Chen, WenqianWang, RuiwuChen, BiyiZhong, XiaoweiKong, HuihuiBai, YunlongZhou, QiangXie, CuihongZhang, JingqunGuo, AngTian, XixiJones, Peter PO'Mara, MeganLiu, YingjieMi, TaoZhang, LinBolstad, JeffSemeniuk, LisaCheng, HongqiangZhang, JianlinChen, JuTieleman, D. PeterGillis, Anne MDuff, Henry JFill, MichaelSong, Long-ShengChen, S R Wayne2015-12-101078-8956http://hdl.handle.net/1885/63730Spontaneous 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.201410.1038/nm.34402015-12-10