A comprehensive overview of the complex world of the endo- and sarcoplasmic reticulum Ca2+-leak channels

Lemos, Fernanda O.; Bultynck, Geert; Parys, Jan B.

doi:10.1016/j.bbamcr.2021.119020

Cited by 45 publications

(33 citation statements)

References 275 publications

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“…Localization in a specific organelle or subset of organelles defines the functional context for many molecules, especially ion and metabolite transporters. For example, there are ion channels and transporters that localize to the plasma membrane or endo/sarcoplasmic reticulum, and even though they might conduct the same ions, they clearly have different impact on cellular function (Butorac et al, 2020; Gandini and Zamponi, 2021; Guse et al, 2021; Lemos et al, 2021; Lopez et al, 2020). Similarly, a large cohort of zinc transporters, responsible for pumping ionic zinc into distinct organelles or in or out of cells, subserve distinct functions, including synaptic modulation (Krall et al, 2021) and co-secretion with milk, in the latter case providing an essential dietary supplement and shaping mammary gland development (McCormick et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

Evolutionary rate covariation identifies SLC30A9 (ZnT9) as a mitochondrial zinc transporter

Kowalczyk

Gbadamosi

Kolor

et al. 2021

Preprint

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Recent advances in genome sequencing have led to the identification of new ion and metabolite transporters, many of which have not been characterized. Due to the variety of subcellular localizations, cargo and transport mechanisms, such characterization is a daunting task, and predictive approaches focused on the functional context of transporters are very much needed. Here we present a case for identifying a transporter localization using evolutionary rate covariation (ERC), a computational approach based on pairwise correlations of amino acid sequence evolutionary rates across the mammalian phylogeny. As a case study, we find that poorly characterized transporter SLC30A9 (ZnT9) uniquely and prominently coevolves with several components of the mitochondrial oxidative phosphorylation chain, suggesting mitochondrial localization. We confirmed this computational finding experimentally using recombinant human SLC30A9. SLC30A9 loss caused zinc mishandling in the mitochondria, suggesting that under normal conditions it acts as a zinc exporter. We therefore propose that ERC can be used to predict the functional context of novel transporters and other poorly characterized proteins.

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Section: Introductionmentioning

confidence: 99%

Evolutionary rate covariation identifies SLC30A9 (ZnT9) as a mitochondrial zinc transporter

Kowalczyk

Gbadamosi

Kolor

et al. 2021

Preprint

View full text Add to dashboard Cite

show abstract

“…Localization in a specific organelle or subset of organelles defines the functional context for many molecules, especially ion and metabolite transporters. For example, there are ion channels and transporters that localize to the plasma membrane or endo/sarcoplasmic reticulum, and even though they might conduct the same ions, they clearly have a different impact on cellular function [1][2][3]. Similarly, a large cohort of zinc transporters, responsible for pumping ionic zinc into distinct organelles or in or out of cells, subserve distinct functions, including synaptic modulation [4] and co-secretion with milk, in the latter case providing an essential dietary supplement and shaping mammary gland development [5].…”

Section: Introductionmentioning

confidence: 99%

Evolutionary rate covariation identifies SLC30A9 (ZnT9) as a mitochondrial zinc transporter

Kowalczyk

Gbadamosi

Kolor

et al. 2021

Biochemical Journal

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Recent advances in genome sequencing have led to the identification of new ion and metabolite transporters, many of which have not been characterized. Due to the variety of subcellular localizations, cargo and transport mechanisms, such characterization is a daunting task, and predictive approaches focused on the functional context of transporters are very much needed. Here we present a case for identifying a transporter localization using evolutionary rate covariation (ERC), a computational approach based on pairwise correlations of amino acid sequence evolutionary rates across the mammalian phylogeny. As a case study, we find that poorly characterized transporter SLC30A9 (ZnT9) coevolves with several components of the mitochondrial oxidative phosphorylation chain, suggesting mitochondrial localization. We confirmed this computational finding experimentally using recombinant human SLC30A9. SLC30A9 loss caused zinc mishandling in the mitochondria, suggesting that under normal conditions it acts as a zinc exporter. We therefore propose that ERC can be used to predict the functional context of novel transporters and other poorly characterized proteins.

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“…The ER folds and assembles newly synthesized proteins destined for trafficking via the secretory pathway, dysregulation of which leads to the unfolded protein response (UPR), reviewed elsewhere 11 , 12 but not covered in this review except regarding Ca 2+ -specific observations. In addition, the ER acts as a principal Ca 2+ store within cells facilitating Ca 2+ signals in the cytosol or multiple organelles via ER-organelle contact sites 8 , 13 – 15 . In this section, we describe effects on secretion via ER-localized Ca 2+ channels or their cytosolic effectors; finally, we note ways in which luminal calcium has been described to affect secretion.…”

Section: Calcium and Secretionmentioning

confidence: 99%

Ca2+ regulation of constitutive vesicle trafficking

Sargeant¹,

Hay²

2022

Fac Rev

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Constitutive vesicle trafficking is the default pathway used by all cells for movement of intracellular cargoes between subcellular compartments and in and out of the cell. Classically, constitutive trafficking was thought to be continuous and unregulated, in contrast to regulated secretion, wherein vesicles are stored intracellularly until undergoing synchronous membrane fusion following a Ca 2+ signal. However, as shown in the literature reviewed here, many continuous trafficking steps can be up- or down-regulated by Ca 2+ , including several steps associated with human pathologies. Notably, we describe a series of Ca 2+ pumps, channels, Ca 2+ -binding effector proteins, and their trafficking machinery targets that together regulate the flux of cargo in response to genetic alterations as well as baseline and agonist-dependent Ca 2+ signals. Here, we review the most recent advances, organized by organellar location, that establish the importance of these components in trafficking steps. Ultimately, we conclude that Ca 2+ regulates an expanding series of distinct mechanistic steps. Furthermore, the involvement of Ca 2+ in trafficking is complex. For example, in some cases, the same Ca 2+ effectors regulate surprisingly distinct trafficking steps, or even the same trafficking step with opposing influences, through binding to different target proteins.

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A comprehensive overview of the complex world of the endo- and sarcoplasmic reticulum Ca2+-leak channels

Cited by 45 publications

References 275 publications

Evolutionary rate covariation identifies SLC30A9 (ZnT9) as a mitochondrial zinc transporter

Evolutionary rate covariation identifies SLC30A9 (ZnT9) as a mitochondrial zinc transporter

Evolutionary rate covariation identifies SLC30A9 (ZnT9) as a mitochondrial zinc transporter

Ca2+ regulation of constitutive vesicle trafficking

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