Title |
The ryanodine receptor store-sensing gate controls Ca2+ waves and Ca2+-triggered arrhythmias
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Published in |
Nature Medicine, January 2014
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DOI | 10.1038/nm.3440 |
Pubmed ID | |
Authors |
Wenqian Chen, Ruiwu Wang, Biyi Chen, Xiaowei Zhong, Huihui Kong, Yunlong Bai, Qiang Zhou, Cuihong Xie, Jingqun Zhang, Ang Guo, Xixi Tian, Peter P Jones, Megan L O'Mara, Yingjie Liu, Tao Mi, Lin Zhang, Jeff Bolstad, Lisa Semeniuk, Hongqiang Cheng, Jianlin Zhang, Ju Chen, D Peter Tieleman, Anne M Gillis, Henry J Duff, Michael Fill, Long-Sheng Song, S R Wayne Chen |
Abstract |
Spontaneous Ca(2+) release from intracellular stores is important for various physiological and pathological processes. In cardiac muscle cells, spontaneous store overload-induced Ca(2+) release (SOICR) can result in Ca(2+) waves, a major cause of ventricular tachyarrhythmias (VTs) and sudden death. The molecular mechanism underlying SOICR has been a mystery for decades. Here we show that a point mutation, E4872A, in the helix bundle crossing region (the proposed gate) of the cardiac ryanodine receptor (RyR2) completely abolishes luminal, but not cytosolic, Ca(2+) activation of RyR2. The introduction of metal-binding histidines at this site converts RyR2 into a luminal Ni(2+)-gated channel. Mouse hearts harboring a heterozygous RyR2 mutation at this site (E4872Q) are resistant to SOICR and are completely protected against Ca(2+)-triggered VTs. These data show that the RyR2 gate directly senses luminal (store) Ca(2+), explaining the regulation of RyR2 by luminal Ca(2+), the initiation of Ca(2+) waves and Ca(2+)-triggered arrhythmias. This newly identified store-sensing gate structure is conserved in all RyR and inositol 1,4,5-trisphosphate receptor isoforms. |
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