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J. Biol. Chem., Vol. 279, Issue 45, 47092-47100, November 5, 2004

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Involvement of Inositol 1,4,5-Trisphosphate in Nicotinic Calcium Responses in Dystrophic Myotubes Assessed by Near-plasma Membrane Calcium Measurement^*

Olivier Basset, François-Xavier Boittin, Olivier M. Dorchies, Jean-Yves Chatton, Cornelis van Breemen¶, and Urs T. Ruegg||

From the Pharmacology Laboratory, School of Pharmacy, University of Lausanne-Geneva, 1211 Geneva, Switzerland, the Department of Physiology and Cellular Imaging Facility, University of Lausanne, 1005 Lausanne, Switzerland, and the ^¶Department of Pharmacology and Therapeutics, University of British Columbia, Vancouver, British Columbia V6T 1Z1, Canada

In skeletal muscle cells, plasma membrane depolarization causes a rapid calcium release from the sarcoplasmic reticulum through ryanodine receptors triggering contraction. In Duchenne muscular dystrophy (DMD), a lethal disease that is caused by the lack of the cytoskeletal protein dystrophin, the cytosolic calcium concentration is known to be increased, and this increase may lead to cell necrosis. Here, we used myotubes derived from control and mdx mice, the murine model of DMD, to study the calcium responses induced by nicotinic acetylcholine receptor stimulation. The photoprotein aequorin was expressed in the cytosol or targeted to the plasma membrane as a fusion protein with the synaptosome-associated protein SNAP-25, thus allowing calcium measurements in a restricted area localized just below the plasma membrane. The carbachol-induced calcium responses were 4.5 times bigger in dystrophic myotubes than in control myotubes. Moreover, in dystrophic myotubes the carbachol-mediated calcium responses measured in the subsarcolemmal area were at least 10 times bigger than in the bulk cytosol. The initial calcium responses were due to calcium influx into the cells followed by a fast refilling/release phase from the sarcoplasmic reticulum. In addition and unexpectedly, the inositol 1,4,5-trisphosphate receptor pathway was involved in these calcium signals only in the dystrophic myotubes. This surprising involvement of this calcium release channel in the excitation-contraction coupling could open new ways for understanding exercise-induced calcium increases and downstream muscle degeneration in mdx mice and, therefore, in DMD.

Received for publication, May 6, 2004 , and in revised form, August 17, 2004.

^* This work was supported by Swiss National Science Foundation Grant 31-68315.02 and by grants from the Swiss Foundation for Research on Muscular Diseases and the Association Française contre les Myopathies. 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 should be addressed. Tel.: 4122-379-3429; Fax: 4122-379-3430; E-mail: Urs.Ruegg{at}pharm.unige.ch.

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