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Puljko, B.;  Stojanović, M.;  Ilic, K.;  Kalanj-Bognar, S.;  Mlinac-Jerkovic, K. Gangliosides and Sodium-Potassium ATPase Activity. Encyclopedia. Available online: https://encyclopedia.pub/entry/24999 (accessed on 17 July 2025).
Puljko B,  Stojanović M,  Ilic K,  Kalanj-Bognar S,  Mlinac-Jerkovic K. Gangliosides and Sodium-Potassium ATPase Activity. Encyclopedia. Available at: https://encyclopedia.pub/entry/24999. Accessed July 17, 2025.
Puljko, Borna, Mario Stojanović, Katarina Ilic, Svjetlana Kalanj-Bognar, Kristina Mlinac-Jerkovic. "Gangliosides and Sodium-Potassium ATPase Activity" Encyclopedia, https://encyclopedia.pub/entry/24999 (accessed July 17, 2025).
Puljko, B.,  Stojanović, M.,  Ilic, K.,  Kalanj-Bognar, S., & Mlinac-Jerkovic, K. (2022, July 11). Gangliosides and Sodium-Potassium ATPase Activity. In Encyclopedia. https://encyclopedia.pub/entry/24999
Puljko, Borna, et al. "Gangliosides and Sodium-Potassium ATPase Activity." Encyclopedia. Web. 11 July, 2022.
Gangliosides and Sodium-Potassium ATPase Activity
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This entry is adapted from the peer-reviewed paper 10.3390/biomedicines10071518

Gangliosides, amphiphilic glycosphingolipids, tend to associate laterally with other membrane constituents and undergo extensive interactions with membrane proteins in cis or trans configurations. Studies of human diseases resulting from mutations in the ganglioside biosynthesis pathway and research on transgenic mice with the same mutations implicate gangliosides in the pathogenesis of epilepsy. Gangliosides are reported to affect the activity of the Na+/K+-ATPase, the ubiquitously expressed plasma membrane pump responsible for the stabilization of the resting membrane potential by hyperpolarization, firing up the action potential and ion homeostasis.

glycosphingolipids lipid rafts membrane microdomains neuronal ion homeostasis GM1 Na+/K+-ATPase sodium-potassium pump epilepsy

1. Short Overview of Gangliosides

Glycolipids are amphiphilic molecules composed of hydrophobic alkyl tails, which anchor them to the phospholipid bilayer, and a hydrophilic oligosaccharide headgroup. Numerous species of glycolipids exist, differing in oligosaccharide headgroups, lipid backbones, and alkyl tails [1]. Gangliosides are glycosphingolipids consisting of a ceramide tail attached by a glycosidic linkage to a glycan headgroup with one or more sialic acid residues [2]. They are harbored in the outer leaflet of the membrane where their ceramide moieties partition them laterally into lipid rafts—spatially and temporally dynamic membrane microdomains that contain other sphingolipids, phospholipids, cholesterol, and specific proteins [3]. Several hundreds of ganglioside structures have been characterized based on differences in oligosaccharide chains or the fatty acids linked to the ceramide [4]. The total mass and specific ganglioside composition vary significantly between different cell types and tissues. The human brain contains up to 30-fold more gangliosides than other tissues [2], and they provide a significant part of neuronal surface glycans [5]. Four gangliosides—GM1, GD1a, GD1b, and GT1b—are the most abundant in the mammalian brain [6], with extraordinary regional pattern differences [7]. Gangliosides are synthesized stepwise by a vast number of glycosyltransferases in a complex biosynthetic pathway in the Golgi apparatus from where they are trafficked to the plasma membrane [8][9]. They play a crucial role in various physiological processes including brain development, aging, and neurodegeneration by modulating the cell signal transduction pathways, neuronal differentiation, and structures and functions of membrane proteins [1][10]. The functions of gangliosides in the central nervous system can be revealed by the physiological manifestations of genetic mutations in the ganglioside biosynthetic pathway, observed both from studies of rare human diseases resulting from mutations in the ganglioside biosynthesis pathway and transgenic mouse models with impaired synthesis of gangliosides [11][12].
Analogously to lipid-protein interactions, a general feature of gangliosides is their capability to associate laterally with other molecules within the membrane [13]. The hydrogen-bonding ability of their headgroups results in extensive cis- or trans- interactions with membrane proteins [6][14]. Cis-interactions with membrane proteins in the same membrane modulate their localization within membrane subdomains, e.g., lipid rafts [15][16][17]. Being lipid raft constituents, gangliosides are implicated in regulation of the activity of plasma membrane proteins, including protein tyrosine kinases. Many receptor tyrosine kinases, including epidermal growth factor receptor (EGFR), platelet-derived growth factor receptor (PDGFR), and insulin receptor (IR) are localized in lipid rafts, and their dimerization and/or recruitment of signaling partners are affected by gangliosides, thus influencing their respective signaling pathways [15][18][19][20]. Furthermore, there is evidence on regulatory effects of gangliosides on the function of the GluR2-AMPA receptor (AMPAR), crucial for learning and memory formation process [21]. Ganglioside GM1 was also shown to promote axonal growth by bringing together the TrkA and laminin-1/beta1 integrin complexes [22]. Ganglioside biology and physiological functions, particularly in mammalian brain, have been exceptionally well described by Schnaar et al. [6][11]. Undoubtedly, a large body of data supports the notion of gangliosides as essential molecular signatures of cell surfaces, where they function as ligands for various glycan-binding proteins, such as bacterial toxins, cell adhesion molecules and receptor kinases [15][18][19][20][21][22][23]. 

2. Potential Role of Gangliosides in the Molecular Pathogenesis of Seizures

Epilepsy is a disease of the central nervous system characterized by pathological neuronal activity. Neuronal hyperactivity leads to abnormal, extensive, and uncontrolled symptomatology which can be presented as motor, sensory, cognitive, or autonomic disturbances. Pathological firing of neurons can have generalized onset, or focal onset with a possibility for bilateral tonic-clonic propagation or of the unknown onset [24]. There are many different causes of epileptic seizures [25], but the main feature of the seizure generation is either abnormal rhythmic and tonic excitation of neurons, or the aberrant interplay between inhibitory and excitatory neurons and altered membrane conductance [26]. Interestingly, several studies have associated mutations in ganglioside biosynthetic genes with epilepsy in humans. Mutations in the ST3GAL5 gene, encoding for the GM3-synthase, result in an early-onset seizure disorder, also known as the salt and pepper syndrome, characterized by motor and cognitive disturbances [27]. GM3-synthase catalyzes the first step in the production of gangliosides by transferring a sialic acid residue to lactosylceramide to form GM3; thus, loss of its catalytic activity prevents the formation of GM3 and other complex gangliosides. Contrary to observed effects of altered GM3 synthase activity in humans, no neurological deficits but altered insulin responsiveness was found in a comparison study on the St3gal5-null mice [28], while mice expressing only the GM3 ganglioside exhibit lethal audiogenic seizures [29]. Furthermore, mutations in human GM3 synthase have been linked to early-onset symptomatic epilepsy syndrome associated with developmental stagnation, blindness, and mitochondrial dysfunction [30][31]. In a study on epileptic patients, quantitative changes in major ganglioside species have been reported, indicating increased expression and immunohistochemical localization of the GD3 ganglioside in the hippocampi of epileptic patients [32]. Ganglioside GD3 is normally present in negligible amounts in the adult human brain; therefore, finding an increase of GD3 in hippocampal tissue in epilepsy is quite compelling. Given that GD3 binds calcium ions with a high-affinity [33][34], accumulation of GD3 may increase the local concentration of extracellular calcium ions, resulting in hyperexcitability. West syndrome, an infantile epilepsy disorder associated with developmental arrest or regression, has also been linked to several mutations in genes involved in ganglioside biosynthesis. Decreased levels of gangliosides GM1 and GD1a were observed in affected patients [35]. Furthermore, mutations in the ST3GAL3 gene, coding for ST3 beta-galactoside α-2,3-sialyltransferase 3, were observed in patients with West syndrome [36], and in two infants suffering from epileptic encephalopathy [37]. Since this enzyme catalyzes the sialylation of glycoproteins in addition to glycolipids in animal models [38], this may suggest that variations in the sialylation pattern on the surface of neuronal cells may cause subtle changes in tissue glycolipid composition that could result in the occurrence of epilepsy [36]. Deficits in another enzyme in the ganglioside biosynthesis pathway, the GM2/GD2 synthase encoded by the B4GALNT1 gene, cause rare hereditary spastic paraplegia accompanied by intellectual and motor disabilities [39], concurrent with severe motor deficits, progressive dysmyelination, and axonal degeneration shown in B4galnt1-null mice [40][41][42]. Studies on mice lacking the GM2/GD2 synthase demonstrated an increased vulnerability of the mice to seizures and the ability of a semisynthetic analog of ganglioside GM1, LIGA 20, to attenuate seizures when administered intraperitoneally [43]. Administration of gangliosides GM1 and GT1b have been reported to stop induced convulsions in animal models [44][45], whilst higher levels of GQ1b ganglioside have been shown to cause seizures in amygdaloid kindling-mice [46]. In the study on amygdaloid kindling-mice, intracerebroventricular administration of total brain gangliosides worsened kindling seizures [47]. Other experimental evidence also points to a complex role of gangliosides in the pathogenesis of seizures. A study on epileptic rats [48] has shown a decrease of the total content of GM1, GD1a, GD1b and GT1b gangliosides, phospholipids, NKA activity and lipid peroxidation levels following seizures. These data indicate that seizure activity leads to changed lipid content and lipid peroxidation status, in addition to altered NKA activity. The authors suggest that all the stated parameters might contribute to the neurophysiopathology of seizures observed in patients suffering from epilepsy [48]. However, the question remains whether the changes in the quantity of particular gangliosides in the brain are a consequence or the actual cause of different types of seizures by modulating functions of membrane proteins involved in seizure pathogenesis.

3. The Effects of Gangliosides on Na+/K+-ATPase

Gangliosides achieve a series of intra- and inter-molecular interactions that shape lateral and spatial membrane organization [49][50][51]. The ceramide part of the molecule accomplishes gangliosides’ dense packing by accommodating cholesterols’ steroid moiety in between two neighboring molecules [49]. In addition, experimental and computational evidence of the effective negative charge abolishment of the first sialic acid carboxylate ion, termed NH-trick, contributes to heavy packing [49][52]. This was previously suggested by Rodriguez et al. [52] who described the existence of a hydrogen bonding interaction between the hydrogen atom of the non-ionized carboxyl group in N-acetylneuraminic acid (Neu5Ac) and the oxygen atom of the carbonyl group in N-acetylgalactosamine (GalNAc), which reduces the dissociation of the Neu5Ac carboxyl group. Furthermore, they also suggested a second hydrogen bonding interaction between the proton of the acetamide group in GalNAc and the carbonyl moiety of the carboxyl group of Neu5Ac.The spatial organization of the oligosaccharide part differs depending on the topology of the microdomain where chalice-shaped conformers accessorize the outer borders, and flat-surfaced conformers occupy the interior [49]. The membrane’s physical properties arising from these unique ganglioside characteristics include curvature, asymmetry, cooperativity, demixing, and metamorphism [53][54]. As gangliosides forge the local lipid environment in a range from nano- to micro-domain, they play a great role in setting up a functional environment for proteins associated with different membrane qualities. As a membrane protein, NKA demands specific lipids in its hydrophobic mismatch region. Although it encompasses a maximum of 33 annular lipids [55], the protein-lipid interface is populated with specific interaction partners revealed by mechanistic and structural studies involving NKA [55][56][57]. The interactive nature of NKA structural elements and membrane lipid constituents induces spatial stability and modulates ion-exchange frequency. Cholesterol can occupy two specific sites: (a) between the α and FXYD subunits, which favors stability, and (b) tightly squeezed between α and β subunits, disabling movement and pumping activity [56]. NKAs’ dependence on cholesterol is evident from systems with cholesterol-poor membranes, e.g., Saccharomyces cerevisiae, where NKA resides in an inactive state with no detectable enzymatic turnover [56]. Furthermore, neutral phospholipids of inner membrane leaflets were suggested to stimulate NKA activity [56], and sphingomyelin and saturated phospholipids inhibit it [56]. Conceptually, NKA’s enzymatic activity is a function of lateral lipid exchange within the annular region, and subtle changes of lipid species within NKA proximity can make enormous changes in the molecules’ activity status. These events of lateral lipid mobility are within gangliosides’ mixing-demixing ability [50], where gangliosides act as lipid sorting machinery providing the optimal mise en scène for a variety of proteins, including NKA. However, there have been only a minor number of studies on how gangliosides affect NKA enzymatic activity, performed on model or physiological systems. It has been established that NKA activity alternates during multiple freeze-thaw cycles due to reshuffling between lipid rafts and bulk membrane fractions accompanied by ganglioside GM1, and with GD1a, GD1b, and GT1b distribution mirroring the changes in NKA activity [58]. These results indicate that gangliosides arrange a distinct lipid environment crucial for proper NKA functioning. Hence, as opposed to investigating the effects on NKA by exogenously adding gangliosides, within real membranes the change of ganglioside composition is achieved between distinct membrane domains. Considering that different gangliosides populate different lipid rafts in various cell types [59], this could be an important means of fine-tuning NKA activity. Furthermore, described pools of non-pumping NKA in epithelial cells are a consequence of NKA positioning within membrane domains with different cholesterol concentrations, caveolae and lipid rafts [60]. Extensive NKA mobility in neuronal membranes [61] could be ganglioside driven, thus utilizing proteins’ different modes of operation and maintaining neuronal membrane homeostasis. Ganglioside-NKA interactions were also investigated by electron spin resonance (ESR) spectroscopy using spin-labeled gangliosides GM1, GM2, GM3, and GD1b and NKA purified from shark rectal glands, in conjunction with other charged membrane lipids. The results indicated gangliosides GM1, GM2, and GM3 exhibit virtually no selectivity in interactions with NKA relative to spin-labeled phosphatidylcholine, whilst GD1b selectivity was considerably lower relative to other phospholipids, possibly due to one more sialic acid residues in its structure [62]. The authors propose that this low selectivity is due to the bulkiness of ganglioside head groups which prevents closer associations with the protein.
Total brain gangliosides isolated from porcine brains reduced NKA activity up to 40% in chicken brain synaptosomal preparations when ganglioside-protein ratios were 1:1, with the kinetics described as a non-competitive inhibition, and the interactions being dependent on temperature, ATP concentration, and preincubation time [63]. Interestingly, the increase in ganglioside concentrations was found not to affect NKA activity in synaptosomal fractions derived from cats suffering from GM1 and GM2 gangliosidosis [64]. In another study on rat brain microsomal preparations, administration of total human brain gangliosides had opposite effects regarding their concentration. The lower concentrations were shown to activate and higher to inhibit NKA activity, with the inhibition being reversible and competitive relative to K+ concentrations [65]. The authors suggest that the inhibition of NKA activity results from conformational changes in the membrane caused by the integration of exogenous gangliosides. In another study, microsomal fractions from adult male rats were treated with total brain gangliosides and various sphingolipid species derived from a patient with Tay–Sachs disease resulting in slight activation of NKA activity [66]. Furthermore, the addition of nanomolar concentrations of exogenous GM1, GD1a, GD1b, GT1b gangliosides to mitochondrial fractions derived from rat brains caused a 26–43% rise in NKA activity under identical conditions, with authors suggesting the phenomenon to be directly linked to alternations in the enzyme’s lipid environment [67]. All the above findings reflected in NKA activity alterations affirm that gangliosides affect the membrane in a different manner depending on membrane specialization and complexity. Ganglioside GM1 itself was found to cause minor inhibition of NKA activity when added to homogenates prepared from rat superior cervical ganglion (SCG) [68][69], but an increase in the activity in nodose ganglia (NG) from adult rats [69][70]. Administration of ganglioside GM1 has been shown to have potential therapeutic properties since it was able to decrease mortality due to ischemia up to 52% in Mongolian gerbils. However, no significant differences were observed in NKA activity between occluded and non-occluded brain hemispheres [71]. The same group has again observed neuroprotective action of GM1 in comparison to the saline treatment of induced ischemia in the gerbil cerebral cortex [72]. In another study, striatal homogenates derived from rat brains injected with convulsion-causing glutaric acid (GA) and pentylenetetrazole (PTZ) were incubated with GM1. A decrease in NKA activity resulting from GA administration was shown to cause seizures in vivo, and an ex vivo decrease in NKA activity to be prevented by GM1 administration, suggesting its possible therapeutic application in the treatment of seizures [44]. More recently, ganglioside GM1 was also found to have neuroprotective properties in hippocampal homogenates from AD models, as it was able to prevent the decrease in NKA activity caused by the Aβ1-42 oligomer administration [73]. GM1 administration was also shown to reduce the effects of hypoxia-reoxygenation in rat heart, as it was able to stabilize NKA activity which was decreased due to hypoxic conditions [74]. In addition, a complete correction of a decrease in NKA activity in nerve homogenates from diabetic rats treated with mixed bovine gangliosides was observed over a five-week period [75].

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Subjects: Biochemistry & Molecular Biology
Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :
Borna Puljko
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Mario Stojanović
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Katarina Ilic
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Svjetlana Kalanj-Bognar
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Kristina Mlinac-Jerkovic
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Update Date: 12 Jul 2022
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