Gangliosides enhance KCl-induced Ca2+ influx and acetylcholine release in brain synaptosomes

Tanaka, Yasukazu; Waki, Hatsue; Kon, Kazuo; Ando, Susumu

doi:10.1097/00001756-199707070-00023

Cited by 39 publications

(29 citation statements)

References 22 publications

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“…However, we found no major synaptic deficits in both null-mutants. This is quite surprising, in view of studies suggesting a synaptic role for gangliosides on the basis of exogenous ganglioside application (Tanaka et al, 1997;Ando et al, 1998), as well as the reported co-localization in lipid rafts of gangliosides and proteins important for neuroexocytosis (Chamberlain et al, 2001;Lang et al, 2001;Taverna et al, 2004;Salaun et al, 2004). The only changes we observed were some extra degree of rundown of transmitter release at high intensity use at the dKO NMJ and a temperature-specific increase in quantal content at 35 C in GD3s-KO NMJs, compared to WT.…”

Section: Discussioncontrasting

confidence: 57%

“…In the light of their known effects on ion-channels and their particular abundance in synaptic regions, gangliosides are thought to play a role in neurotransmitter release, which is critically dependent on presynaptic ion-channel function (Wieraszko and Seifert, 1985;Ramirez et al, 1990;Egorushkina et al, 1993;Takamiya et al, 1996;Tanaka et al, 1997;Furuse et al, 1998;Ando et al, 1998;Meir et al, 1999;Chiavegatto et al, 2000;Bullens et al, 2002;Hakomori, 2003;Proia, 2003). Several important proteins of the release machinery co-localize with gangliosides within lipid rafts (Chamberlain et al, 2001;Lang et al, 2001;Taverna et al, 2004;Salaun et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

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Neuromuscular synaptic function in mice lacking major subsets of gangliosides

et al. 2008

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Section: Discussioncontrasting

confidence: 57%

Section: Introductionmentioning

confidence: 99%

Neuromuscular synaptic function in mice lacking major subsets of gangliosides

et al. 2008

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“…A presynaptic explanation for the changed EPP and MEPP kinetics and quantal size (e.g. increased filling of ACh vesicles) is less likely because gangliosides have been reported to lack effect on ACh synthesis (Tanaka et al, 1997). On the basis of the only relatively small magnitude of the observed kinetic changes of the EPPs and MEPPs in aged GD3s-KO mice, and the EPP amplitude being somewhat increased compared to wild-type, it is not to be expected that successful neuromuscular transmission is endangered.…”

Section: Discussionmentioning

confidence: 96%

“…Gangliosides may be particularly important in synaptic function because they 1) show high expression at synapses (Ando et al, 2004;Waki et al, 1994); 2) co-localize with neuroexocytotic proteins (Chamberlain et al, 2001;Lang et al, 2001;Salaun et al, 2004;Taverna et al, 2004) and 3) influence neurotransmitter release and synaptic plasticity when applied exogenously Egorushkina et al, 1993;Furuse et al, 1998;Ramirez et al, 1990;Tanaka et al, 1997;Wieraszko and Seifert, 1985). In spite of this, we recently showed near-normal synapse function at neuromuscular junctions (NMJs) of mice lacking either complex gangliosides, b/c-series gangliosides or all gangliosides except GM3 ( Fig.1) (Bullens et al, 2002;Zitman et al, 2008), suggesting neurotransmission was supported by GM3 alone or, alternatively, is ganglioside-independent.…”

Section: Introductionmentioning

confidence: 99%

Neuromuscular synaptic transmission in aged ganglioside-deficient mice

Zitman

Todorov

Verschuuren

et al. 2011

Neurobiology of Aging

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Gangliosides are sialylated glycosphingolipids that are present in high density on neuronal membranes, especially at synapses, where they are assumed to play functional or modulating roles. Mice lacking GM2/GD2-synthase express only the simple gangliosides GD3 and GM3 and develop progressive motor behaviour deficits upon ageing, apparently due to failing complex ganglioside-dependent maintenance and/or repair processes or, alternatively, toxic GM3/GD3 accumulation. We investigated the function of neuromuscular junctions (NMJs) of aged (>9 months-old) GM2/GD2-synthase null-mutant mice, because synaptic dysfunction might develop with age and could potentially contribute to the late-onset motor phenotype. In addition, we studied NMJs of old mice lacking GD3-synthase (expressing only O-and aseries gangliosides), which do not show an overt neurological phenotype but may develop subclinical synaptic deficits. Detailed electrophysiological analyses showed subtle changes in presynaptic neurotransmitter release. Acetylcholine release at 40 Hz nerve stimulation at aged GM2/GD2-synthase null-mutant NMJs ran down slightly more pronounced than at wild-type NMJs, and spontaneous acetylcholine release rate at GD3-synthase null-mutant NMJs was somewhat higher than at wild-type, selectively at 25 C bath temperature. Interestingly, we observed faster kinetics of postsynaptic electrophysiological responses at aged GD3-synthase null-mutant NMJs, not previously seen by us at NMJs of young GD3-synthase null-mutants or other types of (aged or young) ganglioside-deficient mice. These kinetic changes might reflect a change in postsynaptic acetylcholine receptor behaviour. Our data indicate that it is highly unlikely that transmission failure at NMJs contributes to the progressive motor defects of aged GM2/GD2-synthase null-mutants and that, despite some kinetic changes of synaptic signals, neuromuscular transmission remains successful in aged GD3-synthase null-mutant mice. Apparently, mutual redundancy of the different gangliosides in supporting presynaptic function, as observed previously by us in young mice, remains adequate upon ageing or, alternatively, gangliosides have only relatively little direct impact on neuromuscular synaptic function, even in aged mice. AbbreviationsACh, acetylcholine; AChR, acetylcholine receptor; EPP, endplate potential; GD3s-KO, α2,8-sialyltransferase knockout; GM2s-KO, β1,4-GalNAc-transferase knockout; MEPP, miniature endplate potential; NMJ, neuromuscular junction; WT, wild-type.Zitman et al., Synaptic function in aged ganglioside-deficient mice 3

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“…Survival of BCG expressing neuronal cells is reasonable since several studies have suggested that complex gangliosides participate in synaptic functions, in particular for regulation of Ca 2ϩ -flux (42)(43)(44)(45). We will now investigate the molecular mechanisms for regulation of ceramide and BCG expression and further analyze the sphingolipid-regulated signaling pathways that are significant for neuronal development.…”

Section: Par-4 and Bcg Expression Is Correlated With Apoptosis And Cementioning

confidence: 99%

Regulation of Apoptosis during Neuronal Differentiation by Ceramide and b-Series Complex Gangliosides

Bieberich

MacKinnon

Silva

et al. 2001

Journal of Biological Chemistry

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Lipid analysis of gestational day E14.5 mouse brain revealed elevation of ceramide to a tissue concentration that induced apoptosis when added to the medium of neuroprogenitor cells grown in cell culture. Elevation of ceramide was coincident with the first appearance of bseries complex gangliosides (BCGs). Expression of BCGs by stable transfection of murine neuroblastoma (F-11) cells with sialyltransferase-II (ST2) resulted in a 70% reduction of ceramide-induced apoptosis. This was most likely due to an 80% reduced expression of prostate apoptosis response-4 (PAR-4). PAR-4 expression and apoptosis were restored by preincubation of ST2-transfected cells with N-butyl deoxinojirimycin (NB-DNJ) or PD98059, two inhibitors of ganglioside biosynthesis or p42/44 mitogen-activated protein (MAPK) kinase, respectively. In sections of day E14.5 mouse brain, the intermediate zone showed intensive staining for complex gangliosides, but only low staining for apoptosis (TUNEL) and PAR-4. Apoptosis and PAR-4 expression, however, were elevated in the ventricular zone which only weakly stained for complex gangliosides. Whole cell patch clamping revealed a 2-fold increased calcium influx in ST2-transfected cells, the blocking of which with nifedipine restored apoptosis to the level of untransfected cells. In serum-free culture, supplementation of the medium with IGF-1 was required to maintain MAPK phosphorylation and the anti-apoptotic effect of BCG expression. BCG-enhanced calcium influx and the presence of insulin-like growth factor-1 may thus activate a cell survival mechanism that selectively protects developing neurons against ceramide-induced apoptosis by up-regulation of MAPK and reduction of PAR-4 expression.Ceramide and gangliosides are sphingolipids that are abundant in the plasma membrane of neuronal cells and are suggested to have a regulatory function in cellular differentiation and apoptosis (1, 2). Ceramide is known to induce differentiation or apoptosis in a variety of different cell types whereas the physiological significance of gangliosides for these processes is still unclear (3, 4). Recent studies with transgenic mice lacking neutral glucosphingolipids (glucosyltransferase knockout) or complex gangliosides (N-acetylgalactosaminyltransferase I knockout) indicate a high incidence of apoptosis in the nervous system during embryonal development or adulthood (5-7).Most recently, the N-acetylgalactosaminyltransferase I/sialyltransferase II (GalNAcT 1 /ST2) double knockout mouse has been reported to show spontaneous death and audiogenic seizures (8). These results prompted us to investigate the role of gangliosides as potential anti-apoptotic effectors during early mouse brain development. Cell survival is crucial in this developmental period because about half of the proliferative neurons and glial cells die by apoptosis between gestational days E12 and E18 (9). This period is coincident with a switch from simple to complex gangliosides in brain tissue at days E14-E16 that has also been found during neuronal differen...

show abstract

Gangliosides enhance KCl-induced Ca2+ influx and acetylcholine release in brain synaptosomes

Cited by 39 publications

References 22 publications

Neuromuscular synaptic function in mice lacking major subsets of gangliosides

Neuromuscular synaptic function in mice lacking major subsets of gangliosides

Neuromuscular synaptic transmission in aged ganglioside-deficient mice

Regulation of Apoptosis during Neuronal Differentiation by Ceramide and b-Series Complex Gangliosides

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