Manganese: Recent advances in understanding its transport and neurotoxicity

Iron and copper metabolism.

https://web.ics.purdue.edu/~wzheng/Publications/Epapers/2003_Zheng%20et%20al%20TAAP_Review.pdf

Brain barrier systems: a new frontier in metal neurotoxicological research.

The understanding of manganese (Mn) biology, in particular its cellular regulation and role in neurological disease, is an area of expanding interest. Mn is an essential micronutrient that is required for the activity of a diverse set of enzymatic proteins (e.g., arginase and glutamine synthase). Although necessary for life, Mn is toxic in excess. Thus, maintaining appropriate levels of intracellular Mn is critical. Unlike other essential metals, cell-level homeostatic mechanisms of Mn have not been identified. In this review, we discuss common forms of Mn exposure, absorption, and transport via regulated uptake/exchange at the gut and blood-brain barrier and via biliary excretion. We present the current understanding of cellular uptake and efflux as well as subcellular storage and transport of Mn. In addition, we highlight the Mn-dependent and Mn-responsive pathways implicated in the growing evidence of its role in Parkinson's disease and Huntington's disease. We conclude with suggestions for future focu...

/pdf/manganese-is-essential-for-neuronal-health-3n5b8s936n.pdf

Manganese Is Essential for Neuronal Health

Essential metals in health and disease.

DMT1 has four names, transports as many as eight metals, may have four or more isoforms and carries out its transport for multiple purposes. This review is a start at sorting out these multiplicities. A G185R mutation results in diminished gastrointestinal iron uptake and decreased endosomal iron exit in microcytic mice and Belgrade rats. Comparison of mutant to normal rodents is one analytical tool. Ectopic expression is another. Antibodies that distinguish the isoforms are also useful. Two mRNA isoforms differ in the 3' UTR: +IRE DMT1 has an IRE (Iron Responsive Element) but -IRE DMT1 lacks this feature. The +/-IRE proteins differ in the distal 18 or 25 amino acid residues after shared identity for the proximal 543 residues. A major function is serving as the apical iron transporter in the lumen of the gut. The +IRE isoform appears to have that role. Another role is endosomal exit of iron. Some evidence indicts the -IRE isoform for this function. In our ectopic expression assay for metal uptake, four metals--Fe2+, Mn2+, Ni2+ and Co2+--respond to the normal DMT1 cDNA but not the G185R mutant. Two metals did not--Cd2+ and Zn2+--and two--Cu2+ and Pb2+--remain to be tested. In competition experiments in the same assay, Cd2+, Cu2+ and Pb2+ inhibit Mn2+ uptake but Zn2+ did not. In rodent mutants, Fe and Mn appear more dependent on DMT1 than Cu and Zn. Experiments based on ectopic expression, specific antibodies that inhibit metal uptake and labeling data indicate that Fe3+ uptake depends on a different pathway in multiple cells. Two isoforms localize differently in a number of cell types. Unexpectedly, the -IRE isoform is in the nuclei of cells with neuronal properties. While the function of -IRE DMT1 in the nucleus is speculative, one may safely infer that this localization identifies new role(s) for this multifunctional transporter. Management of toxic challenges is another function related to metal homeostasis. Airways represent a gateway tissue for metal entry. Preliminary evidence using specific PCR primers and antibodies specific to the two isoforms indicates that -IRE mRNA and protein increase in response to exposure to metal in lungs and in a cell culture model; the +IRE form is unresponsive. Thus the -IRE form could be part of a detoxification system in which +IRE DMT1 does not participate. How does iron status affect other metals' toxicity? In the case of Mn, iron deficiency may enhance cellular responses.

DMT1: A mammalian transporter for multiple metals

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DMT1: A mammalian transporter for multiple metals