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Nat Med. 2014 Feb;20(2):184-92. doi: 10.1038/nm.3440. Epub 2014 Jan 19.

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

Author information

1
The Libin Cardiovascular Institute of Alberta, Department of Physiology and Pharmacology, University of Calgary, Calgary, Alberta, Canada.
2
Division of Cardiovascular Medicine, Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA.
3
1] The Libin Cardiovascular Institute of Alberta, Department of Physiology and Pharmacology, University of Calgary, Calgary, Alberta, Canada. [2].
4
Department of Molecular Biophysics and Physiology, Rush University Medical Center, Chicago, Illinois, USA.
5
Department of Biological Sciences and Institute for Biocomplexity and Informatics, University of Calgary, Calgary, Alberta, Canada.
6
1] Department of Medicine, University of California at San Diego, La Jolla, California, USA. [2].
7
Department of Medicine, University of California at San Diego, La Jolla, California, USA.
8
1] The Libin Cardiovascular Institute of Alberta, Department of Physiology and Pharmacology, University of Calgary, Calgary, Alberta, Canada. [2] Department of Molecular Biophysics and Physiology, Rush University Medical Center, Chicago, Illinois, USA.

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.

PMID:
24441828
PMCID:
PMC4269524
DOI:
10.1038/nm.3440
[Indexed for MEDLINE]
Free PMC Article
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