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Biophys. J. BioFAST: First Published March 24, 2006. doi:10.1529/biophysj.105.076570
© 2006 by the Biophysical Society.

A more recent version of this article appeared on June 15, 2006.
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CHANNELS, RECEPTORS, AND ELECTRICAL SIGNALING

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

Yutaka Hirata 1, Marco de Paula Brotto 1, Noah Weisleder 1, Yi Chu 1, Peihui Lin 1, Xiaoli Zhao 1, Angela Thornton 1, Shinji Komazaki 2, Hiroshi Takeshima 3, Jianjie Ma 1 and Zui Pan 1*

1 UMDNJ-Robert Wood Johnson Medical School, Dept. of Physiology and Biophysics
2 Department of Anatomy, Saitama Medical School
3 Department of Biochemistry, Tohoku University

* To whom correspondence should be addressed. E-mail: panzu{at}umdnj.edu.

Submitted on October 24, 2005
Revised on November 22, 2005
Accepted on 6 March 2006


  Abstract
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 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.

Key Words: CICR, SR Ca2+ stores, VICR, skinned skeletal muscle fiber, small hairpin interference RNA, triad junction




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Copyright © 2006 by the Biophysical Society.