Ganglioside GD1a increases the excitability of voltage-dependent sodium channels

Salazar, Blanca; Castaño, Santiago; Sánchez, Julio César; Romero, Miryam; Recio-Pinto, Esperanza

doi:10.1016/j.brainres.2004.06.055

Cited by 11 publications

(8 citation statements)

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“…In addition, sialic acids and oligosialic acids present on gangliosides can modulate membrane surface charge density, the pH at the membrane surface, and membrane potentials [ 374 ]. In planar lipid bilayers, ganglioside GD1a can increase the excitability of voltage-dependent sodium channels [ 375 ].…”

Section: Functional Aspectsmentioning

confidence: 99%

Ganglioside Biochemistry

2012

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Section: Functional Aspectsmentioning

confidence: 99%

Ganglioside Biochemistry

2012

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“…in modulation of membrane-bound enzymes and ion-channels, cell-adhesion, neuritogenesis and membrane stability (Hakomori, 2003;Hashiramoto et al, 2006;Ledeen and Wu, 2006;Salazar et al, 2004;Sohn et al, 2006;Susuki et al, 2007;Wu et al, 2007;Yates and Rampersaud, 1998). Furthermore, anti-ganglioside autoimmunity and ganglioside turnover deficits cause neurological disorders (Ang et al, 2004;Maegawa et al, 2006;Simpson et al, 2004;Willison and Yuki, 2002).…”

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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“…Gangliosides may affect neuronal membrane protein function through (1) influencing the fluidity of the plasma membrane surrounding the protein (Kappel et al 2000) and (2) an electrostatic influence of the negatively charged sialic acid residues, either directly or indirectly through membrane surface charge (Green & Andersen, 1991; Aubin & Prestegard, 1993; Salazar et al 2004). Studies applying exogenous gangliosides have suggested modulatory actions on membrane‐bound enzymes (Partington & Daly, 1979), ion pumps (Caputto et al 1977; Leon et al 1981) and ion channels (Leon et al 1981; Carlson et al 1994; Kappel et al 2000; Salazar et al 2004), hormone receptors (Bremer & Hakomori, 1982) and proteins involved in the membrane flux and intracellular homeostasis of Ca 2+ (Wu et al 1990; Wu & Ledeen, 1994; Wu et al 2001, 2007. For reviews see Ando, 1983; Lloyd & Furukawa, 1998; Yates & Rampersaud, 1998; Ledeen & Wu, 2002).…”

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Pathophysiological actions of neuropathy‐related anti‐ganglioside antibodies at the neuromuscular junction

Plomp

Willison

2009

The Journal of Physiology

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The outer leaflet of neuronal membranes is highly enriched in gangliosides. Therefore, specific neuronal roles have been attributed to this family of sialylated glycosphingolipids, e.g. in modulation of ion channels and transporters, neuronal interaction and recognition, temperature adaptation, Ca 2+ homeostasis, axonal growth, (para)node of Ranvier stability and synaptic transmission. Recent developmental, ageing and injury studies on transgenic mice lacking subsets of gangliosides indicate that gangliosides are involved in maintenance rather than development of the nervous system and that ganglioside family members are able to act in a mutually compensatory manner. Besides having physiological functions, gangliosides are the likely antigenic targets of autoantibodies present in Guillain-Barré syndrome (GBS), a group of neuropathies with clinical symptoms of motor-and/or sensory peripheral nerve dysfunction. Antibody binding to peripheral nerves is thought to either interfere with ganglioside function or activate complement, causing axonal damage and thereby disturbed action potential conduction. The presynaptic motor nerve terminal at the neuromuscular junction (NMJ) may be a prominent target because it is highly enriched in gangliosides and lies outside the blood-nerve barrier, allowing antibody access. The ensuing neuromuscular synaptopathy might contribute to the muscle weakness in GBS patients. Several groups, including our own, have studied the effects of anti-ganglioside antibodies in ex vivo and in vivo experimental settings at mouse NMJs. Here, after providing a background overview on ganglioside synthesis, localization and physiology, we will review those studies, which clearly show that anti-ganglioside antibodies are capable of binding to NMJs and thereby can exert a variety of pathophysiological effects. Furthermore, we will discuss the human clinical electrophysiological and histological evidence produced so far of the existence of a neuromuscular synaptopathy contributing to muscle weakness in GBS patients.

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Ganglioside GD1a increases the excitability of voltage-dependent sodium channels

Cited by 11 publications

References 50 publications

Ganglioside Biochemistry

Ganglioside Biochemistry

Neuromuscular synaptic transmission in aged ganglioside-deficient mice

Pathophysiological actions of neuropathy‐related anti‐ganglioside antibodies at the neuromuscular junction

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