The role of Zn2+ in shaping intracellular Ca2+ dynamics in the heart

Dorward, Amy M; Stewart, Alan J.; Pitt, Samantha J.

doi:10.1085/jgp.202213206

Cited by 4 publications

(3 citation statements)

References 203 publications

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“…An increase in MG23 expression and activity has been observed when cytosolic Zn 2+ levels rise [114]. This finding is supported by the presence of a common HxxE amino acid sequence conserved on Zrt-/Irt-like protein (ZIP) 1, 2, and 3, known as zinc transporters, where the Zn 2+ binding sites are located [115]. MG23, along with RyR2, adds more explanation on the diastolic SR Ca 2+ leakage.…”

Section: Crosstalk Between Mineralsmentioning

confidence: 83%

Calcium’s Role and Signaling in Aging Muscle, Cellular Senescence, and Mineral Interactions

Terrell,

Choi,

Choi

2023

IJMS

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Calcium research, since its pivotal discovery in the early 1800s through the heating of limestone, has led to the identification of its multi-functional roles. These include its functions as a reducing agent in chemical processes, structural properties in shells and bones, and significant role in cells relating to this review: cellular signaling. Calcium signaling involves the movement of calcium ions within or between cells, which can affect the electrochemical gradients between intra- and extracellular membranes, ligand binding, enzyme activity, and other mechanisms that determine cell fate. Calcium signaling in muscle, as elucidated by the sliding filament model, plays a significant role in muscle contraction. However, as organisms age, alterations occur within muscle tissue. These changes include sarcopenia, loss of neuromuscular junctions, and changes in mineral concentration, all of which have implications for calcium’s role. Additionally, a field of study that has gained recent attention, cellular senescence, is associated with aging and disturbed calcium homeostasis, and is thought to affect sarcopenia progression. Changes seen in calcium upon aging may also be influenced by its crosstalk with other minerals such as iron and zinc. This review investigates the role of calcium signaling in aging muscle and cellular senescence. We also aim to elucidate the interactions among calcium, iron, and zinc across various cells and conditions, ultimately deepening our understanding of calcium signaling in muscle aging.

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Section: Crosstalk Between Mineralsmentioning

confidence: 83%

Calcium’s Role and Signaling in Aging Muscle, Cellular Senescence, and Mineral Interactions

Terrell,

Choi,

Choi

2023

IJMS

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“…It has been reported that low levels of Zn 2+ stimulate kinase activity, whereas high concentration of Zn 2+ inhibits the binding of Ca 2+ / calmodulin and inactivate the substrate phosphorylation activity of CaMPK-2. Moreover, Ca 2+ and Zn 2+ shape each other's intraneuronal dynamics (Dorward et al, 2023).…”

Section: Zinc As a Signaling Moleculementioning

confidence: 99%

Unlocking the brain’s zinc code: implications for cognitive function and disease

Sabouri,

Rostamirad,

Dempski

2024

Front. Biophys.

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Zn2+ transport across neuronal membranes relies on two classes of transition metal transporters: the ZnT (SLC30) and ZIP (SLC39) families. These proteins function to decrease and increase cytosolic Zn2+ levels, respectively. Dysfunction of ZnT and ZIP transporters can alter intracellular Zn2+ levels resulting in deleterious effects. In neurons, imbalances in Zn2+ levels have been implicated as risk factors in conditions such as Alzheimer’s disease and neurodegeneration, highlighting the pivotal role of Zn2+ homeostasis in neuropathologies. In addition, Zn2+ modulates the function of plasma membrane proteins, including ion channels and receptors. Changes in Zn2+ levels, on both sides of the plasma membrane, profoundly impact signaling pathways governing cell development, differentiation, and survival. This review is focused on recent developments of neuronal Zn2+ homeostasis, including the impact of Zn2+ dyshomeostasis in neurological disorders, therapeutic approaches, and the increasingly recognized role of Zn2+ as a neurotransmitter in the brain.

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“…Supra-physiological Zn 2+ concentration eventually caused dysrhythmia; however, bulk protein degradation was inhibited at Zn 2+ concentrations that caused no functional change. Although the exchange of intracellular and extracellular Zn 2+ is not directly linked to the contraction-relaxation cycle, internal Zn 2+ and Ca 2+ are reportedly interactive by competition for an ion channel (Dorward et al 2023 ). Increased extracellular Zn 2+ can be taken up by the heart beginning in minutes as revealed qualitatively by positron emission photometry (Firth et al 2022 ).…”

Section: Over-expression Of Web Proteases Might Require a Potent Dire...mentioning

confidence: 99%

Coordination chemistry suggests that independently observed benefits of metformin and Zn2+ against COVID-19 are not independent

Lockwood

2024

Biometals

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Independent trials indicate that either oral Zn2+ or metformin can separately improve COVID-19 outcomes by approximately 40%. Coordination chemistry predicts a mechanistic relationship and therapeutic synergy. Zn2+ deficit is a known risk factor for both COVID-19 and non-infectious inflammation. Most dietary Zn2+ is not absorbed. Metformin is a naked ligand that presumably increases intestinal Zn2+ bioavailability and active absorption by cation transporters known to transport metformin. Intracellular Zn2+ provides a natural buffer of many protease reactions; the variable “set point” is determined by Zn2+ regulation or availability. A Zn2+-interactive protease network is suggested here. The two viral cysteine proteases are therapeutic targets against COVID-19. Viral and many host proteases are submaximally inhibited by exchangeable cell Zn2+. Inhibition of cysteine proteases can improve COVID-19 outcomes and non-infectious inflammation. Metformin reportedly enhances the natural moderating effect of Zn2+ on bioassayed proteome degradation. Firstly, the dissociable metformin–Zn2+ complex could be actively transported by intestinal cation transporters; thereby creating artificial pathways of absorption and increased body Zn2+ content. Secondly, metformin Zn2+ coordination can create a non-natural protease inhibitor independent of cell Zn2+ content. Moderation of peptidolytic reactions by either or both mechanisms could slow (a) viral multiplication (b) viral invasion and (c) the pathogenic host inflammatory response. These combined actions could allow development of acquired immunity to clear the infection before life-threatening inflammation. Nirmatrelvir (Paxlovid®) opposes COVID-19 by selective inhibition the viral main protease by a Zn2+-independent mechanism. Pending safety evaluation, predictable synergistic benefits of metformin and Zn2+, and perhaps metformin/Zn2+/Paxlovid® co-administration should be investigated.

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The role of Zn2+ in shaping intracellular Ca2+ dynamics in the heart

Cited by 4 publications

References 203 publications

Calcium’s Role and Signaling in Aging Muscle, Cellular Senescence, and Mineral Interactions

Calcium’s Role and Signaling in Aging Muscle, Cellular Senescence, and Mineral Interactions

Unlocking the brain’s zinc code: implications for cognitive function and disease

Coordination chemistry suggests that independently observed benefits of metformin and Zn2+ against COVID-19 are not independent

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