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J. Biol. Chem., Vol. 278, Issue 26, 23594-23599, June 27, 2003

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

Emyr Lloyd-Evans  , Dori Pelled , Christian Riebeling  ¶, Jacques Bodennec  ||, Aviv de-Morgan , Helen Waller  **, Raphael Schiffmann  and Anthony H. Futerman  

From the Department of Biological Chemistry, Weizmann Institute of Science, Rehovot 76100, Israel and the Developmental and Metabolic Neurology Branch, NINDS, National Institutes of Health, Bethesda, Maryland 20892-1260

We recently demonstrated that elevation of intracellular glucosylceramide (GlcCer) levels results in increased functional Ca²⁺ 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 Ca²⁺ release from rat brain microsomes. GlcCer had no direct effect on Ca²⁺ release, but rather augmented agonist-stimulated Ca²⁺ release via RyaRs, through a mechanism that may involve the redox sensor of the RyaR, but had no effect on Ca²⁺ 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 Ca²⁺ mobilization from rat brain microsomes, but both galactosylsphingosine (psychosine) and glucosylsphingosine stimulated Ca²⁺ release, although only galactosylsphingosine mediated Ca²⁺ release via the RyaR. Finally, we demonstrated that GlcCer levels were 10-fold higher in microsomes prepared from the temporal lobe of a type 2 Gaucher disease patient compared with a control, and Ca²⁺ release via the RyaR was significantly elevated, which may be of relevance for explaining the pathophysiology of neuronopathic forms of Gaucher disease.

Received for publication, January 8, 2003 , and in revised form, April 14, 2003.

^* This work was supported by Israel Science Foundation Grant 290/00 and by the Children's Gaucher Research Fund (research{at}childrensgaucher.org). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Present address: Glycobiology Institute, Dept. of Biochemistry, University of Oxford, United Kingdom.

^¶ Supported by a Research Training Network fellowship from the European Union (HPRN-CT-2000-00077).

^|| Supported by a Koschland Scholar award.

^** Present address: Dept. of Experimental Psychology, University of Oxford, United Kingdom.

To whom correspondence should be addressed: Dept. of Biological Chemistry, Weizmann Institute of Science, Rehovot 76100, Israel. Tel.: 972-8-9342704; Fax: 972-8-9344112; E-mail: tony.futerman{at}weizmann.ac.il.

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