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Uncoupling Store-Operated Ca²⁺ Entry and Altered Ca²⁺ Release from Sarcoplasmic Reticulum through Silencing of Junctophilin Genes

Yutaka Hirata ^*, Marco Brotto ^*, Noah Weisleder ^*, Yi Chu ^*, Peihui Lin ^*, Xiaoli Zhao ^*, Angela Thornton ^*, Shinji Komazaki , Hiroshi Takeshima , Jianjie Ma ^* and Zui Pan ^*

^* Department of Physiology and Biophysics, UMDNJ-Robert Wood Johnson Medical School, Piscataway, New Jersey 08854; Department of Anatomy, Saitama Medical School, Saitama 350-0495, Japan; and Department of Biochemistry, Tohoku University, Sendai 980-8575, Japan

Correspondence: Address reprint requests to Zui Pan, Dept. of Physiology and Biophysics, UMDNJ-Robert Wood Johnson Medical School, 683 Hoes Lane, Piscataway, NJ 08854. Tel.: 732-235-4509; Fax: 732-235-4483; E-mail: panzu{at}umdnj.edu.

Junctophilin (JP) mediates the close contact between cell surface and intracellular membranes in muscle cells ensuring efficient excitation-contraction coupling. Here we demonstrate that disruption of triad junction structure formed by the transverse tubular (TT) invagination of plasma membrane and terminal cisternae of sarcoplasmic reticulum (SR) by reduction of JP expression leads to defective Ca²⁺ homeostasis in muscle cells. Using adenovirus with small hairpin interference RNA (shRNA) against both JP1 and JP2 genes, we could achieve acute suppression of JPs in skeletal muscle fibers. The shRNA-treated muscles exhibit deformed triad junctions and reduced store-operated Ca²⁺ entry (SOCE), which is likely due to uncoupled retrograde signaling from SR to TT. Knockdown of JP also causes a reduction in SR Ca²⁺ storage and altered caffeine-induced Ca²⁺ release, suggesting an orthograde regulation of the TT membrane on the SR Ca²⁺ release machinery. Our data demonstrate that JPs play an important role in controlling overall intracellular Ca²⁺ homeostasis in muscle cells. We speculate that altered expression of JPs may underlie some of the phenotypic changes associated with certain muscle diseases and aging.

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