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Table 3 Transporters and their roles in Mn uptake and efflux

From: “Manganese-induced neurotoxicity: a review of its behavioral consequences and neuroprotective strategies”

  Transporter Localization Role in Mn transport Associated pathologies Reference
Mn importers DMT-1 Highly expressed in the basal ganglia Transports both Mn and Fe and a range of other cations. Increased expression of DMT1 has been found in the SNpc of PD patients. Alterations in DMT1 are associated with spinal onset amyotrophic lateral sclerosis, AD onset in males, iron anaemia and restless legs syndrome [3, 50]
ZIP8 and ZIP14 Apical surface of various cell types Regulation of Mn homeostasis (in duodenum, liver, brain, lungs, and kidney) and transfer of Mn, Fe, Zn, and Cd into the cells ZIP 8 and −14 facilitate Cd accumulation, a non-essential toxic metal. MT-null Cd-resistant cells have been found to exhibit suppressed expression of both ZIP8 and ZIP14, suggesting that the down-regulation of both contributes to the decrease in Cd and Mn uptake [229231]
DAT Neurons of SNpc, GP and striatum Reuptake of dopamine into presynaptic vesicles. Also shown to transport Mn Patients chronically exposed to Mn display decreased DAT density and activity. DAT knockout mice exposed to Mn accumulate significantly less Mn in the striatum compared to WT [50, 232]
Ca channels Plasma membrane Voltage-regulated, store-operated Ca2+ channels as well as ionotropic glutamate receptors also facilitate Mn uptake into the brain The number of known ion channel diseases (channelopathies) has increased dramatically and include cystic fibrosis, Bartter syndrome and epilepsy [233, 234]
Choline transporter Plasma membrane Choline uptake was found to be significantly inhibited in the presence of Cd and Mn, but not Cu or Al Prenatal choline deficiency is associated with increased choline transporter mRNA expression in the septum and hippocampus of rats as a compensatory mechanism for acetylcholine synthesis [235, 236]
Citrate transporter Plasma membrane Mn citrate represents the major non-protein-bound species of Mn to enter the brain at the BBB. The influx transfer coefficient for Mn citrate was shown to be greater than that of Mn2 + alone and Tf–Mn3+ Defects in SLC25A1, a mitochondrial citrate carrier, were identified to cause combined D-2- and L-2-hydroxyglutaric aciduria [237, 238]
Tf/TfR Tf in plasma and TfR in the membrane of neurons, microglia, astrocytes and the endothelial cells of the BBB Tf/TfR facilitates Mn3+ influx into the CNS from the blood stream Polymorphisms in TfR gene have been correlated with increased risk of age related macular degeneration (AMD) [57, 237, 239, 240]
Mn exporters Fpn Transmembrane, expressed in the duodenum, liver, spleen, intestine, endothelial cells of the BBB, neurons, oligodendrocytes, astrocytes, choroid plexus and ependymal cells Increased Fpn expression in HEK293 cells is associated with decreased intracellular Mn concentration and attenuated cytotoxicity Mutations in Fpn cause type IV hemochromatosis, commonly known as Fpn disease, characterized by Fe accumulation in reticuloendothelial macrophages [50, 62, 63]
SLC30A10 Cell surface-localized. Present in basal ganglia and liver Mediates Mn efflux from cells Mutations in SLC30A10 that impair Mn export induce hypermanganesemia, dystonia, and polycythemia with a variable degree of hepatic dysfunction [22, 23]
SPCA1 Mainly in Golgi membrane of keratinocytes, liver and brain Imports Mn2+ from the cytosol to the Golgi lumen Monoallelic mutations in SPCA1 are known to cause Hailey-Hailey disease, a blistering skin disorder. Complete loss of function is thought to be unviable [3, 241]
ATP13A2 or PARK9 Transmembrane, localized on the membrane of vacuoles and lysosomes Cation transporting ATPase. Shuttles cations across lysosomal membrane ATP13A2 mutations have been associated with early-onset parkinsonism and Kufor-Rakeb syndrome. [242244]
  1. Abbreviations: AD Alzheimer’s disease, ATP13A2 ATPase type 13A2, DAT dopamine transporter, DMT1 divalent metal transporter 1, Fpn ferroportin, MT, metalothionein, SLC solute carrier, SPCA1 secretory pathway Ca2 + −ATPase isoform 1, Tf transferrin, TfR transferrin receptor
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