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J. Biol. Chem., Vol. 278, Issue 52, 52755-52762, December 26, 2003

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Wolframin Expression Induces Novel Ion Channel Activity in Endoplasmic Reticulum Membranes and Increases Intracellular Calcium^*

Abdullah A. Osman, Mitsuyoshi Saito, Carol Makepeace, M. Alan Permutt, Paul Schlesinger¶, and Mike Mueckler

From the Department of Cell Biology and Physiology and Department of Medicine, Washington University School of Medicine, St. Louis, Missouri 63110

Wolfram syndrome is an autosomal recessive neuro-degenerative disorder associated with juvenile onset non-autoimmune diabetes mellitus and progressive optic atrophy. The disease has been attributed to mutations in the WFS1 gene, which codes for a protein predicted to possess 9–10 transmembrane segments. Little is known concerning the function of the WFS1 protein (wolframin). Endoglycosidase H digestion, immunocytochemistry, and subcellular fractionation studies all indicated that wolframin is localized to the endoplasmic reticulum in rat brain hippocampus and rat pancreatic islet -cells, and after ectopic expression in Xenopus oocytes. Reconstitution of wolframin from oocyte membranes into planar lipid bilayers demonstrated that the protein induced a large cation-selective ion channel that was blocked by Mg²⁺ or Ca²⁺. Inositol triphosphate was capable of activating channels in the fused bilayers that were similar to channel components induced by wolframin expression. Expression of wolframin also increased cytosolic calcium levels in oocytes. Wolframin thus appears to be important in the regulation of intracellular Ca²⁺ homeostasis. Disruption of this function may place cells at risk to suffer inappropriate death decisions, thus accounting for the progressive -cell loss and neuronal degeneration associated with the disease.

Received for publication, September 17, 2003

^* This work was supported in part by National Institutes of Health Grants DK38495 (to M. M.), AR46539 (to P. S.), and DK16746 (to M. A. P.). 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.

^¶ To whom correspondence and reprint requests should be addressed: Dept. of Cell Biology and Physiology, Washington University School of Medicine, 660 S. Euclid Ave., St. Louis, MO 63110. Tel.: 314-362-2223; Fax: 314-362-7463; E-mail: paul{at}cellbio.wustl.edu.

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