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1.4. Perspectives
Accumulating evidence has helped clarify the importance of Zn
transporters in cellular and systemic Mn metabolism through the
mobilization of Mn across the cellular membrane. Simultaneously,
new questions have arisen about their functions. Can these transporters flexibly discriminate between Zn and Mn? Can their Mn
transport activity be flexibly regulated? Considering the properties
of ZNT and ZIP transporters, it would be interesting to consider the
possibility that heterodimerization may occur between ZNT10 and
other ZNT proteins, or between ZIP8 or ZIP14 and other ZIP proteins
to control their Mn/Zn transport activity. ZNT10 has been shown to
heterodimerize with ZNT3,126 although this heterodimerization
needs to be investigated from the perspective of Mn pathophysiology. Answers to these questions need to be obtained for a understanding of Mn homeostasis.
The impairment of Mn homeostasis results in various diseases.
Genetic variation associated with Mn homeostasis likely leads to a
variety of symptoms and risk of diseases. Dietary Mn deficiency is
unlikely to occur in a normal individual; thus, an excess of Mn,
which may be associated with both rare and common neurodegenerative disorders,127 need to be intensively examined in the
future. In patients with parkinsonism caused by mutations in ZNT10
and ZIP14, chelation therapy with disodium calcium edetate is reported to show significant improvement,18,20,95 along with supplementation of iron, which is a competitive inhibitor of intestinal
Mn uptake. Thus, compounds that reduce Mn toxicity may lead to
the discovery and development of drugs for a number of human
diseases associated with altered Mn homeostasis. The recent
emergence of several small molecule inhibitors of ZIP transporters128,129 show the high possibility for novel pharmacological
applications by directly targeting ZNT10, ZIP8, and ZIP14 in human
diseases associated with these transporters. However, these inhibitors have not yet been used in animal studies or in human
patients. Considering ZNT10, ZIP8, and ZIP14 are expressed on the
cell surface, an antibodyedrug conjugate may be useful. In this
regard, an antibodyedrug conjugate consisting of an anti-ZIP6
humanized monoclonal antibody and a microtubule-disrupting
agent provides useful information because it showed the efficacy
in both in vitro and in vivo antitumor activity.130 It is needless to say
that molecular mechanisms underlying the association of ZNT10,
ZIP8, and ZIP14 with Zn and Mn metabolism should be clarified for
potential pharmacological.
Funding
This work was supported by a Grant-in-Aid for Scientific
Research on Innovative Areas “Integrated Bio-metal Science”
(MEXT KAKENHI Grant Number JP19H05770 to H.F. and
JP19H05768 to T.K.).
Declaration of competing interest
Both authors declare no competing financial and non-financial
interests.
131
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