

Animals↗
PubMed1994

Attachment of monophosphoryl lipid A (MPL) to cells and liposomes augments antibody response to membrane-bound gangliosides.

Antibodies to gangliosides are found in low levels in normal individuals, and attempts to augment their production have had limited success. Murine studies suggest that the antibody response to membrane-bound cryptic antigens, such as phospholipids and gangliosides, can be induced and augmented by attaching lipid A to membranes. Therefore, we assessed the ability of monophosphoryl lipid A, a non-toxic derivative of lipid A, to augment antibody response against membrane-associated gangliosides. Anti-ganglioside antibodies were IgM after the first and second immunizations; in contrast, anti-phospholipid antibodies were IgM after the first immunization and IgG after the second immunization. Mice (BALB/c) immunized with MPL-attached human cells as well as mice (C57BL/6J) immunized with MPL-attached syngeneic tumor cells (B16 melanoma) produced a significant IgM response. Mice (C57BL/6J) immunized with MPL-attached liposomes containing GM3 developed significantly higher IgM responses than those immunized with purified gangliosides, MPL or MPL-free B16 cells. However, the antibody response after immunization with MPL-GM3-liposomes is similar to that after immunization with MPL-attached tumor cells, even though the MPL-liposomes contained a 27-fold higher level of gangliosides than the tumor cells. Our results emphasize that co-expression of MPL with membrane-bound gangliosides is necessary to augment the anti-ganglioside antibody response. These findings may shed light on the elevated titers of anti-ganglioside IgM antibodies found in patients with motor neuron diseases, various neuropathies and classical ALS, and are relevant to clearance of circulating immunosuppressive gangliosides in cancer patients.

Adjuvants, Immunologic↗
PubMed1984

Gangliosides, the thyrotropin receptor, and autoimmune thyroid disease.

The thyrotropin (TSH) receptor has been proposed to be composed of a membrane glycoprotein and a membrane ganglioside, the former important in high affinity recognition, the latter vital for message coupling to the adenylate cyclase system. The present study used two approaches, formation of antireceptor monoclonal antibodies and reconstitution, to validate the model and further examine the role of the ganglioside. Three kinds of monoclonal antireceptor antibodies are defined. One group which inhibits TSH binding and TSH functions, i.e., TSH-stimulated adenylate cyclase activity, iodide uptake, and thyroid hormone release, is shown to be directed against the glycoprotein component of the receptor. The second group includes antibodies which mimic TSH in all stimulatory actions, are competitive agonists of TSH, are equivalent to thyroid stimulating antibodies in the sera of patients with Graves' disease, and are directed against the ganglioside component of the receptor. These stimulating monoclonal antibodies are directed against a minor ganglioside membrane component which fractionates as a disialoganglioside. When this ganglioside is incorporated into 1-8 thyroid cells which have a correlated ganglioside deficiency and TSH receptor defect, reconstitution of TSH stimulated adenylate cyclase activity occurs. Whereas the first group of antibodies inhibits TSH-stimulated function, they do not inhibit the stimulatory antibodies which mimic TSH, an observation consistent with the 2 component hypothesis of the receptor model. The third group of antibodies have a mix of properties from the first two groups and suggests that the TSH receptor in situ is an actual complex of the two components or that there are common carbohydrate determinants in the functional sites of each receptor component. Implications of a TSH receptor structure in which its ganglioside and glycoprotein components are in equilibrium with pools of free components and, in turn, components important for cholera toxin, tetanus toxin and interferon receptors are discussed. In regard to the pathogenesis of Graves' disease, the data indicate that thyroid stimulating autoantibodies are autoimmune equivalents of cholera toxin with respect to the importance of ganglioside function. Since antiidiotype studies of antibodies against TSH confirm a structural relationship between receptors for thyrotropin, cholera toxin, and thyroid stimulating autoantibodies, the data establish an unequivocal role for the ganglioside in TSH receptor structure which facilitates interpretation of in vitro experiments aimed at understanding the mechanism of ganglioside-ligand interactions.

Animals↗
PubMed1989

Antibody response after immunization with the gangliosides GM1, GM2, GM3, GD2 and GD3 in the mouse.

The gangliosides GM2, GD2 and GD3 are differentiation antigens expressed on the cell surface of human melanomas and other cancers of neuroectodermal origin. We have compared the antibody response after vaccination with gangliosides GM1, GM2, GM3, GD2 and GD3 in the mouse. Purified gangliosides were injected subcutaneously alone or attached to Salmonella minnesota mutant R595 after pretreatment of the mice with low-dose cyclophosphamide. Spontaneous GM1 antibodies, but not antibodies against the other gangliosides, were detected in many mice, the incidence increasing with age. Purified gangliosides injected alone (in saline) induced no antibody response. R595/GM1 and R595/GD3 vaccination induced consistent high-titer antibody responses. R595/GM2 and R595/GD2 induced occasional antibody responses, and R595/GM3 induced no antibody response. Comparison of the antibody responses induced against these gangliosides in the mouse with those in man reveals that GM1, GM3 and GD2 have a similar immunogenicity in both species while the relative immunogenicity of GM2 and GD3 is reversed. To understand better the basis for these differences, the antibody responses against the five gangliosides in man and the mouse were compared with their known expression in normal tissues. No correlation was detected between ganglioside expression in normal brain and immunogenicity, consistent with this being a cloistered site. The antibody responses did correlate inversely with expression in normal non-brain human and murine tissues. Variations between species of ganglioside immunogenicity may reflect variations in ganglioside expression in normal tissues.

Animals↗
PubMed1997

The presence of foetal ganglioside antigens 3'-isoLM1 and 3'6'-isoLD1 in both glioma tissue and surrounding areas from human brain.

Glioma-associated gangliosides, in particular the expression of foetal gangliosides 3'-isoLM1 and 3'6'-isoLD1, have been investigated in biopsies from 44 patients with astrocytoma grade II, anaplastic astrocytoma, anaplastic oligodendrogliomas, oligodendrogliomas, and glioblastoma multiforme. The total ganglioside content decreased in proportion to the estimated number of tumour cells present in the biopsy. Ganglioside GD3 was increased in 17 of the tumour tissues and in 6 of the surrounding area specimens. In agreement with our previous studies, tumour specimens contained the lactoseries ganglioside 3'-isoLM1 and, as demonstrated for the first time, the disialylated form of the ganglioside, 3'6'-isoLD1. These gangliosides are in normal brain tissue restricted to the developmental period. Most frequent was the expression of ganglioside 3'-isoLM1 which was detected in 92% of the tumour specimens in concentrations varying between just detectable amounts to 13 nmol/g wet weight. In the area surrounding the macroscopic tumour tissue 78% of the specimens expressed 3'-isoLM1 and the values varied between just detectable amounts to 24 nmol/g wet weight. Ganglioside 3'6'-isoLD1 was found in 47% of the tumour biopsies and in only 17% of the specimens taken outside macroscopic tumour tissue. The values varied between non-detectable amounts to 40 nmol/g wet weight of tissue. The expression of 3'-isoLM1 correlated significantly (p < 0.01) to malignancy grade. For 3'6'-isoLD1 a significant (p < 0.05) difference was found between tumour and surrounding tissue. Likewise, 3'6'-isoLD1 correlated significantly (p < 0.05) to malignancy grade. The correlation between 3'-isoLM1 and 3'6'-isoLD1 to malignancy grade and the frequent expression of these gangliosides both in the tumour itself and in its surrounding area should encourage additional studies concerning their biological role in tumour disease.

Adolescent↗
PubMedDate not supplied

Influence of growth environment on the ganglioside composition of an experimental mouse brain tumor.

Ganglioside composition was examined in an experimental mouse brain tumor growing as a solid tumor in vivo and as a cultured cell line in vitro. Gangliosides were also studied in the solid tumor rederived from the cultured tumor cell line. Although GM3-NeuAc was the major ganglioside in both the solid tumor and cultured tumor cells, several gangliosides expressed in the solid tumors (e.g., GM2-NeuGc, GM1, and GM1b) were not expressed in the cultured tumor cells. These gangliosides, however, are major components of mouse macrophages. Furthermore, significant amounts of gangliosides containing N-glycolylneuraminic acid (NeuGc) were found in the solid tumor growing in vivo, but only trace amounts were present in the cultured tumor cells. NeuGc is a common ganglioside sialic acid in mouse nonneural cells, whereas N-acetylneuraminic (NeuAc) is the predominant sialic acid in mouse brain. The trace amounts of NeuGc in the cultured cells are attributed to contamination from the fetal bovine serum. Radiolabeling of the cultured tumor cell gangliosides with [14C]galactose revealed that GM3-NeuAc was the only ganglioside synthesized by the tumor cells. The results suggest that nontumor-infiltrating cells, e.g., macrophages, lymphocytes, and endothelial cells, may contribute significantly to the total ganglioside composition of solid tumors growing in vivo.

Animals↗
PubMed1986

Effects of thyrotropin and thyroid stimulating immunoglobulins on gangliosides labelling of human thyroid cultured pathological cells.

Gangliosides are known to play an important role in different cell processes. We have investigated the effect of TSH on [14C] glucosamine incorporation into gangliosides of cultured pathological cells isolated from colloid nodular goiter, follicular adenoma, and toxic adenoma. The effect of thyroid stimulating immunoglobulins (TSI) has also been similarly studied on primary cultures from colloid nodular goiter and from porcine thyroid cells. Immunoglobulins were purified from sera of Graves' disease patients. Cells were cultured with or without either stimulator and labelled with [14C] glucosamine during 24 h. Total lipid extracts were fractionated on DEAE Sephadex A 25. Eluted gangliosides were analysed by thin layer chromatography, detected by autoradiography and scraped off for radioactivity measurement. Radioactivity was related to the free cholesterol content. The ganglioside pattern of human thyroid cells in primary cultures is found to vary and to closely reflect the ganglioside pattern of the corresponding gland. No ganglioside pattern could be related to a specific thyroid disorder. When cells are treated with TSH, the amount of [14C] glucosamine incorporated in total gangliosides varies according to diseases. The radioactivity incorporated in gangliosides from colloid nodular goiter cells is not similarly affected by TSH and TSI. In porcine thyroid cells, TSH and TSI have the same effect on glucosamine incorporation into gangliosides. Thus it appears that TSH and TSI may differently affect the gangliosides labelling according to the origin of the thyroid cells.

Animals↗
PubMed2006

Gangliosides are not essential for influenza virus infection.

Sialic acid is known to be an essential part of influenza virus receptors, but the specific identity of the receptor molecules on target cells is still not defined. In particular, the relative roles played by cellular sialylglycoproteins and gangliosides in virus entry into target cells remain unclear. To test whether gangliosides are essential for virus infection, we used the GM-95 mutant cell line of mouse B16 melanoma which lacks synthesis of major glycosphingolipids including gangliosides. We found that GM-95 cells grown in serum-containing medium harboured substantial amounts of ganglioside receptors for influenza virus due to incorporation of serum gangliosides. To obtain ganglioside-free cells, we adapted GM-95 cells to growth in defined serum-free (sf) medium. Ganglioside-free GM-95-sf cells could be infected by avian and human influenza A viruses and produced infectious virus progeny demonstrating that gangliosides were neither absolutely necessary for the early nor for the late stages of the infection. However, sensitivity of the GM-95-sf cells to the viruses was 2-4 times lower than that of the ganglioside-containing parent cell line. Further studies are needed to specify whether this effect was due to the lack of gangliosides, neutral glycosphingolipids, or other effects.

Animals↗
PubMed1989

Human brain gangliosides: developmental changes from early fetal stage to advanced age.

The developmental profiles of the four major brain gangliosides, GM1, GD1a, GD1b, and GT1b, were examined in human frontal lobe covering the period from 10 fetal weeks to 80 years of age. The ganglioside concentration increased approx. 3-fold from the 10th gestational week to the age of about 5 years. Gangliosides GM1 and GD1a increased 12-15-fold during the same period. The most rapid increase of GM1 and GD1a occurred around term, during the period for dendrite arborization, outgrowth of axons and synaptogenesis. GT1b showed a quite different developmental curve. It was the major ganglioside during the 3rd to 5th gestational month, whereafter its concentration dropped rapidly to term, from which time the concentration then increased up to 50 years of age. Similar curves were found for the other gangliosides of the b-series, GD3, GD2, GD1b and GQ1b. Ganglioside 3'-isoLM1 was a characteristic early fetal ganglioside which dropped rapidly to the 5th gestational month, reached a small peak around term and then disappeared during adulthood. The concentration of gangliosides of the neolacto series was larger than that of the lacto series during the whole developmental period. In the beginning of the second trimester, 3'-LM1 constituted 2% and LD1 10% of total ganglioside sialic acid. The new findings demonstrate more dynamic changes of the ganglioside patterns during development than noted in previous studies.

Adolescent↗
PubMed1992

Immunosuppression by human gangliosides. II. Carbohydrate structure and inhibition of human NK activity.

Gangliosides shed by tumors enhance tumor formation, possibly by suppressing host antitumor immune function, and gangliosides purified from animal tissues and cultured cells inhibit human cellular immune function in vitro. Determination of immunosuppressive activity of highly purified gangliosides, to uncover structure-activity relationships, is therefore important. Here we have studied a series of gangliosides obtained from human tissue and determined their effects on human natural killer (NK) activity. Total gangliosides from human brain tissue were moderately inhibitory; 100 nmol/ml reduced NK activity of human nonadherent PBMC by 43%. The influence of carbohydrate structure upon inhibitory activity was determined by study of eight highly (HPLC) purified individual gangliosides. Of these, we unexpectedly found that the two minor brain gangliosides with the simplest carbohydrate structures, GM2 and GM3, were very active inhibitors (75 and 47%, respectively, at 50 nmol/ml). In contrast, the structurally more complex major species, GM1, GD1a, GD1b, GT1b, and two other minor gangliosides, GD2 and GD3, were inactive. Reduced effector-target binding in a single-cell binding assay by GM2 but not GM3 suggests different mechanisms of inhibition by these two active gangliosides. Since GM2 and GM3 are present in high concentrations in, and are shed by, several common human tumors (e.g., neuroblastoma, melanoma, and glioma), their ability to inhibit NK cytotoxicity supports the hypothesis of a role of shed tumor gangliosides in the enhancement of tumor formation.

Brain Chemistry↗
PubMed1992

Antibody responses to ganglio-series gangliosides in different strains of inbred mice.

We studied antibody responses after immunization with ganglio-series gangliosides against 10 strains of inbred mice, including Balb/c, C57BL/6, A/J, C3H/HeN, C3H/HeJ, CBA/N, AKR/N, NZB/N, DBA/2 and nu/nu Balb/c. Twelve gangliosides having NeuAc as their sialic acid moiety (GM4, GM3, GM2, GM1, GD3, O-Ac-GD3, GD2, GD1a, GD1b, GT1a, GT1b and GQ1b), four gangliosides having NeuGc (GM3, GM2, GM1 and GD3) and four asialo-gangliosides (GA4, GA3, GA2 and GA1) were injected intravenously adsorbed to Salmonella minnesota. The antibody titers of the mice sera were determined by an enzyme-linked immunosorbent assay and an immune adherence assay. Antibody responses were found to depend not only on the ganglioside used as an immunogen but also on the mouse strain. Gangliosides having a trisaccharide sequence (NeuAc alpha 2----8NeuAc alpha 2----3Gal-) such as GD3, GD2, GD1b, GT1a and GQ1b, in particular O-Ac-GD3, induced high-titer antibody responses, whereas those having a disaccharide sequence (NeuAc alpha 2----3Gal-) such as GM4, GM3, GM2, GM1, GD1a and GT1b induced low-titer antibody responses. On the other hand, gangliosides with NeuGc developed minimum titers. In contrast, asialogangliosides induced much higher responses than the corresponding gangliosides. The differences in ceramide portions of these gangliosides did not appear to be involved in inducing antibody responses. Mice could be divided into three groups according to the magnitude of their antibody responses: Group 1, those that produce the highest antibody responses (C3H/HeN and A/J); Group 2, those that demonstrate moderate antibody titers (Balb/c, C57BL/6, DBA/2 and nu/nu Balb/c); and Group 3, those that make minimum responses (AKR/N, C3H/HeJ, CBA/N and NZB/N). The pattern of reactivity to the various gangliosides was similar in all the strains tested.

Animals↗
PubMed1992

Calcium-ganglioside interactions and synaptic plasticity: effect of calcium on specific ganglioside/peptide (valinomycin, gramicidin A)-complexes in mixed mono- and bilayers.

A controlled exchange of calcium between the extracellular space (mM Ca2+) and the neuroplasm (microM Ca2+) is considered to be an essential prerequisite for almost every stage of neuronal activity. Our research interest is focused on those compounds, which due to their physico-chemical properties and localization within the synaptic membrane might fulfill the task as neuromodulators for functional synaptic proteins. Because of this specific binding properties towards calcium and their peculiar interactions with calcium in model systems gangliosides (amphiphilic sialic acid containing glycosphingolipids) are favorite candidates for a functional involvement in synaptic transmission of information. In this study we used monolayers to investigate the molecular packing and surface potential at the air/water interface, the interaction of gangliosides with the depsipeptide valinomycin (= monovalent ion carrier), and its influenceability by calcium. Furthermore we looked at calcium effects on the single channel conductance and mean channel life-time of the monovalent ion channel gramicidin A in mixed PC/ganglioside bilayers. In pure ganglioside monolayers the addition of 0.01 mM Ca2+ induces monolayer condensation, a rise in collapse pressure (= higher film stability), a shift of phase transition (= change of conformation), and a more negative head group potential (change of electric properties). In mixed ganglioside-valinomycin monolayers the addition of Ca2+ causes phase separation and/or aggregate formation between the ganglioside and the peptide. Single channel conductance fluctuations as well as mean channel life-time were analyzed for gramicidin A incorporated into binary mixed black lipid membranes of negatively charged gangliosides (GM1, GD1a, GT1b, GMix) and neutral lecithin (DOPC) in different molar ratios. At monovalent electrolyte concentrations up to < 250 mM CsCl the single channel conductance was significantly larger in the negatively charged mixed DOPC/ganglioside membranes than in the neutral DOPC membrane. Additionally, in the presence of gangliosides the mean channel life-time is increased. The addition of calcium (0.05 mM) induced a reduction of single channel conductance of gramicidin A in DOPC- and mixed DOPC/ganglioside membranes. These physico-chemical data in connection with new electromicroscopical evidences for a precise localization of calcium, a calcium pump (Ca(2+)-ATPase), a clustered arrangement of gangliosides in synaptic terminals, and biochemical results with regard to activatory nature of exogenous gangliosides for neuronal protein phosphorylation and ATPases, support the hypothesis of a modulatory function of gangliosides in synaptic transmission.

Animals↗
PubMed1992

Gangliosides and regeneration of the goldfish optic nerve in vivo and in vitro.

One to forty days after optic nerve transection, goldfish received an i.p. injection of [3H]proline (proteins), 3HNAcGluc (gangliosides) or [3H]thymidine (DNA). After 1 or 2 days of incorporation, both optic systems were analyzed by biochemical and autoradiographical procedures. In the regenerating retina an enhanced retinal mitotic activity, protein synthesis (up to 2-fold) and ganglioside synthesis (up to 1.5-fold) was found. Simultaneously, a transiently enhanced accumulation (up to 4.5-fold) of axonally transported protein- and ganglioside-bound radioactivity in the regenerating optic nerve stump occurred. These regeneration-related proliferative and metabolic changes were found to be maximal at 6-8 days post lesion, but still measurable after 40 days. Concerning the endogenous ganglioside metabolism, in the regenerating retina no obvious change in ganglioside synthesis and composition could be observed, while in the regenerating optic nerve there was an enhanced accumulation of the ganglioside GP1c. Daily i.p. application of a ganglioside mixture from bovine brain (GMix) or of the monosialoganglioside GM1, did not alter significantly the degree and time course of the above regeneration induced metabolic changes or the regain of visual acuity. Sprouting activity of goldfish retinal explants was found to strongly depend upon a conditioning lesion of the optic nerve, reaching a maximum 8 days after nerve transection. This result strictly coincided with the profile of metabolic changes observed in vivo. Again, daily i.p. or i.o. injection of exogenous gangliosides did not influence the lesion induced increase of retinal sprouting activity. However, in normal, not regenerating animals, a local i.o. injection of GMix or GM1 led to a significant enhancement of the "basal" sprouting activity, normally occurring after lesion of the retina after injection of 0.9% NaCl. This ganglioside related stimulation was maximal at low concentrations (3 micrograms/eye) and did not occur at high concentrations (> 30 micrograms/eye). Injection of the phospholipid phosphatidylcholine or phosphatidylserine had no or a slightly inhibitory effect, when compared to NaCl controls. These data suggest an involvement of gangliosides in the complex process of induction of axonal sprouting.

Acetylglucosamine↗
PubMed2004

Mechanism for the negative regulation of cell proliferation by ganglioside GM3 in high glucose-treated glomerular mesangial cells.

We recently identified ganglioside GM3 as a modulator of glomerular hypertrophy in streptozotocin-induced diabetic rats (Life Sci., 72: 1997-2006, 2003). This study examined whether alteration of ganglioside GM3 expression could modulate the high glucose-induced proliferation of glomerular mesangial cells (GMCs). GMCs isolated from rat kidneys were cultured under normal (5.6 mM) or high (25 mM) glucose condition for 24-72 hrs. Cell proliferation was predominantly stimulated when GMCs were cultured with high glucose as well as 20 microM of d-threo-PDMP, an inhibitor of ganglioside biosynthesis, for 24 hrs, whereas raising ambient glucose significantly reduced the mesangial sialic acid contents. Based upon mobility on high-performance thin-layer chromatography (HPTLC), GMCs showed a complex pattern of ganglioside expression that consisted of three major components of gangliosides, mainly GM3. High glucose induced a significant reduction of ganglioside expression with apparent changes in the composition of major ganglioside GM3, and semi-quantitative analysis by HPTLC showed that ganglioside GM3 was reduced to 62% of GMCs cultured under normal glucose condition. A prominent immunofluorescence microscopy using anti-GM3 monoclonal antibody also showed a dramatic disappearance of immunoreactivity in high glucose-treated GMCs. Moreover, high glucose significantly lowered the Km values of GM3 synthase (16 microM vs. 49 microM), but did not change the Vmax. These results provide the pathophysiological relationship between the high glucose-induced proliferation of GMCs and the decreased expression of ganglioside GM3, indicating a mechanism for the negative regulation of mesangial proliferation by ganglioside GM3. This mechanism may play an important role in the development of diabetic glomerulopathy.

Animals↗
PubMed2000

Ganglioside molecular species containing C18- and C20-sphingosine in mammalian nervous tissues and neuronal cell cultures.

Gangliosides exist as a very complex mixture of species differing in both the hydrophilic and hydrophobic moieties. They are particularly abundant in the central nervous system (CNS), where they have been associated with development and maturation of the brain, neuritogenesis, synaptic transmission, memory formation and synaptic aging. Today, many data suggest that some of the effects exerted by gangliosides are due to interactions with proteins that participate in the transduction of signals through the membrane in membrane microdomains. A specific characteristic of CNS gangliosides is the structure of their long-chain base (LCB). In fact, considering all the mammalian cell sphingolipids, gangliosides, sulphatides, neutral glycosphingolipids, sphingomyelin and ceramides, it would seem that while the LCB with 18 carbons is the main component of all sphingolipids, only CNS gangliosides contain significant amounts of LCB with 20 carbons. C18-Sphingosine is always present in cell gangliosides; the individual ganglioside species containing C18-sphingosine increase during cell differentiation then remain constant during cell aging. Gangliosides containing C20-sphingosine are absent, or present only in traces, in undifferentiated cells but with the onset of cell differentiation they appear, their content slowly but continuously increasing throughout the life span. In this review we discuss the chemistry, physico-chemistry and metabolism of ganglioside species differing in LCB length and introduce the hypothesis that the varying ratio between C18- and C20-gangliosides during CNS development and aging can be instrumental in modulating membrane domain organisation and cell properties.

Acyl Coenzyme A↗
PubMed1998

Glycosphingolipids of skeletal muscle: II. Modulation of Ca2(+)-flux in triad membranes by gangliosides.

Membrane vesicles of rabbit skeletal muscle were prepared and separated by sucrose density gradient centrifugation. The fractions obtained (in the order of increasing density) were sarcolemma (SL), T-tubules (TT), sarcoplasmic reticulum (SR1 and SR2) and triads/mitochondria (Tr/M) as characterized by their specific marker enzymes, ligand binding, and ion flux activities. The distribution of neutral glycosphingolipids and gangliosides in these membrane preparations has been documented in the preceding paper (J. Müthing, U. Maurer, U. Neumann, B. Kniep, and S. Weber-Schürholz, Carbohydr, Res., (1988) 135-145). GM3(Neu5Ac) is the dominant ganglioside, neolacto-series gangliosides are moderately expressed and ganglio-series gangliosides were found in minor quantities, however, all showing different qualitative and quantitative membrane-type specific patterns. The voltage dependent Ca(2+)-channels of skeletal muscle reside prevalently in the triad enriched membrane fractions deduced from highest binding capacity of 1,4-dihydropyridines. Calcium channel complexes of triads were reconstituted into unilamellar phospholipid vesicles of 400 nm defined size and the active 45Ca(2+)-uptake into intravesicular space was measured after incorporation of muscle specific gangliosides into the outer vesicle lipid bilayer in parallel to control liposomes without gangliosides. GM3(Neu5Ac) strongly increased the uptake of 45Ca2+ (+285%) whereas GM3(Neu5Gc) severely inhibited the ion flux (-61%). Neolacto-series gangliosides evoked miscellaneous effects upon 45Ca(2+)-flux depending on isomeric sialic acid configuration, oligosaccharide size and fatty acid chain length of the ceramide portion. VI3Neu5Ac-nLcOse6Cer (C24-fatty acid), IV3Neu5Ac-nLcOse4Cer (C16-fatty acid) and IV6Neu5Ac-nLcOse4Cer (C16-fatty acid) strongly enhanced the 45Ca(2+)-flux (+208, +162, and +120%, respectively, whereas IV3Neu5Ac-nLcOse4Cer (C24-fatty acid), VI3Neu5Ac-nLcOse6Cer (C16-fatty acid) and IV6Neu5Ac-nLcOse4Cer (C24-fatty acid) slightly reduced 45Ca(2+)-flux (-3, -6, and -17%, respectively). Out of all gangliosides tested in this study, GM1 showed the strongest stimulatory effect (+327%). GD1a and GT1b gave rise to remarkable flux-stimulation of +283 and +255%, respectively, whereas GD1b exhibited only a slightly positive effect (+38%). This data suggest a functional role of gangliosides in subcellular muscle membranes giving strong evidence that gangliosides are capable of modulating the cytosolic calcium level of muscle, which regulates muscle contraction.

Animals↗