- Chen, Wenqian;
- Wang, Ruiwu;
- Chen, Biyi;
- Zhong, Xiaowei;
- Kong, Huihui;
- Bai, Yunlong;
- Zhou, Qiang;
- Xie, Cuihong;
- Zhang, Jingqun;
- Guo, Ang;
- Tian, Xixi;
- Jones, Peter P;
- O'Mara, Megan L;
- Liu, Yingjie;
- Mi, Tao;
- Zhang, Lin;
- Bolstad, Jeff;
- Semeniuk, Lisa;
- Cheng, Hongqiang;
- Zhang, Jianlin;
- Chen, Ju;
- Tieleman, D Peter;
- Gillis, Anne M;
- Duff, Henry J;
- Fill, Michael;
- Song, Long-Sheng;
- Chen, SR Wayne
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.