Effects of gangliosides on the activity of the plasma membrane Ca2+-ATPase

Abstract

Control of intracellular calcium concentrations ([Ca2+]i) is essential for neuronal function, and the plasma membrane Ca2+-ATPase (PMCA) is crucial for the maintenance of low [Ca2+]i. We previously reported on loss of PMCA activity in brain synaptic membranes during aging. Gangliosides are known to modulate Ca2+ homeostasis and signal transduction in neurons. In the present study, we observed age-related changes in the ganglioside composition of synaptic plasma membranes. This led us to hypothesize that alterations in ganglioside species might contribute to the age-associated loss of PMCA activity. To probe the relationship between changes in endogenous ganglioside content or composition and PMCA activity in membranes of cortical neurons, we induced depletion of gangliosides by treating neurons with D-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (D-PDMP). This caused a marked decrease in the activity of PMCA, which suggested a direct correlation between ganglioside content and PMCA activity. Neurons treated with neuraminidase exhibited an increase in GM1 content, a loss in poly-sialoganglioside content, and a decrease in PMCA activity that was greater than that produced by D-PDMP treatment. Thus, it appeared that poly-sialogangliosides had a stimulatory effect whereas mono-sialogangliosides had the opposite effect. Our observations add support to previous reports of PMCA regulation by gangliosides by demonstrating that manipulations of endogenous ganglioside content and species affect the activity of PMCA in neuronal membranes. Furthermore, our studies suggest that age-associated loss in PMCA activity may result in part from changes in the lipid environment of this Ca2+ transporter.

Regulation of Membrane Calcium Transport Proteins by the Surrounding Lipid Environment

“…For the latter, the inhibition was shown to be induced by the Tau protein, whose effect surprisingly decreases with aging. Interestingly, age-dependent changes in ganglioside total content and species were observed in rat brain synaptic PMs, with an important increase of the monosialoganglioside GM1, without any modification of the fatty acid composition [237]. These findings are consistent with the age-associated, high-density clustering of GM1 at presynaptic terminals reported previously [342].…”

“…SLs, and especially gangliosides, modulate PMCA activity in a complex pattern. Indeed, in cortical neurons and synaptosomes, polysialogangliosides (e.g., GD1b) stimulate, monosialogangliosides (e.g., GM1) slightly reduce the activity, and non-sialogangliosides (e.g., asialo-GM1) markedly inhibit PMCA2 and 3, predominant in those cells [237,238]. Thus, the sialic acid residues of gangliosides are important for the modulation of PMCA.…”

Gangliosides in the Brain: Physiology, Pathophysiology and Therapeutic Applications

“…Enrichment of the plasma membrane with GM1 resulting from the activity of neuraminidase 3 (NEU3) – a ganglioside-specific sialidase that converts GD1a and GT1b to GM1 – was shown to trigger Ca 2+ influx in neuronal cells through T-type calcium channels, and to induce neuritogenesis ( Wu and Ledeen, 1994 ). In contrast, polysialogangliosides increase, while GM1 decreases the activity of the plasma membrane Ca 2+ -ATPase (PMCA) ( Jiang et al, 2014 ; Huang et al, 2015 ), a transporter that regulates neuronal Ca 2+ homeostasis by exporting cytosolic Ca 2+ to the extracellular environment ( Garcia and Strehler, 1999 ).…”

Sphingolipids and Cell Signaling: Relationship Between Health and Disease in the Central Nervous System

“…Figure 1 summarizes the sphingolipids biosynthetic pathway. GM1 and the GSLs GD1a, GD1b, GT1b, and GQ1b constitute up to 95% of all gangliosides in the brain [7,31] and represent 20-25% of the outer leaflet of neuron membranes [32]. Although these chemical reactions are usually limited to the membrane organelles, the sialyltransferase has been found as membrane-associated enzymes suggesting pivotal roles in the GSL remodeling [33][34][35].…”