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Originally published In Press as doi:10.1074/jbc.M300212200 on April 22, 2003
J. Biol. Chem., Vol. 278, Issue 26, 23594-23599, June 27, 2003
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, 2167321678). 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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Copyright © 2003 by the American Society for Biochemistry and Molecular Biology.
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