Ganglioside modulation of neural cell adhesion molecule and N-cadherin-dependent neurite outgrowth

Doherty, Patrick; Ashton, Sandra V.; Skaper, Stephen D.; Leon, Alberta; Walsh, Frank S.

doi:10.1083/jcb.117.5.1093

Cited by 66 publications

(28 citation statements)

References 40 publications

(43 reference statements)

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“…GM1 ganglioside, one of the few sialoglycoconjugates in nature resistant to sialidase, has been shown to be a pluripotent molecule capable of modulating the activities of a wide variety of membrane proteins including receptors, enzymes, ion channels, and adhesion molecules (Kreutter et al . 1987; Doherty et al . 1992; Fueshko and Schengrund 1992; Carlson et al .…”

Section: Discussionmentioning

confidence: 99%

Potentiation of a sodium–calcium exchanger in the nuclear envelope by nuclear GM1 ganglioside

Xie

et al. 2002

Journal of Neurochemistry

136

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Calcium is recognized as an important intracellular messenger with a pivotal role in the regulation of many cytosolic and nuclear processes. Gangliosides of various types, especially GM1, are known to have a role in some aspects of Ca 2+ regulation, operating through a variety of mechanisms that are gradually coming to light. The present study provides evidence for a sodium-calcium exchanger in the nuclear envelope of NG108-15 neuroblastoma cells that is potently and specifically activated by GM1. Immunoblot analysis revealed an unusually tight association of GM1 with the exchanger in the nuclear envelope but not with that in the plasma membrane. Exchanger and associated GM1 were located in the inner membrane of the nuclear envelope, suggesting this system could function to transfer Ca 2+ between nucleoplasm and the envelope lumen. The GM1-enhanced exchange was blocked by cholera toxin B subunit while C2-ceramide, a recently discovered inhibitor of the exchanger, blocked all transfer. Exchanger activity was significantly elevated in nuclei isolated from cells that were induced to differentiate by KCl + dibutyryl-cAMP, a treatment previously shown to promote up-regulation of nuclear GM1 in conjunction with axonogenesis. Similar enhancement was achieved by addition of exogenous GM1 to nuclei from undifferentiated cells. These results suggest a prominent role for nuclear GM1 in regulation of nuclear Ca 2+ homeostasis. et al. 1991;Kocsis et al. 1994).The present study was undertaken to determine the specific role of GM1, which was suggested to contribute to this altered regulation of nuclear Ca 2+ (Wu et al. 1995b;Ledeen et al. 1998). We have obtained evidence for the presence of a sodium-calcium (Na-Ca) exchanger in the NE that is strongly associated with and potentiated by GM1. This exchanger was detected by immunocytochemistry in the NE of cortical neurons and NG108-15 cells, and its function demonstrated in isolated nuclei from the latter. ] i , intracellular calcium content; Ctx B, cholera toxin B subunit; Ctx B-FITC, cholera toxin B linked to fluoroisothiocyanate; Ctx B-HRP, cholera toxin B linked to horseradish peroxidase; db-cAMP, dibutyryl cyclic AMP; DMEM, Dulbecco's modified Eagle's medium; DTT, dithiothreitol; HPTLC, high-performance thin-layer chromatography; Membr. Mix, mixture of non-nuclear membranes; NE, nuclear envelope; NPP, nuclear pore protein; PBS, phosphate-buffered saline; SDS-PAGE, sodium dodecyl sulfate polyacrylamide gel electrophoresis.

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Section: Discussionmentioning

confidence: 99%

Potentiation of a sodium–calcium exchanger in the nuclear envelope by nuclear GM1 ganglioside

Xie

et al. 2002

Journal of Neurochemistry

136

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“…This is an example of GM1 functioning as modulator of membrane proteins, a general physiologic activity of this ganglioside observed in a diversity of vertebrate cells (Hakomori and Igarashi, 1993; Ledeen et al, 1998). Many such GM1‐modulated proteins have been characterized, including receptors, enzymes, ion channels, and adhesion molecules (Kreutter et al, 1987; Doherty et al, 1992; Fueshko and Schengrund, 1992; Carlson et al, 1994; Ferrari et al, 1995; Mutoh et al, 1995; Saito et al, 1995; Wu et al, 1996, 1997; Pitto et al, 1998; Rampersaud et al, 1999; Wang et al, 1999). Other gangliosides have been reported to similarly influence the activity of membrane proteins (Tsuji et al, 1985; Hakomori and Igarashi, 1993, 1995; Kotani et al, 2000).…”

Section: Discussionmentioning

confidence: 99%

C6 cells express a sodium‐calcium exchanger/GM1 complex in the nuclear envelope but have no exchanger in the plasma membrane: Comparison to astrocytes

Xie

Ledeen

2004

J of Neuroscience Research

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Previous work demonstrated the presence of an isoform of Na(+)/Ca(2+) exchanger in the nuclear envelope of neurons and NG108-15 cells that is tightly associated with GM1 ganglioside and potentiated by the latter. This contrasted with the Na(+)/Ca(2+) exchanger(s) in the plasma membrane, which were suggested to associate more loosely with GM1. To study these aspects of Na(+)/Ca(2+) exchanger expression in nonneuronal neural cells, we have examined nuclear and plasma membrane exchanger patterns in astrocytes and C6 cells, a glia-derived line. We find both cell types contain the tightly associated exchanger/GM1 complex in the nuclear envelope but, surprisingly, only astrocytes possess Na(+)/Ca(2+) exchanger activity in the plasma membrane. This is the first reported example of a cell (C6) with Na(+)/Ca(2+) exchangers in the nuclear envelope but not in the plasma membrane. RT-PCR established the presence of the NCX1 subtype in C6 cells and both NCX1 and NCX2 in astrocytes. Comparison was made with NG108-15 cells, which have Na(+)/Ca(2+) exchangers in both nuclear and plasma membranes, and Jurkat cells, which have no Na(+)/Ca(2+) exchanger in either membrane. Culturing of C6 cells in the presence dibutyryl-cAMP caused upregulation of a high molecular weight isoform of the exchanger together with GM1 in the nuclear envelope, resulting in significant elevation of Na(+)/Ca(2+) exchanger activity in the latter. Application of exogenous GM1 to nuclei from non-treated cells also potentiated exchanger activity, although to a lesser degree. The Na(+)/Ca(2+) exchanger/GM1 complex occurs in the inner membrane of the nuclear envelope, suggesting a functional role in transferring Ca(2+) between nucleoplasm and the envelope lumen.

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“…GM1 itself had only marginal effect on KA-induced seizures in WT and HZT mice but had a more observable effect on the KOs. GM1 is a pluripotent ganglioside known to exert diverse modulatory effects on a variety of membrane receptors, enzymes, ion channels, and adhesion molecules (Kreutter et al, 1987;Doherty et al, 1992;Fueshko and Schengrund, 1992;Carlson et al, 1994;Ferrari et al, 1995;Mutoh et al, 1995;Saito et al, 1995;Wu et al, 1996Wu et al, , 1997Pitto et al, 1998;Rampersaud et al, 1999;Wang et al, 1999). It was shown to have neuroprotective prop- erties in several in vitro and in vivo systems (for review, see Mahadik and Karpiak, 1988;Ledeen, 1989;Skaper et al, 1989).…”

Section: Discussionmentioning

confidence: 99%

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

Wang

et al. 2005

J. Neurosci.

102

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Knock-out (KO) mice lacking gangliotetraose gangliosides attributable to disruption of the gene for GM2/GD2 synthase [GalNAcT (UDP-N-acetylgalactosamine:GM3/GD3 ␤-1,4-N-acetylgalactosaminyltransferase; EC 2.4.1.92)] are revealing key neural functions for the complex gangliosides of brain. This study has found such animals to be highly susceptible to kainic acid (KA)-induced seizures in terms of both seizure severity and duration. Intraperitoneal injection of 25 mg/kg KA produced status epilepticus for ϳ200 min in normal mice or heterozygotes and more than four times longer in the KO mice. The latter group suffered ϳ30% mortality, which increased to ϳ75% at dosage of 30 mg/kg KA, compared with 10 -14% for the other two genotypes at the latter dosage. Nissl staining and terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end labeling assay revealed substantial deterioration of pyramidal neurons attributable to apoptosis in the KO hippocampus, especially the CA3 region. Seizure activity in the KO mouse was only moderately diminished by intraperitoneal injection of GM1 ganglioside, whereas LIGA 20, a semisynthetic analog of GM1, substantially reduced both seizure severity and cell damage. The potency of LIGA 20 was correlated with its enhanced membrane permeability (compared with GM1), as seen in the increased uptake of /Ca2ϩ exchanger located at the inner membrane of the nuclear envelope in KO mice, an exchanger dependent on tight association with GM1 or its analog for optimal activity. These results point to a neuroprotective role for GM1 and its associated exchanger in the nucleus, based on regulation of Ca 2ϩ flux between nucleoplasm and nuclear envelope.

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Ganglioside modulation of neural cell adhesion molecule and N-cadherin-dependent neurite outgrowth

Cited by 66 publications

References 40 publications

Potentiation of a sodium–calcium exchanger in the nuclear envelope by nuclear GM1 ganglioside

Potentiation of a sodium–calcium exchanger in the nuclear envelope by nuclear GM1 ganglioside

C6 cells express a sodium‐calcium exchanger/GM1 complex in the nuclear envelope but have no exchanger in the plasma membrane: Comparison to astrocytes

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

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