Start Me Up: How Can Surrounding Gangliosides Affect Sodium-Potassium ATPase Activity and Steer towards Pathological Ion Imbalance in Neurons?

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. Impaired Na+/K+-ATPase activity has also been hypothesized to cause seizures by several mechanisms. In this review we present different epileptic phenotypes that are caused by impaired activity of Na+/K+-ATPase or changed membrane ganglioside composition. We further discuss how gangliosides may influence Na+/K+-ATPase activity by acting as lipid sorting machinery providing the optimal stage for Na+/K+-ATPase function. By establishing a distinct lipid environment, together with other membrane lipids, gangliosides possibly modulate Na+/K+-ATPase activity and aid in "starting up" and "turning off" this vital pump. Therefore, structural changes of neuronal membranes caused by altered ganglioside composition can be a contributing factor leading to aberrant Na+/K+-ATPase activity and ion imbalance priming neurons for pathological firing.

Plasma Membrane Calcium ATPase-Neuroplastin Complexes Are Selectively Stabilized in GM1-Containing Lipid Rafts.

The recent identification of plasma membrane (Ca2+)-ATPase (PMCA)-Neuroplastin (Np) complexes has renewed attention on cell regulation of cytosolic calcium extrusion, which is of particular relevance in neurons. Here, we tested the hypothesis that PMCA-Neuroplastin complexes exist in specific ganglioside-containing rafts, which could affect calcium homeostasis. We analyzed the abundance of all four PMCA paralogs (PMCA1-4) and Neuroplastin isoforms (Np65 and Np55) in lipid rafts and bulk membrane fractions from GM2/GD2 synthase-deficient mouse brains. In these fractions, we found altered distribution of Np65/Np55 and selected PMCA isoforms, namely PMCA1 and 2. Cell surface staining and confocal microscopy identified GM1 as the main complex ganglioside co-localizing with Neuroplastin in cultured hippocampal neurons. Furthermore, blocking GM1 with a specific antibody resulted in delayed calcium restoration of electrically evoked calcium transients in the soma of hippocampal neurons. The content and composition of all ganglioside species were unchanged in Neuroplastin-deficient mouse brains. Therefore, we conclude that altered composition or disorganization of ganglioside-containing rafts results in changed regulation of calcium signals in neurons. We propose that GM1 could be a key sphingolipid for ensuring proper location of the PMCA-Neuroplastin complexes into rafts in order to participate in the regulation of neuronal calcium homeostasis.