SLC30A10: A novel manganese transporter

Chen, Pan; Bowman, Aaron B.; Mukhopadhyay, Somshuvra; Aschner, Michael

doi:10.1080/21624054.2015.1042648

Cited by 44 publications

(37 citation statements)

References 29 publications

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“…Several recent clinical studies have reported that human subjects with Solute Carrier Family 30 Member 10 (SLC30A10; ZnT10) deficiency/mutation display higher Mn accumulation in the liver 67 and blood 103, 104 , as well as 10 times higher Mn in the basal ganglia, which is associated with dystonia, a typical phenotype of Mn neurotoxicity 105–107 . SLC30A10 was thought to be a zinc exporter, but its amino acid structure is different from other zinc transporters in this family 108 , and it was later suggested that SLC30A10 may not be involved in zinc transport 109 . In contrast, the expression of SLC30A10 is inversely correlated with intracellular Mn accumulation in several in vitro systems, such as Hela cells, chicken DT40 cells and SH-SY5Y cells 100, 110, 111 .…”

Section: Introductionmentioning

confidence: 99%

Influence of iron metabolism on manganese transport and toxicity

et al. 2017

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Although manganese (Mn) is critical for proper function of various metabolic enzymes and cofactors, excess Mn in the brain causes neurotoxicity. While the exact transport mechanism of Mn has not been fully understood, several importers and exporters for Mn have been identified over the past decade. In addition to Mn-specific transporters, it has been demonstrated that iron transporters can mediate Mn transport in the brain and peripheral tissues. However, while the expression of iron transporters is regulated by body iron stores, whether or not disorders of iron metabolism modify Mn homeostasis has not been systematically discussed. The present review will provide an update on the role of altered iron status in the transport and toxicity of Mn.

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Section: Introductionmentioning

confidence: 99%

Influence of iron metabolism on manganese transport and toxicity

et al. 2017

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“…Second, in cell culture, expression of SLC30A10 WT reduces intracellular manganese levels, increases transport of manganese from the cytosol to the cell exterior, and protects against manganese-induced death, but it does not affect intracellular zinc levels or protect against zinc toxicity (13). Finally, in C. elegans, SLC30A10 WT expression protects against manganese but not zinc toxicity (13,17). In the absence of challenging in vitro transport assays, it is not possible to say whether SLC30A10 completely lacks zinc transport activity or whether the presence of more efficient zinc transporters in the above cell-and organism-based experimental systems mask SLC30A10-mediated zinc transport.…”

mentioning

confidence: 99%

Structural Elements in the Transmembrane and Cytoplasmic Domains of the Metal Transporter SLC30A10 Are Required for Its Manganese Efflux Activity

Zogzas

Aschner

Mukhopadhyay

2016

Journal of Biological Chemistry

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105

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Homozygous mutations in SLC30A10 lead to the development of familial manganese-induced parkinsonism. We previously demonstrated that SLC30A10 is a cell surface-localized manganese efflux transporter, and parkinsonism-causing mutations block its trafficking and efflux activity. Interestingly, other transporters in the SLC30 family mediate zinc efflux. Determining the mechanisms that allow SLC30A10 to transport manganese, which are unclear, is essential to understand its role in parkinsonism. Here, we generated a predicted structure of SLC30A10, based on the structure of the bacterial zinc transporter YiiP, and performed functional studies. In YiiP, side chains of residues Asp-45 and Asp-49 in the second and His-153 and Asp-157 in the fifth transmembrane segments coordinate zinc and are required for transport. In SLC30A10, the corresponding residues are Asn-43 and Asp-47 in the second and His-244 and Asp-248 in the fifth transmembrane segments. Surprisingly, although alanine substitution of Asp-248 abolished manganese efflux, that of Asn-43 and Asp-47 did not. Instead, side chains of charged or polar residues adjacent to Asp-248 in the first (Glu-25) or fourth (Asn-127) transmembrane segments were required. Further analyses revealed that residues His-333 and His-350 in the cytoplasmic C-terminal domain were required for full activity. However, the C-terminal domain failed to transfer manganese transport capability to a related zinc transporter. Overall, our results indicate that residues in the transmembrane and C-terminal domains together confer optimal manganese transport capability to SLC30A10 and suggest that the mechanism of ion coordination in the transmembrane domain of SLC30A10 may be substantially different from that in YiiP/other SLC30 proteins.

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“…SLC30A10 (solute carrier family 30 member 10) also plays an important role in Mn transport (Chen et al, 2015). SLC30A10 was originally categorized as a zinc transporter; however, it has a broader role in transporting Mn, iron, copper and other divalent cations (Roth, 2014).…”

Section: Discussionmentioning

confidence: 99%

Neonatal C57BL/6J and parkin mice respond differently following developmental manganese exposure: Result of a high dose pilot study

et al. 2018

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It has been suggested that childhood exposure to neurotoxicants may increase the risk of Parkinson’s disease (PD) or other neurodegenerative disease in adults. Some recessive forms of PD have been linked to loss-of-function mutations in the Park2 gene that encodes for parkin. The purpose of this pilot study was to evaluate whether responses to neonatal manganese (Mn) exposure differ in mice with a Park2 gene defect (parkin mice) when compared with a wildtype strain (C57BL/6J). Neonatal parkin and C57BL/6J littermates were randomly assigned to 0, 11, or 25 mg Mn/kg-day dose groups with oral exposures occurring from postnatal day (PND) 1 through PND 28. Motor activity was measured on PND 19–22 and 29–32. Tissue Mn concentrations were measured in liver, femur, olfactory bulb, frontal cortex, and striatum on PND 29. Hepatic and frontal cortex gene expression of Slc11a2, Slc40a1, Slc30a10, Hamp (liver only), and Park2 were also measured on PND 29. Some strain differences were seen. As expected, decreased hepatic and frontal cortex Park2 expression was seen in the parkin mice when compared with C57BL/6J mice. Untreated parkin mice also had higher liver and femur Mn concentrations when compared with the C57BL/6J mice. Exposure to > 11 mg Mn/kg-day was associated with increased brain Mn concentrations in all mice, no strain difference was observed. Manganese exposure in C57Bl6, but not parkin mice, was associated with a negative correlation between striatal Mn concentration and motor activity. Manganese exposure was not associated with changes in frontal cortex gene expression. Decreased hepatic Slc30a10, Slc40a1, and Hamp expression were seen in PND 29 C57BL/6J mice given 25 mg Mn/kg-day. In contrast, Mn exposure was only associated with decreased Hamp expression in the parkin mice. Our results suggest that the Parkin gene defect did not increase the susceptibility of neonatal mice to adverse health effects associated with high-dose Mn exposure.

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SLC30A10: A novel manganese transporter

Cited by 44 publications

References 29 publications

Influence of iron metabolism on manganese transport and toxicity

Influence of iron metabolism on manganese transport and toxicity

Structural Elements in the Transmembrane and Cytoplasmic Domains of the Metal Transporter SLC30A10 Are Required for Its Manganese Efflux Activity

Neonatal C57BL/6J and parkin mice respond differently following developmental manganese exposure: Result of a high dose pilot study

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