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Dysregulated Zn2+ homeostasis impairs cardiac type-2 ryanodine receptor and mitsugumin 23 functions, leading to sarcoplasmic reticulum Ca2+ leakage
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dc.contributor.author | Reilly-O'Donnell, Benedict | |
dc.contributor.author | Robertson, Gavin B. | |
dc.contributor.author | Karumbi, Angela | |
dc.contributor.author | McIntyre, Connor | |
dc.contributor.author | Bal, Wojciech | |
dc.contributor.author | Nishi, Miyuki | |
dc.contributor.author | Takeshima, Hiroshi | |
dc.contributor.author | Stewart, Alan J. | |
dc.contributor.author | Pitt, Samantha J. | |
dc.date.accessioned | 2017-07-11T12:30:08Z | |
dc.date.available | 2017-07-11T12:30:08Z | |
dc.date.issued | 2017-08-11 | |
dc.identifier | 250269520 | |
dc.identifier | 224af10c-5e50-415a-9524-25b8d75dbd9d | |
dc.identifier | 85027420232 | |
dc.identifier | 000407465300022 | |
dc.identifier.citation | Reilly-O'Donnell , B , Robertson , G B , Karumbi , A , McIntyre , C , Bal , W , Nishi , M , Takeshima , H , Stewart , A J & Pitt , S J 2017 , ' Dysregulated Zn 2+ homeostasis impairs cardiac type-2 ryanodine receptor and mitsugumin 23 functions, leading to sarcoplasmic reticulum Ca 2+ leakage ' , Journal of Biological Chemistry , vol. 292 , no. 32 , pp. 13361-13373 . https://doi.org/10.1074/jbc.M117.781708 | en |
dc.identifier.issn | 0021-9258 | |
dc.identifier.other | ORCID: /0000-0003-4580-1840/work/60195784 | |
dc.identifier.other | ORCID: /0000-0003-2257-1595/work/60196223 | |
dc.identifier.uri | https://hdl.handle.net/10023/11181 | |
dc.description | SJP is supported by a Royal Society of Edinburgh Biomedical Fellowship. Benedict Reilly-O’Donnell is supported by a University of St Andrews 600th Anniversary Scholarship. This work was supported by the British Heart Foundation (grant no: FS/14/69/31001 to SJP) and the Japan Society for the Promotion of Science (Core-to-Core Program awarded to HT). | en |
dc.description.abstract | Aberrant Zn2+ homeostasis is associated with dysregulated intracellular Ca2+ release, resulting in chronic heart failure. In the failing heart a small population of cardiac ryanodine receptors (RyR2) displays sub-conductance-state gating leading to Ca2+ leakage from sarcoplasmic reticulum (SR) stores, which impairs cardiac contractility. Previous evidence suggests contribution of RyR2-independent Ca2+ leakage through an uncharacterized mechanism. We sought to examine the role of Zn2+ in shaping intracellular Ca2+ release in cardiac muscle. Cardiac SR vesicles prepared from sheep or mouse ventricular tissue were incorporated into phospholipid bilayers under voltage-clamp conditions, and the direct action of Zn2+ on RyR2 channel function was examined. Under diastolic conditions, the addition of pathophysiological concentrations of Zn2+ (≥2 nm) caused dysregulated RyR2-channel openings. Our data also revealed that RyR2 channels are not the only SR Ca2+-permeable channels regulated by Zn2+. Elevating the cytosolic Zn2+ concentration to 1 nm increased the activity of the transmembrane protein mitsugumin 23 (MG23). The current amplitude of the MG23 full-open state was consistent with that previously reported for RyR2 sub-conductance gating, suggesting that in heart failure in which Zn2+ levels are elevated, RyR2 channels do not gate in a sub-conductance state, but rather MG23-gating becomes more apparent. We also show that in H9C2 cells exposed to ischemic conditions, intracellular Zn2+ levels are elevated, coinciding with increased MG23 expression. In conclusion, these data suggest that dysregulated Zn2+ homeostasis alters the function of both RyR2 and MG23 and that both ion channels play a key role in diastolic SR Ca2+ leakage. | |
dc.format.extent | 13 | |
dc.format.extent | 2725663 | |
dc.language.iso | eng | |
dc.relation.ispartof | Journal of Biological Chemistry | en |
dc.subject | Calcium | en |
dc.subject | Heart failure | en |
dc.subject | MG23 | en |
dc.subject | RyR2 | en |
dc.subject | Zinc | en |
dc.subject | QD Chemistry | en |
dc.subject | QH301 Biology | en |
dc.subject | RC Internal medicine | en |
dc.subject | NDAS | en |
dc.subject | BDC | en |
dc.subject.lcc | QD | en |
dc.subject.lcc | QH301 | en |
dc.subject.lcc | RC | en |
dc.title | Dysregulated Zn2+ homeostasis impairs cardiac type-2 ryanodine receptor and mitsugumin 23 functions, leading to sarcoplasmic reticulum Ca2+ leakage | en |
dc.type | Journal article | en |
dc.contributor.sponsor | The Royal Society of Edinburgh | en |
dc.contributor.institution | University of St Andrews. School of Medicine | en |
dc.contributor.institution | University of St Andrews. Institute of Behavioural and Neural Sciences | en |
dc.contributor.institution | University of St Andrews. Biomedical Sciences Research Complex | en |
dc.contributor.institution | University of St Andrews. Cellular Medicine Division | en |
dc.identifier.doi | https://doi.org/10.1074/jbc.M117.781708 | |
dc.description.status | Peer reviewed | en |
dc.identifier.url | http://www.jbc.org/content/early/2017/06/19/jbc.M117.781708/suppl/DC1 | en |
dc.identifier.grantnumber | en |
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