Journal article
The ryanodine receptor store-sensing gate controls Ca2+ waves and Ca2+-triggered arrhythmias
Nature medicine, Vol.20(2), pp.184-192
02/2014
DOI: 10.1038/nm.3440
PMCID: PMC4269524
PMID: 24441828
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.
Details
- Title: Subtitle
- The ryanodine receptor store-sensing gate controls Ca2+ waves and Ca2+-triggered arrhythmias
- Creators
- Wenqian Chen - Libin Cardiovascular Institute of AlbertaRuiwu Wang - Libin Cardiovascular Institute of AlbertaBiyi Chen - University of IowaXiaowei Zhong - Libin Cardiovascular Institute of AlbertaHuihui Kong - Libin Cardiovascular Institute of AlbertaYunlong Bai - Libin Cardiovascular Institute of AlbertaQiang Zhou - Libin Cardiovascular Institute of AlbertaCuihong Xie - Libin Cardiovascular Institute of AlbertaJingqun Zhang - Rush University Medical CenterAng Guo - University of IowaXixi Tian - Libin Cardiovascular Institute of AlbertaPeter P Jones - Libin Cardiovascular Institute of AlbertaMegan L O'Mara - University of CalgaryYingjie Liu - Libin Cardiovascular Institute of AlbertaTao Mi - Libin Cardiovascular Institute of AlbertaLin Zhang - Libin Cardiovascular Institute of AlbertaJeff Bolstad - Libin Cardiovascular Institute of AlbertaLisa Semeniuk - Libin Cardiovascular Institute of AlbertaHongqiang Cheng - University of California San DiegoJianlin Zhang - University of California San DiegoJu Chen - University of California San DiegoD Peter Tieleman - University of CalgaryAnne M Gillis - Libin Cardiovascular Institute of AlbertaHenry J Duff - Libin Cardiovascular Institute of AlbertaMichael Fill - Rush University Medical CenterLong-Sheng Song - University of IowaS R Wayne Chen - Libin Cardiovascular Institute of Alberta
- Resource Type
- Journal article
- Publication Details
- Nature medicine, Vol.20(2), pp.184-192
- DOI
- 10.1038/nm.3440
- PMID
- 24441828
- PMCID
- PMC4269524
- NLM abbreviation
- Nat Med
- ISSN
- 1078-8956
- eISSN
- 1546-170X
- Grant note
- R01 HL066100 / NHLBI NIH HHS R01 HL090905 / NHLBI NIH HHS R01 HL082902 / NHLBI NIH HHS R01 HL106968 / NHLBI NIH HHS CIHR
- Language
- English
- Date published
- 02/2014
- Academic Unit
- Cardiovascular Medicine; Fraternal Order of Eagles Diabetes Research Center; Biochemistry and Molecular Biology; Internal Medicine
- Record Identifier
- 9984288718802771
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