The functions of metallothionein and ZIP and ZnT transporters: An overview and perspective

International Journal of Molecular Sciences

Volumn 17, Issue 3, 2016, Pages

  Kimura, Tomoki ^a   Kambe, Taiho ^b  

^a SETSUNAN UNIVERSITY   (Japan)

^b KYOTO UNIVERSITY   (Japan)

Author keywords

Chaperone; Metallothionein; Zinc; ZIP and ZnT transporter

Indexed keywords

COPPER ZINC SUPEROXIDE DISMUTASE; INTERLEUKIN 4; METALLOTHIONEIN; REACTIVE OXYGEN METABOLITE; STAT3 PROTEIN; TRANSCRIPTION FACTOR NFAT; UNCLASSIFIED DRUG; ZINC TRANSPORTER; ZRT AND IRT LIKE PROTEIN; CATION TRANSPORT PROTEIN; REPRESSOR PROTEIN; ZINC; ZIP PROTEIN, HUMAN;

ACRODERMATITIS ENTEROPATHICA; AMINO ACID SEQUENCE; APOPTOSIS; AUTOPHAGY; EPIGENETICS; GENE MUTATION; HUMAN; IMMUNE RESPONSE; NEOPLASM; NONHUMAN; PROTEIN EXPRESSION; PROTEOMICS; REVIEW; SIGNAL TRANSDUCTION; SINGLE NUCLEOTIDE POLYMORPHISM; ZINC HOMEOSTASIS; ZINC METABOLISM; ACRODERMATITIS; ANIMAL; DEFICIENCY; GENE EXPRESSION REGULATION; GENETIC EPIGENESIS; GENETIC PREDISPOSITION; GENETICS; HOMEOSTASIS; METABOLISM; PHYLOGENY;

ACRODERMATITIS; ANIMALS; CATION TRANSPORT PROTEINS; EPIGENESIS, GENETIC; GENE EXPRESSION REGULATION; GENETIC PREDISPOSITION TO DISEASE; HOMEOSTASIS; HUMANS; METALLOTHIONEIN; PHYLOGENY; POLYMORPHISM, SINGLE NUCLEOTIDE; REPRESSOR PROTEINS; ZINC;

EID: 84960121455     PISSN: 16616596     EISSN: 14220067     Source Type: Journal    
DOI: 10.3390/ijms17030336     Document Type: Review

References (165)

1. Thiers, R.E.; Vallee, B.L. Distribution of metals in subcellular fractions of rat liver. J. Biol. Chem. 1957, 226, 911–920. [PubMed]
2. Kambe, T.; Tsuji, T.; Hashimoto, A.; Itsumura, N. The physiological, biochemical, and molecular roles of zinc transporters in zinc homeostasis and metabolism. Physiol. Rev. 2015, 95, 749–784. [CrossRef] [PubMed]
3. Kambe, T.; Yamaguchi-Iwai, Y.; Sasaki, R.; Nagao, M. Overview of mammalian zinc transporters. Cell. Mol. Life Sci. 2004, 61, 49–68. [CrossRef] [PubMed]
4. Coyle, P.; Philcox, J.C.; Carey, L.C.; Rofe, A.M. Metallothionein: The multipurpose protein. Cell. Mol. Life Sci. 2002, 59, 627–647. [CrossRef] [PubMed]
5. Hennigar, S.R.; Kelleher, S.L. Zinc networks: The cell-specific compartmentalization of zinc for specialized functions. Biol. Chem. 2012, 393, 565–578. [CrossRef] [PubMed]
6. Kambe, T. An overview of a wide range of functions of ZnT and ZIP zinc transporters in the secretory pathway. Biosci. Biotechnol. Biochem. 2011, 75, 1036–1043. [CrossRef] [PubMed]
7. Qin, Y.; Dittmer, P.J.; Park, J.G.; Jansen, K.B.; Palmer, A.E. Measuring steady-state and dynamic endoplasmic reticulum and Golgi Zn2+ with genetically encoded sensors. Proc. Natl. Acad. Sci. USA 2011, 108, 7351–7356. [CrossRef] [PubMed]
8. Outten, C.E.; O’Halloran, T.V. Femtomolar sensitivity of metalloregulatory proteins controlling zinc homeostasis. Science 2001, 292, 2488–2492. [CrossRef] [PubMed]
9. Vinkenborg, J.L.; Nicolson, T.J.; Bellomo, E.A.; Koay, M.S.; Rutter, G.A.; Merkx, M. Genetically encoded fret sensors to monitor intracellular Zn2+ homeostasis. Nat. Methods 2009, 6, 737–740. [CrossRef] [PubMed]
10. Eide, D.J. Zinc transporters and the cellular trafficking of zinc. Biochim. Biophys. Acta 2006, 1763, 711–722. [CrossRef] [PubMed]
11. Lichten, L.A.; Cousins, R.J. Mammalian zinc transporters: Nutritional and physiologic regulation. Annu. Rev. Nutr. 2009, 29, 153–176. [CrossRef] [PubMed]
12. Fukada, T.; Kambe, T. Molecular and genetic features of zinc transporters in physiology and pathogenesis. Metallomics 2011, 3, 662–674. [CrossRef] [PubMed]
13. Moleirinho, A.; Carneiro, J.; Matthiesen, R.; Silva, R.M.; Amorim, A.; Azevedo, L. Gains, losses and changes of function after gene duplication: Study of the metallothionein family. PLoS ONE 2011, 6, e18487. [CrossRef] [PubMed]
14. Vasak, M.; Meloni, G. Chemistry and biology of mammalian metallothioneins. J. Biol. Inorg. Chem. 2011, 16, 1067–1078. [CrossRef] [PubMed]
15. Lazo, J.S.; Kondo, Y.; Dellapiazza, D.; Michalska, A.E.; Choo, K.H.; Pitt, B.R. Enhanced sensitivity to oxidative stress in cultured embryonic cells from transgenic mice deficient in metallothionein I and II genes. J. Biol. Chem. 1995, 270, 5506–5510. [CrossRef] [PubMed]
16. Masters, B.A.; Kelly, E.J.; Quaife, C.J.; Brinster, R.L.; Palmiter, R.D. Targeted disruption of metallothionein I and II genes increases sensitivity to cadmium. Proc. Natl. Acad. Sci. USA 1994, 91, 584–588. [CrossRef] [PubMed]
17. Michalska, A.E.; Choo, K.H. Targeting and germ-line transmission of a null mutation at the metallothionein I and II loci in mouse. Proc. Natl. Acad. Sci. USA 1993, 90, 8088–8092. [CrossRef] [PubMed]
18. Kelly, E.J.; Quaife, C.J.; Froelick, G.J.; Palmiter, R.D. Metallothionein I and II protect against zinc deficiency and zinc toxicity in mice. J. Nutr. 1996, 126, 1782–1790. [PubMed]
19. Klaassen, C.D.; Liu, J. Metallothionein transgenic and knock-out mouse models in the study of cadmium toxicity. J. Toxicol. Sci. 1998, 23 (Suppl. 2), 97–102. [CrossRef] [PubMed]
20. Shibuya, K.; Suzuki, J.S.; Kito, H.; Naganuma, A.; Tohyama, C.; Satoh, M. Protective role of metallothionein in bone marrow injury caused by X-irradiation. J. Toxicol. Sci. 2008, 33, 479–484. [CrossRef] [PubMed]
21. Fujiwara, Y.; Satoh, M. Protective role of metallothionein in chemical and radiation carcinogenesis. Curr. Pharm. Biotechnol. 2013, 14, 394–399. [CrossRef] [PubMed]
22. Kimura, T.; Itoh, N.; Takehara, M.; Oguro, I.; Ishizaki, J.I.; Nakanishi, T.; Tanaka, K. Sensitivity of metallothionein-null mice to LPS/D-galactosamine-induced lethality. Biochem. Biophys. Res. Commun. 2001, 280, 358–362. [CrossRef] [PubMed]
23. Inoue, K.; Takano, H.; Shimada, A.; Wada, E.; Yanagisawa, R.; Sakurai, M.; Satoh, M.; Yoshikawa, T. Role of metallothionein in coagulatory disturbance and systemic inflammation induced by lipopolysaccharide in mice. FASEB J. 2006, 20, 533–535. [CrossRef] [PubMed]
24. Mita, M.; Satoh, M.; Shimada, A.; Okajima, M.; Azuma, S.; Suzuki, J.S.; Sakabe, K.; Hara, S.; Himeno, S. Metallothionein is a crucial protective factor against Helicobacter pylori-induced gastric erosive lesions in a mouse model. Am. J. Physiol. Gastrointest. Liver Physiol. 2008, 294, G877–G884. [CrossRef] [PubMed]
25. Ugajin, T.; Nishida, K.; Yamasaki, S.; Suzuki, J.; Mita, M.; Kubo, M.; Yokozeki, H.; Hirano, T. Zinc-binding metallothioneins are key modulators of IL-4 production by basophils. Mol. Immunol. 2015, 66, 180–188. [CrossRef] [PubMed]
26. Miyai, T.; Hojyo, S.; Ikawa, T.; Kawamura, M.; Irie, T.; Ogura, H.; Hijikata, A.; Bin, B.H.; Yasuda, T.; Kitamura, H. et al. Zinc transporter SLC39A10/ZIP10 facilitates antiapoptotic signaling during early B-cell development. Proc. Natl. Acad. Sci. USA 2014, 111, 11780–11785. [CrossRef] [PubMed]
27. Hojyo, S.; Miyai, T.; Fujishiro, H.; Kawamura, M.; Yasuda, T.; Hijikata, A.; Bin, B.H.; Irie, T.; Tanaka, J.; Atsumi, T. et al. Zinc transporter SLC39A10/ZIP10 controls humoral immunity by modulating B-cell receptor signal strength. Proc. Natl. Acad. Sci. USA 2014, 111, 11786–11791. [CrossRef] [PubMed]
28. Sato, M.; Kawakami, T.; Kondoh, M.; Takiguchi, M.; Kadota, Y.; Himeno, S.; Suzuki, S. Development of high-fat-diet-induced obesity in female metallothionein-null mice. FASEB J. 2010, 24, 2375–2384. [CrossRef] [PubMed]
29. Kadota, Y.; Aki, Y.; Toriuchi, Y.; Mizuno, Y.; Kawakami, T.; Sato, M.; Suzuki, S. Deficiency of metallothionein-1 and -2 genes shortens the lifespan of the 129/Sv mouse strain. Exp. Gerontol. 2015, 66, 21–24. [CrossRef] [PubMed]
30. Puttaparthi, K.; Gitomer, W.L.; Krishnan, U.; Son, M.; Rajendran, B.; Elliott, J.L. Disease progression in a transgenic model of familial amyotrophic lateral sclerosis is dependent on both neuronal and non-neuronal zinc binding proteins. J. Neurosci. 2002, 22, 8790–8796. [PubMed]
31. Elliott, J.L. Zinc and copper in the pathogenesis of amyotrophic lateral sclerosis. Prog. Neuropsychopharmacol. Biol. Psychiatry 2001, 25, 1169–1185. [CrossRef]
32. Kimura, T.; Itoh, N.; Andrews, G.K. Mechanisms of heavy metal sensing by metal response element-binding transcription factor-1. J. Health Sci. 2009, 55, 484–494. [CrossRef]
33. Potter, B.M.; Feng, L.S.; Parasuram, P.; Matskevich, V.A.; Wilson, J.A.; Andrews, G.K.; Laity, J.H. The six zinc fingers of metal-responsive element binding transcription factor-1 form stable and quasi-ordered structures with relatively small differences in zinc affinities. J. Biol. Chem. 2005, 280, 28529–28540. [CrossRef] [PubMed]
34. Laity, J.H.; Andrews, G.K. Understanding the mechanisms of zinc-sensing by metal-response element binding transcription factor-1 (MTF-1). Arch. Biochem. Biophys. 2007, 463, 201–210. [CrossRef] [PubMed]
35. Guo, L.; Lichten, L.A.; Ryu, M.S.; Liuzzi, J.P.; Wang, F.; Cousins, R.J. STAT5-glucocorticoid receptor interaction and MTF-1 regulate the expression of ZnT2 (Slc30a2) in pancreatic acinar cells. Proc. Natl. Acad. Sci. USA 2010, 107, 2818–2823. [CrossRef] [PubMed]
36. Langmade, S.J.; Ravindra, R.; Daniels, P.J.; Andrews, G.K. The transcription factor MTF-1 mediates metal regulation of the mouse ZnT1 gene. J. Biol. Chem. 2000, 275, 34803–34809. [CrossRef] [PubMed]
37. Wimmer, U.; Wang, Y.; Georgiev, O.; Schaffner, W. Two major branches of anti-cadmiumdefense in the mouse: MTF-1/metallothioneins and glutathione. Nucleic Acids Res. 2005, 33, 5715–5727. [CrossRef] [PubMed]
38. Lichten, L.A.; Ryu, M.S.; Guo, L.; Embury, J.; Cousins, R.J. MTF-1-mediated repression of the zinc transporter ZIP10 is alleviated by zinc restriction. PLoS ONE 2011, 6, e21526. [CrossRef] [PubMed]
39. Lin, M.C.; Liu, Y.C.; Tam, M.F.; Lu, Y.J.; Hsieh, Y.T.; Lin, L.Y. PTEN interacts with metal-responsive transcription factor 1 and stimulates its transcriptional activity. Biochem. J. 2012, 441, 367–377. [CrossRef] [PubMed]
40. Chen, L.; Ma, L.; Bai, Q.; Zhu, X.; Zhang, J.; Wei, Q.; Li, D.; Gao, C.; Li, J.; Zhang, Z. et al. Heavy metal-induced metallothionein expression is regulated by specific protein phosphatase 2A complexes. J. Biol. Chem. 2014, 289, 22413–22426. [CrossRef] [PubMed]
41. Ogo, O.A.; Tyson, J.; Cockell, S.J.; Howard, A.; Valentine, R.A.; Ford, D. The zinc finger protein ZNF658 regulates the transcription of genes involved in zinc homeostasis and affects ribosome biogenesis through the zinc transcriptional regulatory element. Mol. Cell. Biol. 2015, 35, 977–987. [CrossRef] [PubMed]
42. Kagi, J.H.; Valee, B.L. Metallothionein: A cadmium- and zinc-containing protein from equine renal cortex. J. Biol. Chem. 1960, 235, 3460–3465. [PubMed]
43. Suhy, D.A.; Simon, K.D.; Linzer, D.I.; O’Halloran, T.V. Metallothionein is part of a zinc-scavenging mechanism for cell survival under conditions of extreme zinc deprivation. J. Biol. Chem. 1999, 274, 9183–9192. [CrossRef] [PubMed]
44. Palmiter, R.D. Constitutive expression of metallothionein-III (MT-III), but not MT-I, inhibits growth when cells become zinc deficient. Toxicol. Appl. Pharmacol. 1995, 135, 139–146. [CrossRef] [PubMed]
45. Krezel, A.; Maret, W. Thionein/metallothionein control Zn(II) availability and the activity of enzymes. J. Biol. Inorg. Chem. 2008, 13, 401–409. [CrossRef] [PubMed]
46. Costello, L.C.; Fenselau, C.C.; Franklin, R.B. Evidence for operation of the direct zinc ligand exchange mechanism for trafficking, transport, and reactivity of zinc in mammalian cells. J. Inorg. Biochem. 2011, 105, 589–599. [CrossRef] [PubMed]
47. Pinter, T.B.; Stillman, M.J. Kinetics of zinc and cadmium exchanges between metallothionein and carbonic anhydrase. Biochemistry 2015, 54, 6284–6293. [CrossRef] [PubMed]
48. Maret, W. Redox biochemistry of mammalian metallothioneins. J. Biol. Inorg. Chem. 2011, 16, 1079–1086. [CrossRef] [PubMed]
49. Aras, M.A.; Aizenman, E. Redox regulation of intracellular zinc: Molecular signaling in the life and death of neurons. Antioxid. Redox Signal. 2011, 15, 2249–2263. [CrossRef] [PubMed]
50. Fukada, T.; Kambe, T. Zinc Signals in Cellular Functions and Disorders; Springer: Tokyo, Japan, 2014.
51. Zeng, J.; Heuchel, R.; Schaffner, W.; Kagi, J.H. Thionein (apometallothionein) can modulate DNA binding and transcription activation by zinc finger containing factor Sp 1. FEBS Lett. 1991, 279, 310–312. [CrossRef]
52. Zeng, J.; Vallee, B.L.; Kagi, J.H. Zinc transfer from transcription factor IIIA fingers to thionein clusters. Proc. Natl. Acad. Sci. USA 1991, 88, 9984–9988. [CrossRef] [PubMed]
53. Maret, W.; Li, Y. Coordination dynamics of zinc in proteins. Chem. Rev. 2009, 109, 4682–4707. [CrossRef] [PubMed]
54. Maret, W. Metals on the move: Zinc ions in cellular regulation and in the coordination dynamics of zinc proteins. Biometals 2011, 24, 411–418. [CrossRef] [PubMed]
55. Wang, Y.; Hodgkinson, V.; Zhu, S.; Weisman, G.A.; Petris, M.J. Advances in the understanding of mammalian copper transporters. Adv. Nutr. 2011, 2, 129–137. [CrossRef] [PubMed]
56. Kambe, T.; Weaver, B.P.; Andrews, G.K. The genetics of essential metal homeostasis during development. Genesis 2008, 46, 214–228. [CrossRef] [PubMed]
57. Kim, B.E.; Nevitt, T.; Thiele, D.J. Mechanisms for copper acquisition, distribution and regulation. Nat. Chem. Biol. 2008, 4, 176–185. [CrossRef] [PubMed]
58. Miles, A.T.; Hawksworth, G.M.; Beattie, J.H.; Rodilla, V. Induction, regulation, degradation, and biological significance of mammalian metallothioneins. Crit. Rev. Biochem. Mol. Biol. 2000, 35, 35–70. [CrossRef] [PubMed]
59. Miura, N.; Koizumi, S. [Heavy metal responses of the human metallothionein isoform genes]. Yakugaku Zasshi 2007, 127, 665–673. [CrossRef] [PubMed]
60. Colvin, R.A.; Holmes, W.R.; Fontaine, C.P.; Maret, W. Cytosolic zinc buffering and muffling: Their role in intracellular zinc homeostasis. Metallomics 2010, 2, 306–317. [CrossRef] [PubMed]
61. Forma, E.; Krzeslak, A.; Wilkosz, J.; Jozwiak, P.; Szymczyk, A.; Rozanski, W.; Brys, M. Metallothionein 2A genetic polymorphisms and risk of prostate cancer in a polish population. Cancer Genet. 2012, 205, 432–435. [CrossRef] [PubMed]
62. Krzeslak, A.; Forma, E.; Chwatko, G.; Jozwiak, P.; Szymczyk, A.; Wilkosz, J.; Rozanski, W.; Brys, M. Effect of metallothionein 2A gene polymorphism on allele-specific gene expression and metal content in prostate cancer. Toxicol. Appl. Pharmacol. 2013, 268, 278–285. [CrossRef] [PubMed]
63. Krzeslak, A.; Forma, E.; Jozwiak, P.; Szymczyk, A.; Smolarz, B.; Romanowicz-Makowska, H.; Rozanski, W.; Brys, M. Metallothionein 2A genetic polymorphisms and risk of ductal breast cancer. Clin. Exp. Med. 2014, 14, 107–113. [CrossRef] [PubMed]
64. Joshi, B.; Ordonez-Ercan, D.; Dasgupta, P.; Chellappan, S. Induction of human metallothionein 1G promoter by VEGF and heavy metals: Differential involvement of E2F and metal transcription factors. Oncogene 2005, 24, 2204–2217. [CrossRef] [PubMed]
65. Fujie, T.; Segawa, Y.; Kimura, T.; Fujiwara, Y.; Yamamoto, C.; Satoh, M.; Naka, H.; Kaji, T. Induction of metallothionein isoforms by copper diethyldithiocarbamate in cultured vascular endothelial cells. J. Toxicol. Sci. 2016. in press.
66. Ma, H.; Su, L.; Yue, H.; Yin, X.; Zhao, J.; Zhang, S.; Kung, H.; Xu, Z.; Miao, J. Hmbox1 interacts with MT2A to regulate autophagy and apoptosis in vascular endothelial cells. Sci. Rep. 2015, 5. [CrossRef] [PubMed]
67. Peng, B.; Gu, Y.; Xiong, Y.; Zheng, G.; He, Z. Microarray-assisted pathway analysis identifies MT1X & NFαB as mediators of TCRP1-associated resistance to cisplatin in oral squamous cell carcinoma. PLoS ONE 2012, 7, e51413.
68. Nakane, H.; Hirano, M.; Ito, H.; Hosono, S.; Oze, I.; Matsuda, F.; Tanaka, H.; Matsuo, K. Impact of metallothionein gene polymorphisms on the risk of lung cancer in a Japanese population. Mol. Carcinog. 2015, 54 (Suppl. 1), E122–E128. [CrossRef] [PubMed]
69. Imoto, A.; Okada, M.; Okazaki, T.; Kitasato, H.; Harigae, H.; Takahashi, S. Metallothionein-1 isoforms and vimentin are direct PU.1 downstream target genes in leukemia cells. J. Biol. Chem. 2010, 285, 10300–10309. [CrossRef] [PubMed]
70. Hirako, N.; Nakano, H.; Takahashi, S. A PU.1 suppressive target gene, metallothionein 1G, inhibits retinoic acid-induced NB4 cell differentiation. PLoS ONE 2014, 9, e103282. [CrossRef] [PubMed]
71. Kimura, T.; Itoh, N. Function of metallothionein in gene expression and signal transduction: Newly found protective role of metallothionein. J. Health Sci. 2008, 54, 251–260. [CrossRef]
72. Kita, K.; Miura, N.; Yoshida, M.; Yamazaki, K.; Ohkubo, T.; Imai, Y.; Naganuma, A. Potential effect on cellular response to cadmium of a single-nucleotide AÑG polymorphism in the promoter of the human gene for metallothionein IIA. Hum. Genet. 2006, 120, 553–560. [CrossRef] [PubMed]
73. Yoshida, M.; Ohta, H.; Yamauchi, Y.; Seki, Y.; Sagi, M.; Yamazaki, K.; Sumi, Y. Age-dependent changes in metallothionein levels in liver and kidney of the Japanese. Biol. Trace Elem. Res. 1998, 63, 167–175. [CrossRef] [PubMed]
74. Miura, N. Individual susceptibility to cadmium toxicity and metallothionein gene polymorphisms: With references to current status of occupational cadmium exposure. Ind. Health 2009, 47, 487–494. [CrossRef] [PubMed]
75. Majumder, S.; Ghoshal, K.; Li, Z.; Bo, Y.; Jacob, S.T. Silencing of metallothionein-I gene in mouse lymphosarcoma cells by methylation. Oncogene 1999, 18, 6287–6295. [CrossRef] [PubMed]
76. Ghoshal, K.; Majumder, S.; Li, Z.; Dong, X.; Jacob, S.T. Suppression of metallothionein gene expression in a rat hepatoma because of promoter-specific DNA methylation. J. Biol. Chem. 2000, 275, 539–547. [CrossRef] [PubMed]
77. Ghoshal, K.; Datta, J.; Majumder, S.; Bai, S.; Dong, X.; Parthun, M.; Jacob, S.T. Inhibitors of histone deacetylase and DNA methyltransferase synergistically activate the methylated metallothionein I promoter by activating the transcription factor MTF-1 and forming an open chromatin structure. Mol. Cell. Biol. 2002, 22, 8302–8319. [CrossRef] [PubMed]
78. Li, Y.; Kimura, T.; Huyck, R.W.; Laity, J.H.; Andrews, G.K. Zinc-induced formation of a coactivator complex containing the zinc-sensing transcription factor MTF-1, p300/CBP, and Sp 1. Mol. Cell. Biol. 2008, 28, 4275–4284. [CrossRef] [PubMed]
79. Okumura, F.; Li, Y.; Itoh, N.; Nakanishi, T.; Isobe, M.; Andrews, G.K.; Kimura, T. The zinc-sensing transcription factor MTF-1 mediates zinc-induced epigenetic changes in chromatin of the mouse metallothionein-I promoter. Biochim. Biophys. Acta. 2011, 1809, 56–62. [CrossRef] [PubMed]
80. Rao, S.; Procko, E.; Shannon, M.F. Chromatin remodeling, measured by a novel real-time polymerase chain reaction assay, across the proximal promoter region of the IL-2 gene. J. Immunol. 2001, 167, 4494–4503. [CrossRef] [PubMed]
81. De La Serna, I.L.; Carlson, K.A.; Hill, D.A.; Guidi, C.J.; Stephenson, R.O.; Sif, S.; Kingston, R.E.; Imbalzano, A.N. Mammalian SEI-SNF complexes contribute to activation of the hsp70 gene. Mol. Cell. Biol. 2000, 20, 2839–2851. [CrossRef] [PubMed]
82. Kurita, H.; Ohsako, S.; Hashimoto, S.; Yoshinaga, J.; Tohyama, C. Prenatal zinc deficiency-dependent epigenetic alterations of mouse metallothionein-2 gene. J. Nutr. Biochem. 2013, 24, 256–266. [CrossRef] [PubMed]
83. Kimura, T.; Li, Y.; Okumura, F.; Itoh, N.; Nakanishi, T.; Sone, T.; Isobe, M.; Andrews, G.K. Chromium(VI) inhibits mouse metallothionein-I gene transcription by preventing the zinc-dependent formation of an MTF-1-p300 complex. Biochem. J. 2008, 415, 477–482. [CrossRef] [PubMed]
84. Majumder, S.; Kutay, H.; Datta, J.; Summers, D.; Jacob, S.T.; Ghoshal, K. Epigenetic regulation of metallothionein-I gene expression: Differential regulation of methylated and unmethylated promoters by DNA methyltransferases and methyl CpG binding proteins. J. Cell. Biochem. 2006, 97, 1300–1316. [CrossRef] [PubMed]
85. Schnekenburger, M.; Talaska, G.; Puga, A. Chromium cross-links histone deacetylase 1-DNA methyltransferase 1 complexes to chromatin, inhibiting histone-remodeling marks critical for transcriptional activation. Mol. Cell. Biol. 2007, 27, 7089–7101. [CrossRef] [PubMed]
86. Huang, L.; Tepaamorndech, S. The SLC30 family of zinc transporters—A review of current understanding of their biological and pathophysiological roles. Mol. Asp. Med. 2013, 34, 548–560. [CrossRef] [PubMed]
87. Jeong, J.; Eide, D.J. The SLC39 family of zinc transporters. Mol. Asp. Med. 2013, 34, 612–619. [CrossRef] [PubMed]
88. Fujishiro, H.; Okugaki, S.; Yasumitsu, S.; Enomoto, S.; Himeno, S. Involvement of DNA hypermethylation in down-regulation of the zinc transporter ZIP8 in cadmium-resistant metallothionein-null cells. Toxicol. Appl. Pharmacol. 2009, 241, 195–201. [CrossRef] [PubMed]
89. Kumar, L.; Michalczyk, A.; McKay, J.; Ford, D.; Kambe, T.; Hudek, L.; Varigios, G.; Taylor, P.E.; Ackland, M.L. Altered expression of two zinc transporters, SLC30A5 and SLC30A6, underlies a mammary gland disorder of reduced zinc secretion into milk. Genes Nutr. 2015, 10. [CrossRef] [PubMed]
90. Zhang, Y.; Yang, J.; Cui, X.; Chen, Y.; Zhu, V.F.; Hagan, J.P.; Wang, H.; Yu, X.; Hodges, S.E.; Fang, J. et al. A novel epigenetic CREB-miR-373 axis mediates ZIP4-induced pancreatic cancer growth. EMBO Mol. Med. 2013, 5, 1322–1334. [CrossRef] [PubMed]
91. Weaver, B.P.; Andrews, G.K. Regulation of zinc-responsive Slc39a5 (Zip5) translation is mediated by conserved elements in the 31-untranslated region. Biometals 2012, 25, 319–335. [CrossRef] [PubMed]
92. Kambe, T. Zinc Transport: Regulation. Encycl. Inorg. Bioinorg. Chem. 2013. [CrossRef]
93. Dufner-Beattie, J.; Huang, Z.L.; Geiser, J.; Xu, W.; Andrews, G.K. Mouse ZIP1 and ZIP3 genes together are essential for adaptation to dietary zinc deficiency during pregnancy. Genesis 2006, 44, 239–251. [CrossRef] [PubMed]
94. Dufner-Beattie, J.; Huang, Z.L.; Geiser, J.; Xu, W.; Andrews, G.K. Generation and characterization of mice lacking the zinc uptake transporter ZIP3. Mol. Cell. Biol. 2005, 25, 5607–5615. [CrossRef] [PubMed]
95. Peters, J.L.; Dufner-Beattie, J.; Xu, W.; Geiser, J.; Lahner, B.; Salt, D.E.; Andrews, G.K. Targeting of the mouse Slc39a2 (Zip2) gene reveals highly cell-specific patterns of expression, and unique functions in zinc, iron, and calcium homeostasis. Genesis 2007, 45, 339–352. [CrossRef] [PubMed]
96. Kambe, T.; Geiser, J.; Lahner, B.; Salt, D.E.; Andrews, G.K. Slc39a1 to 3 (subfamily II) Zip genes in mice have unique cell-specific functions during adaptation to zinc deficiency. Am. J. Physiol. Regul. Integr. Comp. Physiol. 2008, 294, R1474–R1481. [CrossRef] [PubMed]
97. Kelleher, S.L.; Lopez, V.; Lonnerdal, B.; Dufner-Beattie, J.; Andrews, G.K. Zip3 (Slc39a3) functions in zinc reuptake from the alveolar lumen in lactating mammary gland. Am. J. Physiol. Regul. Integr. Comp. Physiol. 2009, 297, R194–R201. [CrossRef] [PubMed]
98. Qian, J.; Xu, K.; Yoo, J.; Chen, T.T.; Andrews, G.; Noebels, J.L. Knockout of Zn transporters Zip-1 and Zip-3 attenuates seizure-induced ca1 neurodegeneration. J. Neurosci. 2011, 31, 97–104. [CrossRef] [PubMed]
99. Kury, S.; Dreno, B.; Bezieau, S.; Giraudet, S.; Kharfi, M.; Kamoun, R.; Moisan, J.P. Identification of SLC39A4, a gene involved in acrodermatitis enteropathica. Nat. Genet. 2002, 31, 239–240. [CrossRef] [PubMed]
100. Wang, K.; Zhou, B.; Kuo, Y.M.; Zemansky, J.; Gitschier, J. A novel member of a zinc transporter family is defective in acrodermatitis enteropathica. Am. J. Hum. Genet. 2002, 71, 66–73. [CrossRef] [PubMed]
101. Schmitt, S.; Kury, S.; Giraud, M.; Dreno, B.; Kharfi, M.; Bezieau, S. An update on mutations of the SLC39A4 gene in acrodermatitis enteropathica. Hum. Mutat. 2009, 30, 926–933. [CrossRef] [PubMed]
102. Kambe, T.; Hashimoto, A.; Fujimoto, S. Current understanding of ZIP and ZnT zinc transporters in human health and diseases. Cell. Mol. Life Sci. 2014, 71, 3281–3295. [CrossRef] [PubMed]
103. Geiser, J.; Venken, K.J.; De Lisle, R.C.; Andrews, G.K. A mouse model of acrodermatitis enteropathica: Loss of intestine zinc transporter ZIP4 (Slc39a4) disrupts the stem cell niche and intestine integrity. PLoS Genet. 2012, 8, e1002766. [CrossRef] [PubMed]
104. Dufner-Beattie, J.; Weaver, B.P.; Geiser, J.; Bilgen, M.; Larson, M.; Xu, W.; Andrews, G.K. The mouse acrodermatitis enteropathica gene Slc39a4 (Zip4) is essential for early development and heterozygosity causes hypersensitivity to zinc deficiency. Hum. Mol. Genet. 2007, 16, 1391–1399. [CrossRef] [PubMed]
105. Guo, H.; Jin, X.; Zhu, T.; Wang, T.; Tong, P.; Tian, L.; Peng, Y.; Sun, L.; Wan, A.; Chen, J. et al. SLC39A5 mutations interfering with the BMP/TGF-α pathway in non-syndromic high myopia. J. Med. Genet. 2014, 51, 518–525. [CrossRef] [PubMed]
106. Geiser, J.; De Lisle, R.C.; Andrews, G.K. The zinc transporter Zip5 (Slc39a5) regulates intestinal zinc excretion and protects the pancreas against zinc toxicity. PLoS ONE 2013, 8, e82149. [CrossRef] [PubMed]
107. Waterworth, D.M.; Ricketts, S.L.; Song, K.; Chen, L.; Zhao, J.H.; Ripatti, S.; Aulchenko, Y.S.; Zhang, W.; Yuan, X.; Lim, N. et al. Genetic variants influencing circulating lipid levels and risk of coronary artery disease. Arterioscler. Thromb. Vasc. Biol. 2010, 30, 2264–2276. [CrossRef] [PubMed]
108. Ehret, G.B.; Munroe, P.B.; Rice, K.M.; Bochud, M.; Johnson, A.D.; Chasman, D.I.; Smith, A.V.; Tobin, M.D.; Verwoert, G.C.; Hwang, S.J. et al. Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk. Nature 2011, 478, 103–109. [CrossRef] [PubMed]
109. Galvez-Peralta, M.; He, L.; Jorge-Nebert, L.F.; Wang, B.; Miller, M.L.; Eppert, B.L.; Afton, S.; Nebert, D.W. ZIP8 zinc transporter: Indispensable role for both multiple-organ organogenesis and hematopoiesis in utero. PLoS ONE 2012, 7, e36055. [CrossRef] [PubMed]
110. Kim, J.H.; Jeon, J.; Shin, M.; Won, Y.; Lee, M.; Kwak, J.S.; Lee, G.; Rhee, J.; Ryu, J.H.; Chun, C.H. et al. Regulation of the catabolic cascade in osteoarthritis by the zinc-ZIP8-MTF1 axis. Cell 2014, 156, 730–743. [CrossRef] [PubMed]
111. Park, J.H.; Hogrebe, M.; Gruneberg, M.; DuChesne, I.; von der Heiden, A.L.; Reunert, J.; Schlingmann, K.P.; Boycott, K.M.; Beaulieu, C.L.; Mhanni, A.A. et al. SLC39A8 deficiency: A disorder of manganese transport and glycosylation. Am. J. Hum. Genet. 2015, 97, 894–903. [CrossRef] [PubMed]
112. Boycott, K.M.; Beaulieu, C.L.; Kernohan, K.D.; Gebril, O.H.; Mhanni, A.; Chudley, A.E.; Redl, D.; Qin, W.; Hampson, S.; Kury, S. et al. Autosomal-recessive intellectual disability with cerebellar atrophy syndrome caused by mutation of the manganese and zinc transporter gene SLC39A 8. Am. J. Hum. Genet. 2015, 97, 886–893. [CrossRef] [PubMed]
113. Zhao, L.; Oliver, E.; Maratou, K.; Atanur, S.S.; Dubois, O.D.; Cotroneo, E.; Chen, C.N.; Wang, L.; Arce, C.; Chabosseau, P.L. et al. The zinc transporter ZIP12 regulates the pulmonary vascular response to chronic hypoxia. Nature 2015, 524, 356–360. [CrossRef] [PubMed]
114. Giunta, C.; Elcioglu, N.H.; Albrecht, B.; Eich, G.; Chambaz, C.; Janecke, A.R.; Yeowell, H.; Weis, M.; Eyre, D.R.; Kraenzlin, M. et al. Spondylocheiro dysplastic form of the ehlers-danlos syndrome—An autosomal-recessive entity caused by mutations in the zinc transporter gene SLC39A 13. Am. J. Hum. Genet. 2008, 82, 1290–1305. [CrossRef] [PubMed]
115. Fukada, T.; Civic, N.; Furuichi, T.; Shimoda, S.; Mishima, K.; Higashiyama, H.; Idaira, Y.; Asada, Y.; Kitamura, H.; Yamasaki, S. et al. The zinc transporter SLC39A13/ZIP13 is required for connective tissue development; its involvement in BMP/TGF-α signaling pathways. PLoS ONE 2008, 3, e3642. [CrossRef]
116. Hojyo, S.; Fukada, T.; Shimoda, S.; Ohashi, W.; Bin, B.H.; Koseki, H.; Hirano, T. The zinc transporter SLC39A14/ZIP14 controls G-protein coupled receptor-mediated signaling required for systemic growth. PLoS ONE 2011, 6, e18059. [CrossRef] [PubMed]
117. Beker Aydemir, T.; Chang, S.M.; Guthrie, G.J.; Maki, A.B.; Ryu, M.S.; Karabiyik, A.; Cousins, R.J. Zinc transporter ZIP14 functions in hepatic zinc, iron and glucose homeostasis during the innate immune response (endotoxemia). PLoS ONE 2012, 7, e48679. [CrossRef] [PubMed]
118. Aydemir, T.B.; Sitren, H.S.; Cousins, R.J. The zinc transporter Zip14 influences c-Met phosphorylation and hepatocyte proliferation during liver regeneration in mice. Gastroenterology 2012, 142, 1536–1546. [CrossRef] [PubMed]
119. Jenkitkasemwong, S.; Wang, C.Y.; Coffey, R.; Zhang, W.; Chan, A.; Biel, T.; Kim, J.S.; Hojyo, S.; Fukada, T.; Knutson, M.D. SLC39A14 is required for the development of hepatocellular iron overload in murine models of hereditary hemochromatosis. Cell Metab. 2015, 22, 138–150. [CrossRef] [PubMed]
120. Andrews, G.K.; Wang, H.; Dey, S.K.; Palmiter, R.D. Mouse zinc transporter 1 gene provides an essential function during early embryonic development. Genesis 2004, 40, 74–81. [CrossRef] [PubMed]
121. Chowanadisai, W.; Lonnerdal, B.; Kelleher, S.L. Identification of a mutation in SLC30A2 (ZnT-2) in women with low milk zinc concentration that results in transient neonatal zinc deficiency. J. Biol. Chem. 2006, 281, 39699–39707. [CrossRef] [PubMed]
122. Lasry, I.; Seo, Y.A.; Ityel, H.; Shalva, N.; Pode-Shakked, B.; Glaser, F.; Berman, B.; Berezovsky, I.; Goncearenco, A.; Klar, A. et al. A dominant negative heterozygous G87R mutation in the zinc transporter, ZnT-2 (SLC30A2), results in transient neonatal zinc deficiency. J. Biol. Chem. 2012, 287, 29348–29361. [CrossRef] [PubMed]
123. Itsumura, N.; Inamo, Y.; Okazaki, F.; Teranishi, F.; Narita, H.; Kambe, T.; Kodama, H. Compound heterozygous mutations in SLC30A2/ZnT2 results in low milk zinc concentrations: A novel mechanism for zinc deficiency in a breast-fed infant. PLoS ONE 2013, 8, e64045. [CrossRef] [PubMed]
124. Miletta, M.C.; Bieri, A.; Kernland, K.; Schoni, M.H.; Petkovic, V.; Fluck, C.E.; Eble, A.; Mullis, P.E. Transient neonatal zinc deficiency caused by a heterozygous G87R mutation in the zinc transporter ZnT-2 (SLC30A2) gene in the mother highlighting the importance of Zn2+ for normal growth and development. Int. J. Endocrinol. 2013, 2013. [CrossRef] [PubMed]
125. Lova Navarro, M.; Vera Casano, A.; Benito Lopez, C.; Fernandez Ballesteros, M.D.; Godoy Diaz, D.J.; Crespo Erchiga, A.; Romero Brufau, S. Transient neonatal zinc deficiency due to a new autosomal dominant mutation in gene SLC30A2 (ZnT-2). Pediatr. Dermatol. 2014, 31, 251–252. [CrossRef] [PubMed]
126. Lee, S.; Hennigar, S.R.; Alam, S.; Nishida, K.; Kelleher, S.L. Essential role for zinc transporter 2 (ZnT2)-mediated zinc transport in mammary gland development and function during lactation. J. Biol. Chem. 2015, 290, 13064–13078. [CrossRef] [PubMed]
127. Adlard, P.A.; Parncutt, J.M.; Finkelstein, D.I.; Bush, A.I. Cognitive loss in zinc transporter-3 knock-out mice: A phenocopy for the synaptic and memory deficits of Alzheimer’s disease? J. Neurosci. 2010, 30, 1631–1636. [CrossRef] [PubMed]
128. Sindreu, C.; Palmiter, R.D.; Storm, D.R. Zinc transporter ZnT-3 regulates presynaptic ERK1/2 signaling and hippocampus-dependent memory. Proc. Natl. Acad. Sci. USA 2011, 108, 3366–3370. [CrossRef] [PubMed]
129. Martel, G.; Hevi, C.; Friebely, O.; Baybutt, T.; Shumyatsky, G.P. Zinc transporter 3 is involved in learned fear and extinction, but not in innate fear. Learn. Mem. 2010, 17, 582–590. [CrossRef] [PubMed]
130. Cole, T.B.; Wenzel, H.J.; Kafer, K.E.; Schwartzkroin, P.A.; Palmiter, R.D. Elimination of zinc from synaptic vesicles in the intact mouse brain by disruption of the ZnT3 gene. Proc. Natl. Acad. Sci. USA 1999, 96, 1716–1721. [CrossRef] [PubMed]
131. Hildebrand, M.S.; Phillips, A.M.; Mullen, S.A.; Adlard, P.A.; Hardies, K.; Damiano, J.A.; Wimmer, V.; Bellows, S.T.; McMahon, J.M.; Burgess, R. et al. Loss of synaptic Zn2+ transporter function increases risk of febrile seizures. Sci. Rep. 2015, 5. [CrossRef] [PubMed]
132. Huang, L.; Gitschier, J. A novel gene involved in zinc transport is deficient in the lethal milk mouse. Nat. Genet. 1997, 17, 292–297. [CrossRef] [PubMed]
133. McCormick, N.H.; Lee, S.; Hennigar, S.R.; Kelleher, S.L. ZnT4 (SLC30A4)-null (“lethal milk”) mice have defects in mammary gland secretion and hallmarks of precocious involution during lactation. Am. J. Physiol. Regul. Integr. Comp. Physiol. 2015, 310, R33–R40. [CrossRef] [PubMed]
134. Inoue, K.; Matsuda, K.; Itoh, M.; Kawaguchi, H.; Tomoike, H.; Aoyagi, T.; Nagai, R.; Hori, M.; Nakamura, Y.; Tanaka, T. Osteopenia and male-specific sudden cardiac death in mice lacking a zinc transporter gene, Znt 5. Hum. Mol. Genet. 2002, 11, 1775–1784. [CrossRef] [PubMed]
135. Nishida, K.; Hasegawa, A.; Nakae, S.; Oboki, K.; Saito, H.; Yamasaki, S.; Hirano, T. Zinc transporter Znt5/Slc30a5 is required for the mast cell-mediated delayed-type allergic reaction but not the immediate-type reaction. J. Exp. Med. 2009, 206, 1351–1364. [CrossRef] [PubMed]
136. Huang, L.; Yu, Y.Y.; Kirschke, C.P.; Gertz, E.R.; Lloyd, K.K. Znt7 (Slc30a7)-deficient mice display reduced body zinc status and body fat accumulation. J. Biol. Chem. 2007, 282, 37053–37063. [CrossRef] [PubMed]
137. Sladek, R.; Rocheleau, G.; Rung, J.; Dina, C.; Shen, L.; Serre, D.; Boutin, P.; Vincent, D.; Belisle, A.; Hadjadj, S. et al. A genome-wide association study identifies novel risk loci for type 2 diabetes. Nature 2007, 445, 881–885. [CrossRef] [PubMed]
138. Saxena, R.; Voight, B.F.; Lyssenko, V.; Burtt, N.P.; de Bakker, P.I.; Chen, H.; Roix, J.J.; Kathiresan, S.; Hirschhorn, J.N.; Daly, M.J. et al. Genome-wide association analysis identifies loci for type 2 diabetes and triglyceride levels. Science 2007, 316, 1331–1336. [PubMed]
139. Zeggini, E.; Weedon, M.N.; Lindgren, C.M.; Frayling, T.M.; Elliott, K.S.; Lango, H.; Timpson, N.J.; Perry, J.R.; Rayner, N.W.; Freathy, R.M. et al. Replication of genome-wide association signals in UK samples reveals risk loci for type 2 diabetes. Science 2007, 316, 1336–1341. [CrossRef] [PubMed]
140. Scott, L.J.; Mohlke, K.L.; Bonnycastle, L.L.; Willer, C.J.; Li, Y.; Duren, W.L.; Erdos, M.R.; Stringham, H.M.; Chines, P.S.; Jackson, A.U. et al. A genome-wide association study of type 2 diabetes in Finns detects multiple susceptibility variants. Science 2007, 316, 1341–1345. [CrossRef] [PubMed]
141. O’Halloran, T.V.; Kebede, M.; Philips, S.J.; Attie, A.D. Zinc, insulin, and the liver: A menage a trois. J. Clin. Investig. 2013, 123, 4136–4139. [CrossRef] [PubMed]
142. Pound, L.D.; Sarkar, S.A.; Benninger, R.K.; Wang, Y.; Suwanichkul, A.; Shadoan, M.K.; Printz, R.L.; Oeser, J.K.; Lee, C.E.; Piston, D.W. et al. Deletion of the mouse Slc30a8 gene encoding zinc transporter-8 results in impaired insulin secretion. Biochem. J. 2009, 421, 371–376. [CrossRef] [PubMed]
143. Nicolson, T.J.; Bellomo, E.A.; Wijesekara, N.; Loder, M.K.; Baldwin, J.M.; Gyulkhandanyan, A.V.; Koshkin, V.; Tarasov, A.I.; Carzaniga, R.; Kronenberger, K. et al. Insulin storage and glucose homeostasis in mice null for the granule zinc transporter ZnT8 and studies of the type 2 diabetes-associated variants. Diabetes 2009, 58, 2070–2083. [CrossRef] [PubMed]
144. Lemaire, K.; Ravier, M.A.; Schraenen, A.; Creemers, J.W.; van de Plas, R.; Granvik, M.; van Lommel, L.; Waelkens, E.; Chimienti, F.; Rutter, G.A. et al. Insulin crystallization depends on zinc transporter ZnT8 expression, but is not required for normal glucose homeostasis in mice. Proc. Natl. Acad. Sci. USA 2009, 106, 14872–14877. [CrossRef] [PubMed]
145. Wijesekara, N.; Dai, F.F.; Hardy, A.B.; Giglou, P.R.; Bhattacharjee, A.; Koshkin, V.; Chimienti, F.; Gaisano, H.Y.; Rutter, G.A.; Wheeler, M.B. Beta cell-specific Znt8 deletion in mice causes marked defects in insulin processing, crystallisation and secretion. Diabetologia 2010, 53, 1656–1668. [CrossRef] [PubMed]
146. Tamaki, M.; Fujitani, Y.; Hara, A.; Uchida, T.; Tamura, Y.; Takeno, K.; Kawaguchi, M.; Watanabe, T.; Ogihara, T.; Fukunaka, A. et al. The diabetes-susceptible gene SLC30A8/ZnT8 regulates hepatic insulin clearance. J. Clin. Investig. 2013, 123, 4513–4524. [CrossRef] [PubMed]
147. Flannick, J.; Thorleifsson, G.; Beer, N.L.; Jacobs, S.B.; Grarup, N.; Burtt, N.P.; Mahajan, A.; Fuchsberger, C.; Atzmon, G.; Benediktsson, R. et al. Loss-of-function mutations in SLC30A8 protect against type 2 diabetes. Nat. Genet. 2014, 46, 357–363. [CrossRef] [PubMed]
148. Wenzlau, J.M.; Juhl, K.; Yu, L.; Moua, O.; Sarkar, S.A.; Gottlieb, P.; Rewers, M.; Eisenbarth, G.S.; Jensen, J.; Davidson, H.W. et al. The cation efflux transporter ZnT8 (Slc30A8) is a major autoantigen in human type 1 diabetes. Proc. Natl. Acad. Sci. USA 2007, 104, 17040–17045. [CrossRef] [PubMed]
149. Quadri, M.; Federico, A.; Zhao, T.; Breedveld, G.J.; Battisti, C.; Delnooz, C.; Severijnen, L.A.; di Toro Mammarella, L.; Mignarri, A.; Monti, L. et al. Mutations in SLC30A10 cause parkinsonism and dystonia with hypermanganesemia, polycythemia, and chronic liver disease. Am. J. Hum. Genet. 2012, 90, 467–477. [CrossRef] [PubMed]
150. Tuschl, K.; Clayton, P.T.; Gospe, S.M., Jr.; Gulab, S.; Ibrahim, S.; Singhi, P.; Aulakh, R.; Ribeiro, R.T.; Barsottini, O.G.; Zaki, M.S. et al. Syndrome of hepatic cirrhosis, dystonia, polycythemia, and hypermanganesemia caused by mutations in SLC30A10, a manganese transporter in man. Am. J. Hum. Genet. 2012, 90, 457–466. [CrossRef] [PubMed]
151. Leyva-Illades, D.; Chen, P.; Zogzas, C.E.; Hutchens, S.; Mercado, J.M.; Swaim, C.D.; Morrisett, R.A.; Bowman, A.B.; Aschner, M.; Mukhopadhyay, S. SLC30A10 is a cell surface-localized manganese efflux transporter, and parkinsonism-causing mutations block its intracellular trafficking and efflux activity. J. Neurosci. 2014, 34, 14079–14095. [CrossRef] [PubMed]
152. Marger, L.; Schubert, C.R.; Bertrand, D. Zinc: An underappreciated modulatory factor of brain function. Biochem. Pharmacol. 2014, 91, 426–435. [CrossRef] [PubMed]
153. Maverakis, E.; Fung, M.A.; Lynch, P.J.; Draznin, M.; Michael, D.J.; Ruben, B.; Fazel, N. Acrodermatitis enteropathica and an overview of zinc metabolism. J. Am. Acad. Dermatol. 2007, 56, 116–124. [CrossRef] [PubMed]
154. Andrews, G.K. Regulation and function of Zip4, the acrodermatitis enteropathica gene. Biochem. Soc. Trans. 2008, 36, 1242–1246. [CrossRef] [PubMed]
155. Krezel, A.; Maret, W. Zinc-buffering capacity of a eukaryotic cell at physiological pZn. J. Biol. Inorg. Chem. 2006, 11, 1049–1062. [CrossRef] [PubMed]
156. Fujimoto, S.; Itsumura, N.; Tsuji, T.; Anan, Y.; Tsuji, N.; Ogra, Y.; Kimura, T.; Miyamae, Y.; Masuda, S.; Nagao, M. et al. Cooperative functions of ZnT1, metallothionein and ZnT4 in the cytoplasm are required for full activation of TNAP in the early secretory pathway. PLoS ONE 2013, 8, e77445. [CrossRef] [PubMed]
157. Ishihara, K.; Yamazaki, T.; Ishida, Y.; Suzuki, T.; Oda, K.; Nagao, M.; Yamaguchi-Iwai, Y.; Kambe, T. Zinc transport complexes contribute to the homeostatic maintenance of secretory pathway function in vertebrate cells. J. Biol. Chem. 2006, 281, 17743–17750. [CrossRef] [PubMed]
158. Fukunaka, A.; Suzuki, T.; Kurokawa, Y.; Yamazaki, T.; Fujiwara, N.; Ishihara, K.; Migaki, H.; Okumura, K.; Masuda, S.; Yamaguchi-Iwai, Y. et al. Demonstration and characterization of the heterodimerization of ZnT5 and ZnT6 in the early secretory pathway. J. Biol. Chem. 2009, 284, 30798–30806. [CrossRef] [PubMed]
159. Fukunaka, A.; Kurokawa, Y.; Teranishi, F.; Sekler, I.; Oda, K.; Ackland, M.L.; Faundez, V.; Hiromura, M.; Masuda, S.; Nagao, M. et al. Tissue nonspecific alkaline phosphatase is activated via a two-step mechanism by zinc transport complexes in the early secretory pathway. J. Biol. Chem. 2011, 286, 16363–16373. [CrossRef] [PubMed]
160. Hamza, I.; Faisst, A.; Prohaska, J.; Chen, J.; Gruss, P.; Gitlin, J.D. The metallochaperone Atox1 plays a critical role in perinatal copper homeostasis. Proc. Natl. Acad. Sci. USA 2001, 98, 6848–6852. [CrossRef] [PubMed]
161. Miyayama, T.; Suzuki, K.T.; Ogra, Y. Copper accumulation and compartmentalization in mouse fibroblast lacking metallothionein and copper chaperone, Atox 1. Toxicol. Appl. Pharmacol. 2009, 237, 205–213. [CrossRef] [PubMed]
162. Jeney, V.; Itoh, S.; Wendt, M.; Gradek, Q.; Ushio-Fukai, M.; Harrison, D.G.; Fukai, T. Role of antioxidant-1 in extracellular superoxide dismutase function and expression. Circ. Res. 2005, 96, 723–729. [CrossRef] [PubMed]
163. El Meskini, R.; Culotta, V.C.; Mains, R.E.; Eipper, B.A. Supplying copper to the cuproenzyme peptidylglycine α-amidating monooxygenase. J. Biol. Chem. 2003, 278, 12278–12284. [CrossRef]
164. Lutsenko, S.; Barnes, N.L.; Bartee, M.Y.; Dmitriev, O.Y. Function and regulation of human copper-transporting ATPases. Physiol. Rev. 2007, 87, 1011–1046. [CrossRef] [PubMed]
165. Cherezov, V.; Hofer, N.; Szebenyi, D.M.; Kolaj, O.; Wall, J.G.; Gillilan, R.; Srinivasan, V.; Jaroniec, C.P.; Caffrey, M. Insights into the mode of action of a putative zinc transporter CzrB in thermus thermophilus. Structure 2008, 16, 1378–1388. [CrossRef] [PubMed]