The ryanodine receptor store-sensing gate controls Ca2+ waves and Ca2+-triggered arrhythmias

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 and Chen, S. R. Wayne (2014) The ryanodine receptor store-sensing gate controls Ca2+ waves and Ca2+-triggered arrhythmias. Nature Medicine, 20 2: 184-192. doi:10.1038/nm.3440


Author 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, S. R. Wayne
Title The ryanodine receptor store-sensing gate controls Ca2+ waves and Ca2+-triggered arrhythmias
Formatted title
The ryanodine receptor store-sensing gate controls Ca2+ waves and Ca2+-triggered arrhythmias
Journal name Nature Medicine   Check publisher's open access policy
ISSN 1078-8956
1546-170X
Publication date 2014-02-01
Year available 2014
Sub-type Article (original research)
DOI 10.1038/nm.3440
Volume 20
Issue 2
Start page 184
End page 192
Total pages 9
Place of publication New York, NY, United States
Publisher Nature Publishing Group
Language eng
Formatted abstract
Spontaneous Ca2+ release from intracellular stores is important for various physiological and pathological processes. In cardiac muscle cells, spontaneous store overload–induced Ca2+ release (SOICR) can result in Ca2+ 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, Ca2+ activation of RyR2. The introduction of metal-binding histidines at this site converts RyR2 into a luminal Ni2+-gated channel. Mouse hearts harboring a heterozygous RyR2 mutation at this site (E4872Q) are resistant to SOICR and are completely protected against Ca2+-triggered VTs. These data show that the RyR2 gate directly senses luminal (store) Ca2+, explaining the regulation of RyR2 by luminal Ca2+, the initiation of Ca2+ waves and Ca2+-triggered arrhythmias. This newly identified store-sensing gate structure is conserved in all RyR and inositol 1,4,5-trisphosphate receptor isoforms.
Keyword Biochemistry & Molecular Biology
Cell Biology
Medicine, Research & Experimental
Biochemistry & Molecular Biology
Cell Biology
Research & Experimental Medicine
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Non HERDC
School of Chemistry and Molecular Biosciences
 
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Created: Fri, 14 Feb 2014, 00:04:32 EST by Dr Megan O'mara on behalf of School of Chemistry & Molecular Biosciences