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Dysregulated Zn2+ homeostasis impairs cardiac type-2 ryanodine receptor and mitsugumin 23 functions, leading to sarcoplasmic reticulum Ca2+ leakage

Research output: Contribution to journalArticle

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Dysregulated Zn2+ homeostasis impairs cardiac type-2 ryanodine receptor and mitsugumin 23 functions, leading to sarcoplasmic reticulum Ca2+ leakage. / Reilly-O'Donnell, Benedict; Robertson, Gavin B.; Karumbi, Angela; McIntyre, Connor; Bal, Wojciech; Nishi, Miyuki ; Takeshima, Hiroshi; Stewart, Alan J.; Pitt, Samantha J.

In: Journal of Biological Chemistry, Vol. 292, No. 32, 11.08.2017, p. 13361-13373.

Research output: Contribution to journalArticle

Harvard

Reilly-O'Donnell, B, Robertson, GB, Karumbi, A, McIntyre, C, Bal, W, Nishi, M, Takeshima, H, Stewart, AJ & Pitt, SJ 2017, 'Dysregulated Zn2+ homeostasis impairs cardiac type-2 ryanodine receptor and mitsugumin 23 functions, leading to sarcoplasmic reticulum Ca2+ leakage' Journal of Biological Chemistry, vol. 292, no. 32, pp. 13361-13373. https://doi.org/10.1074/jbc.M117.781708

APA

Reilly-O'Donnell, B., Robertson, G. B., Karumbi, A., McIntyre, C., Bal, W., Nishi, M., ... Pitt, S. J. (2017). Dysregulated Zn2+ homeostasis impairs cardiac type-2 ryanodine receptor and mitsugumin 23 functions, leading to sarcoplasmic reticulum Ca2+ leakage. Journal of Biological Chemistry, 292(32), 13361-13373. https://doi.org/10.1074/jbc.M117.781708

Vancouver

Reilly-O'Donnell B, Robertson GB, Karumbi A, McIntyre C, Bal W, Nishi M et al. Dysregulated Zn2+ homeostasis impairs cardiac type-2 ryanodine receptor and mitsugumin 23 functions, leading to sarcoplasmic reticulum Ca2+ leakage. Journal of Biological Chemistry. 2017 Aug 11;292(32):13361-13373. https://doi.org/10.1074/jbc.M117.781708

Author

Reilly-O'Donnell, Benedict ; Robertson, Gavin B. ; Karumbi, Angela ; McIntyre, Connor ; Bal, Wojciech ; Nishi, Miyuki ; Takeshima, Hiroshi ; Stewart, Alan J. ; Pitt, Samantha J. / Dysregulated Zn2+ homeostasis impairs cardiac type-2 ryanodine receptor and mitsugumin 23 functions, leading to sarcoplasmic reticulum Ca2+ leakage. In: Journal of Biological Chemistry. 2017 ; Vol. 292, No. 32. pp. 13361-13373.

Bibtex - Download

@article{224af10c5e50415a952425b8d75dbd9d,
title = "Dysregulated Zn2+ homeostasis impairs cardiac type-2 ryanodine receptor and mitsugumin 23 functions, leading to sarcoplasmic reticulum Ca2+ leakage",
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) display 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+ (≥2nM) 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.",
keywords = "Calcium, Heart failure, MG23, RyR2, Zinc",
author = "Benedict Reilly-O'Donnell and Robertson, {Gavin B.} and Angela Karumbi and Connor McIntyre and Wojciech Bal and Miyuki Nishi and Hiroshi Takeshima and Stewart, {Alan J.} and Pitt, {Samantha J.}",
note = "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).",
year = "2017",
month = "8",
day = "11",
doi = "10.1074/jbc.M117.781708",
language = "English",
volume = "292",
pages = "13361--13373",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC",
number = "32",

}

RIS (suitable for import to EndNote) - Download

TY - JOUR

T1 - Dysregulated Zn2+ homeostasis impairs cardiac type-2 ryanodine receptor and mitsugumin 23 functions, leading to sarcoplasmic reticulum Ca2+ leakage

AU - Reilly-O'Donnell, Benedict

AU - Robertson, Gavin B.

AU - Karumbi, Angela

AU - McIntyre, Connor

AU - Bal, Wojciech

AU - Nishi, Miyuki

AU - Takeshima, Hiroshi

AU - Stewart, Alan J.

AU - Pitt, Samantha J.

N1 - 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).

PY - 2017/8/11

Y1 - 2017/8/11

N2 - 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) display 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+ (≥2nM) 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.

AB - 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) display 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+ (≥2nM) 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.

KW - Calcium

KW - Heart failure

KW - MG23

KW - RyR2

KW - Zinc

UR - http://www.jbc.org/content/early/2017/06/19/jbc.M117.781708/suppl/DC1

U2 - 10.1074/jbc.M117.781708

DO - 10.1074/jbc.M117.781708

M3 - Article

VL - 292

SP - 13361

EP - 13373

JO - Journal of Biological Chemistry

T2 - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 32

ER -

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ID: 250269520