Glucosylceramide and Glucosylsphingosine Modulate Calcium Mobilization from Brain Microsomes via Different Mechanisms

Abstract

We recently demonstrated that elevation of intracellular glucosylceramide (GlcCer) levels results in increased functional Ca 2؉ stores in cultured neurons, and suggested that this may be due to modulation of ryanodine receptors (RyaRs) by GlcCer (Korkotian, E., Schwarz, A., Pelled, D., Schwarzmann, G., Segal, M. and Futerman, A. H. (1999) J. Biol. Chem. 274, 21673-21678). We now systematically examine the effects of exogenously added GlcCer, other glycosphingolipids (GSLs) and their lyso-derivatives on Ca 2؉ release from rat brain microsomes. GlcCer had no direct effect on Ca 2؉ release, but rather augmented agonist-stimulated Ca 2؉ release via RyaRs, through a mechanism that may involve the redox sensor of the RyaR, but had no effect on Ca 2؉ release via inositol 1,4,5-trisphosphate receptors. Other GSLs and sphingolipids, including galactosylceramide, lactosylceramide, ceramide, sphingomyelin, sphingosine 1-phosphate, sphinganine 1-phosphate, and sphingosylphosphorylcholine had no effect on Ca 2؉ mobilization from rat brain microsomes, but both galactosylsphingosine (psychosine) and glucosylsphingosine stimulated Ca 2؉ release, although only galactosylsphingosine mediated Ca 2؉ release via the RyaR. Finally, we demonstrated that GlcCer levels were ϳ10-fold higher in microsomes prepared from the temporal lobe of a type 2 Gaucher disease patient compared with a control, and Ca 2؉ release via the RyaR was significantly elevated, which may be of relevance for explaining the pathophysiology of neuronopathic forms of Gaucher disease.

CNS expression of glucocerebrosidase corrects α-synuclein pathology and memory in a mouse model of Gaucher-related synucleinopathy

“…The divergent genotype-phenotype correlation between human Gaucher and mouse models has been previously documented (28). GlcSph is a putative neurotoxin that can affect neuronal calcium mobilization (2,37) and might contribute to the development of cognitive deficits in Gba1 D409V/D409V mice. The Gaucher Gba1 D409V/D409V mouse model, recapitulating some of the cardinal features of synucleinopathies, is a valuable tool to address questions of disease mechanism and potential therapy.…”

Unbiased Cell-based Screening in a Neuronal Cell Model of Batten Disease Highlights an Interaction between Ca2+ Homeostasis, Autophagy, and CLN3 Protein Function

“…Notably, we did not observe a significantly altered sensitivity to cell death of the CbCln3 ⌬ex7/8/⌬ex7/8 cells to low dose thapsigargin treatment compared with wild type cells, perhaps due to the changes we observed in the other intracellular Ca 2ϩ stores, which may serve to protect the cells from Ca 2ϩ -mediated excitotoxicity. Chronic CLN3 loss-of-function has also been reported to alter lipid microdomain architecture, which may influence Ca 2ϩ channel complex formation and activity, and it has been demonstrated that glycolipids, such as the gangliosides, can alter SERCA activity (9,24,44,60,61). Hence, future work delineating the role of CLN3 in regulating lipids may shed further light on the altered Ca 2ϩ handling observed in CLN3-deficient cells.…”

Glucosylsphingosine Induces Itch-Scratch Responses in Mice

“…It is not clear what mechanism is involved in the Gsp-induced ISRs. One possibility is from that Gsp mobilized the calcium via a mechanism independent of ryanodine receptor (Lloyd-Evans et al, 2003). Therefore calcium mobilization by Gsp might induce the scratch response.…”