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Mitsugumin 23 is a putative zinc regulated sarcoplasmic reticulum calcium leak channel
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dc.contributor.advisor | Pitt, Samantha Jane | |
dc.contributor.author | Dorward, Amy | |
dc.coverage.spatial | xxviii, 364 p. | en_US |
dc.date.accessioned | 2021-11-26T13:01:31Z | |
dc.date.available | 2021-11-26T13:01:31Z | |
dc.date.issued | 2022-06-17 | |
dc.identifier.uri | https://hdl.handle.net/10023/24409 | |
dc.description.abstract | Cardiac ion homeostasis is vital for efficient cardiac function. Intracellular Ca²⁺ dyshomeostasis and sarcoplasmic reticulum (SR) Ca²⁺ leak are considered hallmarks of heart failure. Disrupted intracellular Zn²⁺ signalling is also prevalent in heart failure, with raised Zn²⁺ levels observed in cardiomyocytes under ischaemic conditions. Adverse effects of elevated Zn²⁺ levels on cardiac function are widely reported, including reduced contractile force and aberrant Ca²⁺ handling. The molecular mechanisms linking dysregulated Zn²⁺ and Ca²⁺ signalling remain poorly understood. MG23 is a newly identified, Ca²⁺-permeable cation channel located on the SR/endoplasmic reticulum. Recently, the activity of MG23 was shown to be modulated by pathological [Zn²⁺]. The aim of this project was to investigate the role of MG23 as a Zn²⁺-regulated Ca²⁺ leak channel and to determine how altered [Zn²⁺] shapes intracellular Ca²⁺ dynamics. Using isolated mouse cardiomyocytes, this study showed that MG23 protein expression increased following hypoxia (≤ 1% O₂; 3-24 hours). Live cell imaging demonstrated that intracellular Zn²⁺ levels are elevated in cells exposed to hypoxia, coinciding with a significant reduction in SR Ca²⁺ levels. Decreased SR Ca²⁺ was not observed following treatment with Zn²⁺-chelator TPEN at early hypoxic time points (3 hours). Strikingly, decreased SR Ca²⁺ content was not observed in cardiomyocytes isolated from Mg23-KO hearts until 24 hours hypoxia. This provides the first evidence that MG23 activity is regulated by Zn²⁺ leading to increased SR Ca²⁺ leak. In heart failure, intracellular [Zn²⁺] is elevated to levels that increase MG23 activity. This study reveals that Zn²⁺ modulation of MG23 occurs across multiple species including mouse and human. Glutamic acid residue 79 in human MG23 was identified as a potential site for controlling Zn²⁺ modulation of channel activity. MG23 may therefore be a novel target in the design of therapeutic interventions for treatment of heart failure where SR Ca²⁺ leak is exacerbated. | en_US |
dc.description.sponsorship | "This work was supported by the British Heart Foundation [reference FS/17/9/32676]." -- Funding | en |
dc.language.iso | en | en_US |
dc.publisher | University of St Andrews | |
dc.rights | Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International | * |
dc.rights.uri | http://creativecommons.org/licenses/by-nc-nd/4.0/ | * |
dc.subject | Calcium | en_US |
dc.subject | Zinc | en_US |
dc.subject | Heart failure | en_US |
dc.subject | Mitsugumin 23 | en_US |
dc.subject | SR calcium leak | en_US |
dc.subject.lcc | QH603.S27D7 | |
dc.subject.lcsh | Sarcoplasmic reticulum | en |
dc.subject.lcsh | Intracellular calcium | en |
dc.subject.lcsh | Heart failure | en |
dc.title | Mitsugumin 23 is a putative zinc regulated sarcoplasmic reticulum calcium leak channel | en_US |
dc.type | Thesis | en_US |
dc.contributor.sponsor | British Heart Foundation | en_US |
dc.type.qualificationlevel | Doctoral | en_US |
dc.type.qualificationname | PhD Doctor of Philosophy | en_US |
dc.publisher.institution | The University of St Andrews | en_US |
dc.rights.embargodate | 2026-11-05 | |
dc.rights.embargoreason | Thesis restricted in accordance with University regulations. Print and electronic copy restricted until 5th November 2026 | en |
dc.identifier.doi | https://doi.org/10.17630/sta/148 | |
dc.identifier.grantnumber | FS/17/9/32676 | en_US |
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