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PubMed1984

Effects of ganglioside GM1 on the thermotropic behavior of cholera toxin B subunit.

The B, or binding, subunit of cholera enterotoxin forms a pentameric ring structure in the intact toxin, and also when the subunit is isolated from the A subunit. The thermal denaturation of the B subunit ring was examined by differential scanning calorimetry in the presence and absence of ganglioside GM1, its natural 'receptor'. In the absence of ganglioside an irreversible endotherm was observed with maximal excess apparent heat capacity, Cmax, at 74.6 degrees C. When the ganglioside was added in increasing amounts, multiple transitions were observed at higher temperatures, the most prominent having a Cmax at 90.8 degrees C. At high ganglioside concentrations, the 74.6 degrees C transition was not observed. In addition to the thermodynamic results a model is proposed for the interaction of GM1 and B subunit pentamer. This model is derived independently of the calorimetric results (but is consistent with such data) and is based upon considerations of the geometry of the GM1 micelle B subunit pentamer.

Binding Sites↗
PubMedDate not supplied

Adenylate cyclase system of the rat striatum: regulatory properties and the effects of gangliosides.

The activity and regulatory properties of the adenylate cyclase system of the rat striatum were studied. Agents such as Gpp(NH)p, forskolin, and NaF were found to show classical in vitro stimulation of adenylate cyclase activity in the striatum membrane fraction. Dosage of rats with a preparation containing gangliosides (30 mg/kg, 6 i.p. injections) led to prolonged reductions in basal striatal adenylate cyclase activity. Two weeks after ganglioside administration, enzyme activity was reduced by 48% and remained lower than in controls (by 18%) even a month after injections. In vitro studies of the effects of gangliosides on adenylate cyclase activity in whole brain and striatal synaptosomes from rats showed that gangliosides have modulating actions on the adenylate cyclase system of the striatum, mainly due to changes in the catalytic function of the enzyme itself, and have no significant effect on the GTP-binding center of G-protein.

1-Methyl-3-isobutylxanthine↗
PubMed1985

In situ immunological determination of basic carbohydrate structures of gangliosides on thin-layer plates.

An immunological method for the determination of the basic carbohydrate structure of gangliosides by using a thin-layer chromatographic immunostaining technique was developed. After high-performance thin-layer chromatography of gangliosides, the chromatogram is treated with a 0.4% polyisobutylmethacrylate solution. Arthrobacter ureafaciens neuraminidase is then applied to the separated gangliosides in situ on the chromatographic plate. This procedure will remove both external and internal sialic acid residues from the core oligosaccharide backbone. The resulting glycolipid products are then incubated with anti-Gg4 serum and 125I-staphylococcal protein A, successively, and exposed to an X-ray film. Through a highly specific binding, the anti-Gg4 antibody detects only those gangliosides having the oligosaccharide backbone of Gg4.

Antibodies↗
PubMed1984

Evidence of a distribution difference between two gangliosides in bilayer membranes.

Freeze-etch electron microscopy, a platinum shadowing technique, has been used to compare the lateral distribution of several gangliosides in bilayer model membranes by directly visualizing bound lectin molecules. In particular, GM1 and GD1a, major components of brain ganglioside, were studied in phase-separated mixtures of dipalmitoyl- and dielaidoylphosphatidylcholines exposed to Ricinus communis agglutinin and wheat germ agglutinin. The distribution of glycolipid showed evidence of microheterogeneity in that bound lectin tended to occur in clusters of several or more molecules. With GD1a as receptor such clusters were small and very uniformly distributed over the membrane surface. Somewhat larger, irregularly spaced clusters of up to a dozen lectin particles were more typical of membranes bearing GM1 and, in addition, there were occasional extensive patches of bound lectin coexisting with areas apparently devoid of glycolipid receptor in phase-separated mixtures of dipalmitoyl- and dielaidoylphosphatidylcholine. Gangliosides in the latter mixtures were not obviously influenced in their lateral distribution by the presence of coexisting fluid and rigid domains. These basic observations seem to extend to bilayer membranes containing mixtures of two gangliosides. The patterns of lectin binding were not grossly affected by incubation time or history of warming and cooling. This study was extended to bilayers of pure dipalmitoylphosphatidylcholine in expectation that the distinctive features characteristic of the P beta' phase of this lipid might accentuate any behavioural differences between GM1 and GD1a. GM1 was found to exist preferentially in the 'trough' regions between P beta' ripples, while GD1a showed no apparent preferential arrangement. Given that bound lectins adequately reflect glycolipid distribution in membranes, it would appear that structurally different glycolipids from the same host membrane can assume different distributions on the basis of interactions with defined lipid host matrices.

Freeze Fracturing↗
PubMed1982

GM3 and GD3 are the major gangliosides of rat fetal intestine.

Gangliosides were extracted from intestine of rat fetuses on each day between 17 days of gestation and 1 day after birth. They were purified from the lipid extract by DEAE-Sephadex chromatography. Two major gangliosides are found at the earliest time: GD3 and GM3. Their contributions to the ganglioside content are, respectively, 48.2 and 33.7%. Between 19 days of gestation and birth, a 3.5-fold increase of the total ganglioside concentration is observed which is due to sharp rise of the GM3 concentration. In GD3 and GM3 of rat fetal intestine, sialic acid is exclusively N-acetylneuraminic acid and fatty acids are all non-hydroxylated.

Animals↗
PubMed1986

Regulation of GM2 ganglioside metabolism in cultured cells.

GM2-ganglioside (II3NeuAcGgOse3Cer) is a minor component of adult nervous tissue, but is probably an oncofetal antigen. Its biological role is unknown, but several lines of evidence indicate its potential role in cell adhesion both in the retina and in oligodendrocytes. The biosynthesis of GM2-ganglioside appears to be tightly regulated, since it is a key intermediate in complex ganglioside synthesis. The specific GM3: hexosaminyl-transferase is activated under conditions which activate cyclic AMP-dependent protein kinase, and cell transformation with retroviruses inactivates it. Catabolism of GM2 requires the concerted action of three gene products (alpha-chain, beta-chain and activator protein in a thermolabile alpha beta 2 AP complex referred to as HexA). Defects in either three components results in the neuronal storage of GM2 ganglioside and the manifestations of Tay-Sachs Disease in children or motor neuron disease in adults.

Animals↗
PubMed1985

Isolation of variants of BALB/c 3T3 cells defective in complex ganglioside biosynthesis.

In an attempt to clarify the relationship between altered glycosphingolipid metabolism and other aspects of the transformed phenotype, we have isolated variants of BALB/c 3T3 cells (clone A31) which are defective in synthesis of the more complex gangliosides (GM2, GM1 and GD1a). The selection protocol was based on the specificity of cholera toxin for ganglioside GM1, and the ability to lyse cells which bound toxin using anti-toxin and complement. Following treatment of cells with ethane methane sulfonate (EMS), populations resistant to lysis were obtained after 5-6 rounds of selection, despite a low and rather variable killing efficiency (75-95%). Five out of six clones isolated from such populations showed reduced toxin-binding capacity and loss of gangliosides more complex than GM3, as determined by metabolic labelling with [1-14C] palmitate. An identical phenotype was displayed by a variant isolated from a non-mutagenized population of cells. The phenotype remained stable for several months in culture and for over at least 40 cell doublings. Ganglioside nomenclature is according to Svennerholm [24].

Animals↗
PubMed1981

Abnormal maturation of cerebral cortex and behavioral deficit in adult rats after neonatal administration of antibodies to ganglioside.

Five-day-old rats received a single injection (50 microliter) of antiserum to ganglioside into the cisterna magna and were compared to control animals injected with the antiserum which had been absorbed with pure GM1 ganglioside to remove the specific antibodies. Both groups showed normal rates of body growth. However, animals receiving antiganglioside serum had, at 60 days of age, impaired performance when tested on a complex learning task (DRL) as well as chemical and morphological alterations in the somatosensory cerebral cortex. Gross morphology and wet weight of whole brain were normal in both groups. Microchemical analysis of somatosensory isocortex revealed a normal content of total solids, protein, and DNA. However, ganglioside sialic acid, galactocerebroside, and RNA were decreased by 31%, 32% and 25% of control values, respectively (P less than 0.01). Quantitative measurements of oblique dendrites of Golgi-stained cortical pyramidal neurons revealed a 31% decrease in the number of spines. Additionally, the majority of spines were of the stubby configuration, whereas dendrites from controls were populated predominately by thin spines. These observations suggest that antibodies to GM1 ganglioside interfere with optimal neonatal development on both dendrites and myelin in cerebral cortex. The results provide an animal model in which an immunologically-mediated disturbance of cortical development is associated with chronic behavioral impairment.

Animals↗
PubMed1984

Regenerative capacity of the goldfish visual system is affected by antibodies specific to gangliosides injected intraocularly.

An association between gangliosides and neuronal regeneration in goldfish is demonstrated in the present study. A single intraocular injection of affinity purified anti-GM1 antibodies administered simultaneously with crush injury of the optic nerve, inhibits the regenerating process as expressed by two parameters: protein synthesis in the retina and in vitro sprouting ability from the retina. The retinal level of several gangliosides (such as GD3, GD1a, GD1b and GT1b) is enhanced during regeneration. Although GM1 appears to be a minor retinal ganglioside, antibodies to GM1 exert a marked effect on retinal regenerative process. It is assumed that such antibodies could interact with more abundant retinal gangliosides such as GD1b which shows enhanced biosynthesis during regeneration and which shares a similar disaccharide terminal residue with GM1.

Animals↗
PubMed1994

Exogenously applied gangliosides (GM1, GD1a and Gmix) fail to facilitate the induction of long-term potentiation (LTP) in the slices of hippocampus and superior colliculus of the guinea pig.

To confirm the effect of gangliosides on the facilitation of the induction of long-term potentiation (LTP), slices of hippocampus and superior colliculus from guinea pig were prepared. One group of slices was incubated in the standard medium containing gangliosides (GM1, GD1a, or a mixture of gangliosides from bovine brain, each at a concentration of 70 microM) for 2 h. The other group of slices was incubated in the standard medium only. In both groups of slices, tetanic stimulation induced LTP in a similar manner. In low Ca2+ (1 mM) medium, LTP was not induced in either group of slices. Thus, the present experiments could not confirm previous reports indicating that exogenously applied gangliosides facilitate the induction of LTP.

Animals↗
PubMed1988

Ganglioside potentiation of NGF-independent conditioned medium enhancement of neuritic outgrowth from spinal cord and ciliary ganglia explants.

Culture medium conditioned (CM) by embryonic chick skeletal muscle or RN22 Schwannoma cells enhanced dramatically the neuritic development of chick embryonic spinal cord slices explanted onto a collagen substratum. The addition of a mixture of bovine brain gangliosides (BBG) or the monosialoganglioside GM1 to this medium potentiated the nerve growth factor (NGF)-independent CM-mediated neuritogenesis. A 3-4 fold increase in spinal cord outgrowth was due to increased neurite number, length and branching. The ability of the gangliosides to potentiate the positive neuritogenic action of CM was not limited solely to spinal cord cultures since similar results were obtained in parallel studies employing organized cultures of embryonic chick ciliary ganglia. These studies demonstrate the ability of gangliosides to enhance the trophic action of factor(s) present in CM. They suggest further that gangliosides may play a modulatory role in the development of the nervous system.

Animals↗
PubMed2006

Ganglioside GM2 modulates the erythrocyte Ca2+-ATPase through its binding to the calmodulin-binding domain and its 'receptor'.

We have previously demonstrated that gangliosides were able to modulate the plasma membrane Ca2+-ATPase (PMCA) from porcine brain synaptosomes and porcine erythrocytes [Y. Zhao, X. Fan, F. Yang, X. Zhang, Arch. Biochem. Biophys. 427 (2004) 204-212 and J. Zhang, Y. Zhao, J. Duan, F. Yang, X. Zhang, Arch. Biochem. Biophys. 444 (2005) 1-6]. The results indicated that the PMCA from porcine erythrocytes responded to gangliosides was different from that from synaptosomes, suggesting that the effects of gangliosides on the PMCA are isoform specific. Most interestingly, GM2 activated the PMCA from porcine erythrocytes at lower concentrations, but inhibited it at higher concentrations. In the present study, we found that GD1b, GM1 and GM3 did not affect the calpain digested PMCA from porcine erythrocytes or the intact enzyme in the presence of calmodulin, while GM2 inhibited it. Moreover, a synthetic peptide of 17 amino acid residues corresponding to the 'receptor' of the calmodulin-binding domain of the enzyme interfered with the inhibition of the enzyme by GM2 in competition assays. Taken together, our results suggested that gangliosides GD1b, GM1, GM2 (lower concentrations) and GM3 stimulated the PMCA by the interaction with calmodulin-binding domain, while the interaction of GM2 with the 'receptor' of the calmodulin-binding domain of the enzyme led to the inhibition of the enzyme.

Animals↗
PubMed2003

Loss of hepatocyte co-operative activity after inhibition of ganglioside GM1 synthesis and shedding.

Pretreatment of hepatocyte cultures with 1 microM d-l-threo-1-phenyl-2-hexadecanoylamino-3-pyrrolidino-1-propanol-HCL (PPPP) for 24 h decreased the ganglioside GM1 content of the cells by approximately 50% and that of the conditioned medium by 90%. No rhythm in the rate of protein synthesis was detected in dense cultures pretreated with PPPP, but was observed in control dense cultures. Conditioned medium from control dense cultures induced synchrony in sparse cultures, which were non-synchronous in their own medium. In contrast, conditioned medium from dense cultures pretreated with PPPP did not synchronize sparse cultures. Since protein synthesis rhythm is a marker of cell synchronization, i.e. their co-operative activity, then non-oscillatory behavior means loss of cell co-operation. The protein synthesis rhythm was restored 24 h after hepatocytes were transferred to PPPP-free medium. Restoration was more rapid when 0.9 microM gangliosides (standard mixture from bovine brain) were added to the medium just after the withdrawal of PPPP. These novel results concerning the loss of rhythm of protein synthesis in low GM1 ganglioside medium support the conclusion that ganglioside is implicated in the regulation of cell co-operative activity.

Animals↗
PubMed1992

Differentiation of Neuro-2a neuroblastoma cells by an antibody to GM3 ganglioside.

A monoclonal antibody against GM3 ganglioside (GM3Ab) was found to trigger differentiation of Neuro-2a cells in culture. The differentiation of Neuro-2a cells by GM3Ab was accompanied by increased levels of intracellular serotonin and amino acid neurotransmitters viz. aspartate, glutamate, glutamine, glycine and taurine. Further study indicated that the increase in the serotonin level was not due to a higher rate of serotonin synthesis but rather to a higher rate of active transport of serotonin from the medium. Studies on the cell surface gangliosides revealed that unlike the proliferating cells, the GM3Ab-mediated differentiated cells contained higher gangliosides in addition to GM3 and GM2 gangliosides. Analysis of total cellular proteins indicated the appearance of a 25 kDa protein, pI 5.4, in the GM3Ab-treated cells--a small amount of this protein was observed in dibutyryl cAMP (Bt2cAMP)-treated cells, however, the protein was totally absent in the 5-bromo-2'-deoxyuridine (BrdU)-treated cells. Investigation of the mode of action of GM3Ab indicated that the cellular differentiation was due to increased cAMP accumulation resulting from an increase in the adenylate cyclase activity. Further studies with different agents affecting protein kinase C (PKC) activity and direct assay of PKC ruled out the possibility that GM3Ab mediated its effect via PKC. This GM3Ab-induced differentiation could be inhibited by protein kinase A (PKA) inhibitor, H8, but could not be inhibited by sphingosine, an inhibitor of PKC. Pertussis toxin could mimic the effect of GM3Ab, suggesting that GM3Ab caused the elevation in the adenylate cyclase activity by reducing the Gi-protein inhibition of the adenylate cyclase. The data suggests that GM3Ab, after interaction with cell surface GM3, elevated intracellular cAMP level by withdrawing the inhibitory effect of some undefined factor(s) present in culture medium which normally keeps adenylate cyclase activity low through activation of Gi-protein.

Amino Acids↗
PubMed1998

Glycosphingolipids of skeletal muscle: I. Subcellular distribution of neutral glycosphingolipids and gangliosides in rabbit skeletal muscle.

Membrane vesicles were prepared from rabbit skeletal muscle, separated by sucrose density gradient centrifugation and characterized by their specific marker enzymes, ligand binding, and ion flux activities. 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). Their glycosphingolipid compositions were analyzed by biochemical and immunochemical methods with specific antibodies (TLC immunostaining) and characteristic patterns were obtained from respective membrane fractions, expressed on a protein basis. Glucosylceramide, the main neutral glycosphingolipid of rabbit muscle, was found in SL and TT fractions, whereas SR and Tr/M vesicles lack this compound. Lactosylceramide was selectively recovered in the SR1 fraction. GM3(Neu5Ac), the main ganglioside in rabbit muscle, was found to account for 64% in the SL, 13% in the TT, 7% in the SR1, 3% in the SR2 and 13% in the Tr/M fractions. IV3Neu5Ac-nLcOse4Cer was mostly abundant in SL and decreased in the order SL > TT, Tr/M > SR1, SR2. IV6Neu5Ac-nLcOse4Cer was only detected in the SL and Tr/M fractions in noteworthy quantities. Ganglioseries gangliosides GM1, GD1a, GD1b and GT1b displayed homogeneous distribution patterns in each membrane preparation. They were expressed only in small amounts but mainly in SL, TT and Tr/M vesicles and to less extent in SR1 and SR2 fractions. The presence of GM3(Neu5Ac) in the SL as well as on subcellular level was confirmed in transverse muscle cryosections by means of indirect immunofluorescence microscopy. The SL was brightly stained, but considerable intracellular fluorescence was observed as expected from the biochemical analyses. Thus, the neutral GSL and ganglioside expression of the SL and the intracellular membraneous network is different in skeletal muscle both in terms of quantitative and qualitative GSL composition as demonstrated in details by means of biochemical and immunochemical techniques. The modulatory functions of GM3 and gangliosides of the neolacto- and ganglio-series towards the voltage dependent Ca(2+)-channel, largely preponderant in the triads-containing Tr/M fraction, is the subject of the accompanying paper (J. Müthing, U. Maurer, and S. Weber-Schürholz, Carbohydr. Res., 307 (1998) 147-157).

Animals↗
PubMed1999

Gangliosides GM1 and GD1b are not polarized in mature hippocampal neurons.

Analysis of the binding of cholera toxin to ganglioside GM1 in both living and fixed neurons, and comparison with the distribution of defined axonal and dendritic proteins, demonstrates that ganglioside GM1 is distributed in a non-polarized manner over the axonal and dendritic plasma membranes of mature, cultured hippocampal neurons. Likewise, ganglioside GD1b is also distributed in a non-polarized manner. These results suggest that a recent report [Ledesma, M.D. et al. EMBO J. 18 (1999) 1761-1771] proposing that ganglioside GM1 is highly enriched on the axonal versus dendritic membrane of hippocampal neurons may need to be re-evaluated.

Animals↗
PubMed1980

Binding of intraluminal toxin in cholera: trial of GM1 ganglioside charcoal.

A study was undertaken to investigate whether toxin produced in the gut lumen contributes significantly to clinical illness and whether binding such toxin by GM1 ganglioside adsorbed onto charcoal could alter the clinical course of disease. 46 patients with severe cholera receiving standard intravenous therapy were randomly assigned to one of three groups: GM1 ganglioside-charcoal (16), charcoal alone (16), or water (14). The results demonstrated that patients were given sufficient GM1 ganglioside-charcoal to bind all luminal toxin produced by Vibrio cholerae in their intestines. Patients treated with GM1 ganglioside tended to have a greater reduction in purging than patients treated with either charcoal alone or water. This difference was statistically significant soon after beginning medication (8-15 h) and the reduction in fluid-loss was especially pronounced in patients with very severe initial purging who had been ill only for a short time before admission. These results suggest that toxin produced in the gut lumen increases fluid-loss early in cholera, but that later in the course of disease, toxin which is inaccessible to luminal binding agents in the major stimulus of purging.

Adolescent↗
PubMed2002

Ganglioside reactive antibodies of IgG and IgM class in sera of patients with differentiated thyroid cancer.

We searched for the presence of ganglioside reactive antibodies in sera of patients with differentiated thyroid cancer (DTC). Sera were screened by ELISA with plates coated with GM3(NeuAc), GM3(NeuGc), GM2, GM1, FucGM1, GD3, GD1a or GD1b gangliosides. Ganglioside reactive antibodies were detected more frequently in sera of patients with DTC than in sera of healthy persons, in keeping with the possibility of autoimmunization during carcinogenesis. Antibodies of IgM and IgG classes reactive with FucGM1 occurred most often. However, the infrequent occurrence of ganglioside reactive antibodies, their low titer and lack of correlation between their presence and clinical condition of the patients indicate that determination of these antibodies has no diagnostic value in DTC.

Antigens, Differentiation↗