Physiol Rev 95: 749 –784, 2015
Published June 17, 2015; doi:10.1152/physrev.00035.2014
THE PHYSIOLOGICAL, BIOCHEMICAL, AND
MOLECULAR ROLES OF ZINC TRANSPORTERS IN
ZINC HOMEOSTASIS AND METABOLISM
Taiho Kambe, Tokuji Tsuji, Ayako Hashimoto, and Naoya Itsumura
Division of Integrated Life Science, Graduate School of Biostudies, Kyoto University, Kyoto, Japan
Kambe T, Tsuji T, Hashimoto A, Itsumura N. The Physiological, Biochemical, and Molecular
Roles of Zinc Transporters in Zinc Homeostasis and Metabolism. Physiol Rev 95: 749–784,
2015; Published June 17, 2015; doi:10.1152/physrev.00035.2104.—Zinc is involved in
a variety of biological processes, as a structural, catalytic, and intracellular and intercellular signaling component. Thus zinc homeostasis is tightly controlled at the whole
body, tissue, cellular, and subcellular levels by a number of proteins, with zinc transporters being
particularly important. In metazoan, two zinc transporter families, Zn transporters (ZnT) and Zrt-,
Irt-related proteins (ZIP) function in zinc mobilization of influx, efflux, and compartmentalization/
sequestration across biological membranes. During the last two decades, significant progress has
been made in understanding the molecular properties, expression, regulation, and cellular and
physiological roles of ZnT and ZIP transporters, which underpin the multifarious functions of zinc.
Moreover, growing evidence indicates that malfunctioning zinc homeostasis due to zinc transporter
dysfunction results in the onset and progression of a variety of diseases. This review summarizes
current progress in our understanding of each ZnT and ZIP transporter from the perspective of zinc
physiology and pathogenesis, discussing challenging issues in their structure and zinc transport
mechanisms.
L
I.
II.
III.
IV.
V.
VI.
VII.
VIII.
INTRODUCTION
SYSTEMIC AND CELLULAR ZINC...
STRUCTURAL, BIOCHEMICAL, AND...
CELLULAR AND PHYSIOLOGICAL...
CELLULAR AND PHYSIOLOGICAL...
ZnT AND ZIP TRANSPORTERS IN...
ZnT AND ZIP TRANSPORTER...
CONCLUSIONS AND FUTURE...
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I. INTRODUCTION
Zinc is the second most abundant trace element (after iron)
essential for all living organisms. Zinc exists as a divalent
cation (Zn2⫹) and is not redox active under physiological
conditions, which explains why zinc performs multifarious
physiological roles in a variety of biological processes
2⫹
(TABLE 1). This feature of Zn
hampered its detection, and
clarification of the dynamic state of zinc was a challenge
until recent improvements in zinc-imaging techniques became available, including small fluorescent sensor molecules, FRET molecules designed to sense zinc ions, X-ray
fluorescence microscopy, and laser ablation inductively
coupled, plasma mass spectrometry (99, 174, 335, 338,
412, 425).
For zinc to perform its diverse bioactive roles, a number of
specific systems to transport zinc across the biological membrane are required. Thus zinc transport proteins are indis-
pensable for the physiology of zinc. In particular, Zn transporter (ZnT) and Zrt-, Irt-related proteins (ZIP) contribute
to a wide array of physiological and cellular functions (e.g.,
immune, endocrine, reproductive, skeletal, and neuronal)
by tightly controlling zinc homeostasis. The physiological
importance of this homeostasis in humans is illustrated by
the deleterious consequences of inherited diseases (reviewed
in Refs. 110, 111, 191, 194).
In this review, recent progress in our understanding of the
physiological and cellular roles of ZnT and ZIP transporters is summarized. Molecular links between the dysfunction
of these transporters with diseases are also discussed, along
with brief descriptions of phenotypes of knockout and mutant model organisms. Besides ZnT and ZIP transporters, a
number of other membrane transport proteins such as calcium channels have been shown to be involved in zinc homeostasis (40), but these are not discussed here. Some literature refers to “ZIP” as a “channel” (243, 401); however,
in this review, “ZIP” is described as a “transporter.”
A. The Essentiality of Zinc for Life and in
Human Physiology
Zinc is a trace nutrient indispensable for life. The importance of zinc for living organisms was first recognized in
1869 in Aspergillus niger (344). Subsequently, zinc was
found to be essential for the normal development of plants
(277) and for normal growth of rats (411) and birds (301).
0031-9333/15 Copyright © 2015 the American Physiological Society
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KAMBE ET AL.
Table 1. Representative examples of a wide variety of zinc functions
Zinc Functions
Structural component
Catalytic factor
Signaling mediator
(Zinc signaling)
Comments
Zinc fingers
C2H2-like finger; classical zinc finger motif, transcription factor TFIIIA, 20–30
amino acid sequence
Zinc ribbon; many transcription factors, ribosomal proteins, RanBP
Treble clefs; RING finger domain, Arf-GAP domain, LIM domain, FYVE domain,
PHD domain, MYND domain, nuclear receptor DNA-binding domain, GATA,
PKC
Zinc necklaces; TAZ domain in transcriptional adaptor protein CBP/p300
Interprotein binding mediator (e.g., zinc hock motif)
Crystallization of peptides such as insulin
Enzyme cofactors in six main enzyme classes
Oxidoreductase; alcohol dehydrogenase, sorbitol dehydrogenase
Transferase; the major function of zinc is not catalytic in this class (only 34% are
catalytic)*
Hydrolase; carboxypeptidases, alkaline phosphatases, angiotensin-converting
enzyme
Lyase; carbonic anhydrase, ␦-aminolevulinic acid dehydratase
Isomerase; phosphomannose isomerase
Ligase; the major function of zinc is not catalytic in this class (only 39% are
catalytic)*
Extracellular zinc signaling
Neuromodulating functions in the central nervous system
Activating zinc receptor (ZnR/GPR39)
Reducing insulin secretion and suppressing hepatic insulin clearance
Intracellular zinc signaling
Second messenger functions
Inhibition of enzyme activity (caspases, protein tyrosine phosphatases,
phosphodiesterases)
Modulation of signaling pathways (PKC, ERK, JAK/STAT, BMP/TGF-␤, NF-␬B,
cAMP-CREB, PI3K/Akt, B-cell receptor)
Zinc wave; zinc release in cytosol from perinuclear region
Zinc spark; zinc ejection from oocyte, which is necessary for the egg-to-embryo
transition
Reference Nos.
6, 119, 222,
263, 421
165, 361
364
5, 420, 421
5
5
112
104, 367, 394
28, 372
124, 396
112
111, 156
140, 161, 175,
266, 427
111, 112, 144,
146, 156
401, 451
211, 342
*Percentages refer to EC numbers associated with zinc enzymes of known structure (5).
However, not until 1961 was zinc identified as an essential
micronutrient for humans, with symptoms of severe anemia, growth retardation, hypogonadism, skin abnormalities, and mental lethargy attributed to nutritional zinc deficiencies (332). After this seminal finding, many symptoms
caused by zinc deficiency have been described, including
persistent diarrhea, alopecia, taste disorders, immune insufficiency, brain dysfunctions, impairment of wound healing,
loss of appetite, chronic inflammation, liver disease, and
neuropsychological changes such as emotional instability,
irritability, and depression (reviewed in Refs. 80, 147, 267,
329, 356, 395, 421).
ized countries. Zinc supplementation in humans has the potential
to decrease diarrhea mortality in children as well as the incidence
of infections and to improve immune functions (142, 314, 331,
416). Moreover, the efficacy of zinc supplements in boosting
health and well-being is revealed in various cases: in growth and
body weight gain of children in the meta-analysis (43) and in
decreasing incidences of blindness and the risk of developing agerelated macular degeneration (2). Zinc has low toxicity and is
generally considered to be safe; however, excessive amounts of
zinc can be toxic, e.g., leading to inadequate absorption of copper
(42). The roles of zinc in human health have been extensively
reviewed previously (347).
Zinc deficiency still remains a substantial global public health
problem (147, 330, 357). Zinc deficiency in developing countries
is estimated to be responsible for 4% of the global morbidity and
mortality of young children (314). In contrast, an increase in
marginal zinc deficiency is evident in older people in industrial-
B. Zinc Biochemistry
750
Unlike iron and copper, zinc is redox neutral and is reactive as a
Lewis acid in biological reactions. Because of these features, zinc
plays key roles as a structural, catalytic, and signaling component.
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ROLE OF ZINC TRANSPORTERS IN ZINC HOMEOSTASIS AND METABOLISM
As a structural component in proteins, the association of zinc
with proteins/peptides was first verified by crystallization of insulin with zinc (364). The “zinc finger” motif was first found in the
transcription factor TFIIIA of Xenopus (284). Zinc fingers are
now grouped into more than 20 classes of structurally distinct
modules and are known to be a functional motif that interacts
with a variety of proteins, lipids, and nucleic acids (6, 26, 119,
222, 227) (TABLE 1), clearly indicating the importance of zinc
in cellular biochemistry. In catalytic functions, zinc can activate substrates in enzymes by stabilizing negative charges, because of its strong Lewis acid property (264). After the first
identification of zinc in erythrocyte carbonic anhydrase as a
zinc-dependent enzyme (205), the presence of zinc has been
recognized in many enzymes in all six classes defined in the
Enzyme Commission (EC) system (5, 420, 421) (TABLE 1).
Within proteins, zinc can be coordinated by nitrogen, oxygen, and sulfur atoms and can have different coordination
numbers (216, 263). The zinc proteome estimates that
⬃9% of proteins are zinc proteins in eukaryotes with the
number substantially greater in higher organisms. The
number of zinc proteins encoded by humans is ⬃10% (4).
In zinc proteomes, the number of zinc-binding motifs is
counted primarily based on mining for intramolecular zincbinding sites. Intermolecular zinc-binding sites consisting of
an interface between two or more proteins are generally
difficult to identify (7, 265), although a number of important examples have been found (165, 361). Additionally,
the prediction of transient zinc binding sites cannot be identified using sequence homology. Thus the size of zinc proteomes may grow in the future (45).
C. Zinc Signaling
In addition to the roles of zinc described above, zinc is
functional as a signaling mediator (TABLE 1), leading to the
concept that zinc is the “the calcium of the 21st century”
(104). The signaling functions of zinc occur by increases in
zinc (Zn2⫹) concentrations triggered by stimuli. Zinc-activated signaling is associated with pathophysiological functions (111, 156) and therefore has therapeutic potential.
Extracellular release of zinc acts as a signaling mediator in
endocrine, paracrine, and autocrine systems. In the central
nervous system, zinc, which is released from presynaptic
neurons upon excitation into synaptic clefts, modulates
synaptic transmission by binding to various transporters
and receptor channels on postsynaptic neurons (104, 367,
394). Zinc, coreleased from pancreatic ␤-cells along with
insulin by glucose stimuli, can suppress hepatic insulin clearance (396) and reduce insulin secretion from the ␤-cells (124,
396). Extracellular release of zinc binds to various cell surface
proteins, and the most intriguing protein is the zinc receptor,
the G protein-coupled receptor 39 (GPR39) (28, 372).
Zinc plays crucial signaling roles as a second messenger in
the cytosol (111, 156), where zinc signaling is caused by
zinc influx, which originates from extracellular sites and
from intracellular organelles. Zinc released from the perinuclear area, including the endoplasmic reticulum (ER), is
referred to as a “zinc wave,” which has been shown to be
important for cell signaling functions (401, 451). Moreover, zinc, liberated from cytosolic proteins with oxidationsensitive zinc-binding sites such as metallothionein (MT)
via oxidative stimuli, is also involved in intracellular zinc
signaling (11, 141). Intracellular zinc signaling is divided
into several classes according to the timescale in which it
acts (reviewed in Refs. 111, 144, 146, 156). “Fast” or
“early” zinc signaling occurs within seconds to minutes
after stimulation and does not require transcription of proteins (143, 451). Conversely, “late” zinc signaling requires
biosynthesis of proteins to control cytosolic zinc concentrations and occurs over a period of hours after stimulation
(215). The word “late” zinc signaling is generally used, to
contrast with the word “fast” or “early” zinc signaling.
This term describes downstream effects mediated through
changes in gene expression, not signaling events. Importantly, intracellular zinc signaling targets a number of enzymes involved in cellular signaling, including protein tyrosine phosphatases (PTPs) (41, 448), phosphodiesterases
(PDEs) (161, 427), calcineurin (14), caspases (285, 423),
and various kinases such as mitogen-activated protein kinase (MAPK) and protein kinase C (PKC) (72, 149). Physiological levels of intracellular free Zn2⫹ concentrations
regulate these enzymes, e.g., inhibition of caspase-3, T-cell
PTP, and PTP-1B is achieved with IC50 values below 10,
200, and 17 nM, respectively (140, 266). Inhibition of the
activity of PTPs by zinc is generally operative in intracellular zinc signaling. The enzymatic activity of caspase-9 is
reversibly inhibited by zinc binding to cysteine and histidine
residues in the active site (175), and similar reversible inhibition mechanisms operate in other enzymes such as PTPs (141).
Specifically, inhibition of PTP-1B activity by zinc is probably
mediated via a cysteinyl-phosphate intermediate (23). Zinc
signaling has been extensively reviewed previously (112).
D. A History of the Discovery of ZIP and ZnT
Zinc Transporters
The first zinc transporter protein, Zrc1, was identified in
Saccharomyces cerevisiae (199) and confers resistance
against high concentrations of cations, including zinc.
Subsequently, COT1 of S. cerevisiae and CzcD of Cupriavidus (formerly Ralstonia) metallidurans strain
CH34 were identified (64, 298) and also confer resistance
against zinc and other metals such as cobalt, manganese,
and cadmium. The three proteins show high sequence
homology in the transmembrane (TM) regions [the cation efflux domain (pfam01545)] (18). Thus their homolog
proteins are named cation diffusion facilitator (CDF) proteins
(313), which are found at all phylogenetic levels (115, 196,
286). CDF proteins from mammals were identified a few years
later, with the first transporter ZnT1 identified by an elegant
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KAMBE ET AL.
strategy involving the conferment of zinc resistance to zincsensitive mutant BHK cells (309). After this discovery, other
ZnT transporters were identified using mutant BHK cells and
yeast, as well as EST and genome databases (189, 196, 239,
250). ZnT transporters are assigned to the Solute Carrier family 30A (SLC30A) (310) and designated ZnT1-ZnT10 (FIGURE 1A). However, ZnT9 is probably a misnomer, because ZnT9 acts as nuclear receptor coactivator with
sequence homology to a cation efflux domain (51) (see
sect. IV).
Compared with ZnT transporters, the identification of ZIP
transporters is more complicated. ZIP6, which was referred
to as LIV-1 initially, was identified as an estrogen-inducible
gene associated with estrogen-regulated growth of human
breast cancer cells (259). However, its contribution to zinc
homeostasis was confirmed later (399, 405). The first characterized member of ZIP transporters was the iron-regulated transporter 1 (Irt1) of Arabidopsis thaliana (92).
Then, zinc-regulated transporter 1 (Zrt1) and Zrt2 were
discovered in S. cerevisiae using the sequence of Irt1 (460,
461). The “ZIP (Zrt-, Irt-related protein)” was named after
the original members Irt and Zrt (96, 131). ZIP transporters
are found in all kingdoms of life (115, 196, 363). Soon
afterwards, mammalian ZIP members, ZIP2 and ZIP1,
were characterized as zinc transporters that facilitate the
A ZnT transporters
B ZIP transporters
752
FIGURE 1. Structural features and functional
domains and motifs of ZnT and ZIP transporters. A: the generalized domain structure of ZnT
such as the TM domains, the positions of histidine residues (fitting to HX1– 6H), and those of
serine, arginine, and lysine residues are shown.
B: the generalized domain structure of ZIP, including the TM domains, metalloprotease-like
motif, the CPALLY motif, and the positions of
histidine residues (fitting to HX1– 6H) are shown.
The length of amino acid residues in both transporters is shown on the right. [Modified from
Fukada and Kambe (110) with permission from
The Royal Society of Chemistry.]
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ROLE OF ZINC TRANSPORTERS IN ZINC HOMEOSTASIS AND METABOLISM
uptake of zinc into the cells (116, 117). The completion of
the human genome sequence led to the identification of all
ZIP members in mammals (196, 239). ZIP transporters
constitute 14 members designated ZIP1-ZIP14 (FIGURE 1B)
and are assigned to the SLC39A family (93, 184). ZIP members mainly transport zinc, but can also mobilize iron (120,
247), manganese, and cadmium (107, 127, 183).
Currently, a number of mutations responsible for inherited disorders have been identified in ZnT and ZIP transporter genes and
are therefore of particular clinical interest (194) (see sect. VI).
II. SYSTEMIC AND CELLULAR ZINC
HOMEOSTASIS
A. Zinc Homeostasis in the Body
The adult human body contains ⬃2–3 g of zinc. Approximately 60% of zinc is stored in skeletal muscle, ⬃30% in
bone, ⬃5% in the liver and skin, and the remaining 2–3%
in other tissues (181) (FIGURE 2). Serum zinc accounts for
only ⬃0.1% of the body’s zinc, ⬃80% of which is loosely
bound to albumin and ⬃20% of that is tightly bound to
␣2-macroglobulin (17, 346). In the body, ⬃0.1% of the
body zinc is replenished daily through diet. The absorption
of zinc in the duodenum and jejunum is strictly regulated; it
increases up to 90% when dietary zinc is limited (398),
whereas zinc release, when in excess, is facilitated by the
gastrointestinal secretion, sloughing mucosal cells and integument, and renal excretion (148, 219). Humans appear
to have the capacity to regulate whole body zinc content
over a 10-fold change in intake (213).
In general, more than 30 proteins, including ZnT and ZIP
transporters, operate under strict coordinated regulation
for the maintenance of systemic and cellular zinc homeostasis in mammals; however, humoral mediators, which
indicate the zinc status in a cell or tissue to other organs
that import and store zinc, have not been identified in
Dietary zinc
Duodenum,
Jejunum
Absorption
Liver
[~5%]
Brain
Serum zinc
[~0.1%]
Bone
[~30%]
Skin
[~5%]
FIGURE 2. Scheme for zinc distribution in
the body. Dietary zinc is absorbed in the
small intestine (duodenum and jejunum) and
then distributed to peripheral tissues. Approximately 60% of zinc is stored in skeletal
muscle, ⬃30% in bones, and ⬃5% is stored
in the liver and skin. The remaining percentage is distributed to other tissues such as
the brain, kidney, and pancreas. Excess zinc
is excreted through gastrointestinal secretion, sloughing mucosal cells, and integument. Zinc distribution in the body is elaborately controlled through coordinated regulation by ZnT and ZIP transporters.
Pancreas
Skeletal muscle
[~60%]
Kidney
Gastrointestinal secretion
Sloughing mucosal cells and integument
Renal excretion
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KAMBE ET AL.
zinc metabolism. This is in contrast to iron metabolism,
where a short peptide hormone hepcidin plays a critical
role in systemic iron homeostasis (296). The recent finding that a low-molecular-weight (2 kDa) zinc-regulated
humoral factor, which is likely induced in zinc deficiency,
controls gene expression particularly associated with
immune functions and development in smooth muscle
cells is interesting (304) and suggests that a short peptide
operates as a humoral factor in systemic zinc homeostasis.
(265, 305) (see sect. IC). The labile zinc concentrations in
intracellular organelles have been measured as 0.14 pM
in the mitochondria (311), 0.2 pM in the mitochondrial
matrix (279), 0.9 pM in the ER, and ⬃0.2 pM in the
Golgi (337), while much higher (⬃300 pM and 5 nM)
concentrations in the mitochondria and the ER are also
described (48). This huge discrepancy in zinc concentrations in the ER and Golgi has not been explained in
convincing detail, although the differences may be due to
changes of ligand binding or improper folding caused by
variables such as pH or the oxidizing environment in
their lumen, because the values were measured by different FRET systems. The precise determination of labile
zinc concentrations in the cytosol and lumen in subcellular compartments is of current interest and further importance.
B. Cellular Zinc Distribution
In cells, zinc is distributed in the cytoplasm (50%), nucleus (30 – 40%), and membrane (10%) (146, 408). The
total cellular zinc concentration is thought to range between tens and hundreds of micromolar (61, 221, 309).
Zinc is, however, bound with a myriad of proteins and
sequestered into organelles and vesicles, and thus the
cytosolic labile (“free”) zinc ion concentration is very
low and is considered to range between the picomolar
and low nanomolar (305, 337, 366, 425) (FIGURE 3).
Several lines of evidence indicate that the zinc concentration fluctuates in response to various stimuli, as illustrated by the “zinc wave” (see above) (451) and “zinc
spark” (see below) (211) phenomena, and temporal fluctuations of zinc play crucial functions in zinc signaling
The cellular and subcellular zinc homeostasis is achieved
through sophisticated regulation of uptake, distribution,
storage, and efflux, in which ZnT and ZIP transporters
play fundamental roles. Zinc mobilization between intracellular vesicles and organelles by these transporters also
contributes to buffer perturbations of cytosolic zinc homeostasis, which is termed “buffering” and “muffling”
(62, 262). Buffering and muffling are important in situations of excess zinc conditions and also play a role in zinc
ion fluctuations (265).
~100 μM
(even up to 300 μM)
Zinc spark
(oocyte)
ZIP
ZnT
Synaptic vesicles
(neurons)
ZIP
Insulin granules
(pancreatic β cells)
pM ~ low nM
(Cytosol)
(mast cells)
(Paneth cells)
TGN
Golgi apparatus
~0.2 pM
(Golgi)
Zinc wave
ER
0.9 pM or 5 nM
(ER)
MT
Nucleus
0.14 pM or 300 pM
(Mitochondria)
Metalloproteins
ZnT
754
FIGURE 3. Scheme for zinc distribution in
cells. ZnT (green arrows) and ZIP (red arrows) transporters coordinate to regulate
cellular zinc homeostasis. The total cellular
zinc concentration is considered to be 10s–
100s ␮M, but almost all zinc ions (Zn2⫹) in
the cytosol are tightly bound to a host of metalloproteins and MTs, or sequestered into or
released from intracellular organelles/vesicles through ZnT or ZIP transporters, respectively. Thus the labile (“free”) Zn2⫹ concentration in the cytosol is very low (considered to range between the picomolar and low
nanomolar levels). The labile Zn2⫹ concentrations in some subcellular compartments are
also shown. However, there is no current
consensus about the values in the ER and
Golgi. The labile Zn2⫹ is present in the mitochondria, but the route to enter has not been
clarified. High amounts of labile zinc accumulate in specialized secretory compartments,
such as synaptic vesicles and insulin granules, in a number of cells. The cellular zinc
concentration fluctuates through various
ways, such as zinc waves and zinc sparks
(see text). Yellow circles, Zn2⫹; pink circles,
glutamate.
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ROLE OF ZINC TRANSPORTERS IN ZINC HOMEOSTASIS AND METABOLISM
C. Zinc Containing Vesicles/Granules in
Cells
Zinc has the unique feature that high amounts of chelatable
and labile zinc are accumulated in a number of cells and
tissues (FIGURE 3). The most well-known is in telencephalic
neurons (151, 316); ⬃20% of zinc is found within the synaptic vesicles of a subset of glutamatergic neurons in the
hippocampus and cerebral cortex (60) (see sect. IVC). Zinc
released from synaptic vesicles is estimated to reach ⬃100
␮M (426), and even up to 300 ␮M (13). The prostate (138,
276) is another tissue where the accumulation of zinc is 3to 15-fold higher than levels found in other soft tissues (200
nmol zinc/g wet wt on average) (103). However, high zinc
levels are drastically reduced in prostate cancer and carcinomas (125), indicating the importance of zinc in proper
prostate metabolism (65). High levels of zinc accumulate in
pancreatic ␤-cells (457), which is required for insulin crystallization. Similarly, a high concentration of zinc is detected in the growth hormone-containing, dense-core secretory granules of anterior pituitary cells (319, 410), as well
as submandibular salivary gland epithelial and myoepithelial cells (105), sperm cells (77), pancreatic exocrine cells
(223), pigment epithelial cells in the retina (3), Paneth cells
in the intestine (289), and mast cells (136). Importantly, the
biological and physiological roles of zinc in these cells and
tissues remain poorly understood.
Zinc accumulation in subcellular compartments is found in
specific processes. For example, large amounts of zinc are
imported and localized in the cortical granules of oocytes
during meiotic maturation from the prophase I to the metaphase (211, 218, 342), which is required for growth arrest
after the first meiotic division (211). The accumulated zinc
is ejected from the oocyte to decrease bioavailable zinc during egg activation immediately following intracellular calcium oscillations, which is termed the “zinc spark” (211). In
addition to zinc-containing granules and vesicles detected
under normal physiological conditions, zinc also accumulates in subcellular compartments under particular pathological conditions. When cells are cultured in high zinc conditions, cytosolic vesicles containing high amounts of zinc
appear and are often referred to as zincosomes (31, 441).
However, the intracellular vesicles and organelles corresponding to zincosomes are not clearly defined. High zinc
accumulation has been reported in lysosomal compartments of cells treated with drugs (58), and in neurons for
some neurodegenerative diseases and their model cells (91,
224, 415).
D. Metallothioneins and MTF-1
A portion of the cytosolic zinc pool (5–15%) is bound by
MTs. There are ⬃12 in humans and 4 in mice (70). MTs are
composed of 61– 68 amino acids, including 20 –21 cysteines, and can incorporate up to 7 atoms of zinc and other
divalent metals with different affinities. The zinc-binding
domain is divided into two clusters: the more stable ␣-domain and the more reactive ␤-domain. The number of zinc
atoms bound to MT is heterogeneous in vivo, e.g., ⬃10% of
MT is present as the apo-protein in the liver (220). MTs are
not simply important for cytosolic zinc storage but are functional as zinc acceptors and donors. Because their sulfur
donors coordinating zinc are redox reactive, oxidation of
the sulfur donors leads to the release of zinc, which contributes to intracellular zinc signaling (see sect. IC).
In mice, expression of Mt-I and Mt-II is increased significantly by excess zinc through binding of metal-response
element-binding transcription factor-1 (MTF-1) to the
metal response element (MRE, 5=-TGCRCnCGGCCC-3=)
in the promoter (387). MTF-1, the only zinc-sensing transcription factor in vertebrates (444), has six C2H2 zincfinger domains, which contribute to the zinc-sensing and
metal-dependent transcriptional activation functions, and
function as DNA-binding domains (226). When cellular
zinc levels increase, MTF-1 plays a central role in zinc homeostasis by increasing transcription of a host of genes
involved in reducing the toxicity of high zinc concentrations, such as MTs, ZnT1, and ZnT2 (134, 229, 387), and
in addition, repressing expression of a set of genes involved
in zinc uptake such as ZIP10 (241, 449). In the latter case,
MTF-1 physically impairs Pol II movement (241). MTF-1 is
essential for embryonic liver development (132); however,
the relationship of zinc to this process remains unclear.
Intriguingly, various zinc-sensing transcription factors have
been identified in all kingdoms of life, but their homologs
have not been identified in vertebrates (55).
III. STRUCTURAL, BIOCHEMICAL, AND
MOLECULAR ASPECTS OF ZnT AND
ZIP ZINC TRANSPORTERS
Nine ZnT and 14 ZIP transporters have been identified and
characterized over the past two decades (110, 197, 239)
(FIGURE 4). ATP hydrolysis is not required for their zinc
mobilization across the biological membrane and thus these
proteins are assigned to the SLC family members (see sect.
ID). The expression levels of “active” zinc transporters at
cellular sites, where they normally operate, is critical for
defining net zinc transport (191), because zinc (Zn2⫹) does
not require a redox reaction when crossing the cellular
membrane, unlike iron and copper. Thus both ZnT and ZIP
transporters are indispensable for tightly controlled integrated processes of zinc uptake and efflux, sequestration
and release across biological membranes, and a wide variety
of zinc functions (see TABLE 1).
A. ZnT Transporters
ZnT transporters mobilize zinc from the cytosol into the
extracellular space and the lumens of intracellular compart-
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KAMBE ET AL.
ZIP1
ZIP2
ZIP3
ZIP4
ZIP5
ZIP6
ZIP8
ZIP9
ZIP10 ZIP12 ZIP14
ZnT4
ZnT3
ZnT8
Synaptic vesicles
(neurons)
Insulin granules
(pancreatic β cells)
ZnT2
Secretory vesicles
(mammary epithelial cells)
ZnT4
ZnT10
Golgi apparatus
ZnT7
TGN
ZIP9
ZIP11
ZIP13
ZnT5-ZnT6
ER
ZIP7
ZIP8
ZnT2
ZnT10
Nucleus
FIGURE 4. Subcellular localization and the
direction of zinc transport of ZnT and ZIP
transporters. The primary localization of ZnT
(green arrows) and ZIP (red arrows) transporters in cells is shown according to available
information. This illustrates a static view of
their localization, because most ZnT and ZIP
transporters dynamically change their subcellular localization in response to various stimuli
(191). The cytosolic zinc is transported into or
out of the different subcellular compartments,
including the cell-specific secretory compartments such as synaptic vesicles or insulin
granules. TGN, trans-Golgi network.
ZnT4
Early endosomes
Endosomes/Lysosomes
ZnT1
ments, and most of the ZnT transporters operate by transporting zinc into the luminal sides (172, 189, 239, 310)
(FIGURES 4 AND 5A). There is no structural information of
ZnT transporters; however, there is a body of information
describing the structure of a bacterial homolog, YiiP (67,
135, 254, 255) (FIGURE 5B), which greatly contributes to
our understanding of ZnT transporters. YiiP has six TM
helices with cytosolic NH2 and COOH termini and functions as a homodimer. TM helices I, II, IV, and V form the
compact four-helix bundle where four conserved hydrophilic residues of TM helices II and V (three aspartic acids
and one histidine, DD-HD) form a intramembranous zincbinding site (FIGURE 5B). The tetrahedral coordination of
zinc by DD-HD is essential, because mutation of aspartic
acid residues in the DD-HD motif to nonliganding alanine
abolishes zinc transport activity (439). In the zinc transport
process, the TM helices of the monomers move closer together, and the cytoplasmic part of the four-helix bundle
moves away from the TM helix III–VI pair (67, 135, 254,
255).
YiiP effluxes zinc, which is coupled with proton influx in a
1:1 zinc for proton exchange stoichiometry (49). The zinc/
proton (Zn2⫹/H⫹) exchange mechanism is conserved in
ZnT transporters (303, 375) and involves an alternating
access mechanism (67, 135). In this mechanism, YiiP forms
inward- and outward-facing conformations, both of which
are able to bind Zn2⫹ or H⫹, and the extracellular proton
provides a driving force for exporting Zn2⫹ from the cytosol (67). A leucine residue in TM helix V, which is next to
756
the conserved histidine (H) forming the intramembranous
zinc-binding site and is located at the interface between the
TM helix III–VI pair and the four-helix bundle, is suggested
to be important as a principal hydrophobic barrier to control the opening of the intercavity water portal (135). The
cytosolic COOH-terminal portion of YiiP forms a binuclear
zinc-binding site, which may function to stabilize YiiP homodimers. Alternatively, this region may sense zinc ion concentrations and regulate zinc transport activity of YiiP
through triggering a scissor-like conformational change
and thereby modulating the coordination of Zn2⫹ at the
intramembranous zinc-binding site in the four-helix bundle
(254, 255). In this autoregulation mechanism, YiiP operates
allosterically in a zinc-regulated manner. Compared with
the TM helices domain, the cytosolic COOH-terminal portion forming the binuclear zinc-binding site has a high degree of sequence variability, but has been shown to be a
highly conserved metallochaperone-like structure with an
␣␤␤␣ fold in bacterial ZnT homologs (52, 155, 255). Thus
the operation mechanism of zinc transport should be conserved among CDF members, including ZnT transporters.
Based on the structural properties of YiiP, ZnT transporters
have been biochemically characterized. ZnT transporters
are predicted to have six TM helices with the exception that
ZnT5 has a long NH2-terminal portion with nine putative
TM helices. ZnT transporters form homodimers (114, 180,
230, 231, 291, 353, 391), again with the exception that
ZnT5 forms heterodimers with ZnT6 (114, 195, 230). The
cytosolic COOH-terminal portion, which is important for
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ROLE OF ZINC TRANSPORTERS IN ZINC HOMEOSTASIS AND METABOLISM
their dimerization (114, 353), contributes to other proteinprotein interactions and enables ZnT transporters to control the activity of counterpart proteins or to be controlled
by counterpart proteins (114, 186, 189, 355).
ZnT transporters are functional in a Zn2⫹/H⫹ exchange
manner (303, 375), in which two aspartic acids and two
A
Zn2+
Zn2+
H+
I
IV
histidines of TM helices II and V (HD-HD) in the four-helix
bundle are thought to form an intramembranous zinc-binding site (FIGURE 5C). The introduction of mutations in the
HD-HD motif abolishes zinc transport activity (106, 113,
303, 375). The position of the histidine in TM helix II
probably plays an important role in determining metal
substrate specificity, because substitution of HD-HD to
II
H+
Extracellular or
luminal side
VI III
V
D
Zn2+
H
Zn2+
H
D
Cytosol
NH2
H2N
Histidine-rich loop
H+
Zn2+
Zn2+
H+
Zn2+ Zn2+
HOOC
B
C
COOH
FIGURE 5. Putative topologies of ZnT
transporters. A: the schematic topology of
ZnT transporter, proposed based on the
X-ray structure of their E. coli homolog, YiiP
(254, 255) shown in B. ZnT transporters
are thought to operate as Y-shaped dimers
with six TM helices (except for ZnT5). TM
helices I, II, IV, and V probably form a compact four-helix bundle where four conserved hydrophilic residues (HD-HD) of TM
helices II and V form the intramembranous
zinc-binding site. ZnT transporters are
functional as Zn2⫹/H⫹ exchangers. The cytosolic histidine-rich loop is thought to be
implicated in sensing and translocating zinc
to the HD-HD site. The actual protein length
of each transporter is shown in FIGURE
1A. B: the ribbon representation of the
homodimeric YiiP structure (PDB 3H90).
The side view (left) and top view (right) from
the extracellular side are shown. Yellow
spheres represent bound zinc ions in zincbinding sites. TM helices II and V are colored by blue and purple, respectively. C: the
sequences of TM helices II and V of YiiP and
human ZnT transporters are aligned. The
highlighted conserved hydrophilic residues
in multiple alignments are predicted to
form the intramembranous zinc-binding
site. The indicated TM helices of ZnT5 correspond to TM helices XI and XIV.
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KAMBE ET AL.
A
Glycosylation
PrP-like
ectodomain
H2N
NH2
CPALLY
motif
HOOC
I
IV II II
VIII VII VI V
Zn
COOH
Extracellular or
luminal side
I
2+
H
Zn2+
H
Cytosol
CHEXPHEXGD motif
Zn2+
Zn2+
B
FIGURE 6. Predicted topologies of ZIP
transporters. A: the predicted membrane topology of ZIP transporter is shown. ZIP transporters are thought to form homodimers
with eight TM helices. The highlighted two
histidine residues in TM helices IV and V are
speculated to be involved in an intramembranous zinc-binding site. The members of the
LIV-1 subfamily are characterized by a long
extracellular amino-terminal portion containing the CPALLY motif and the CHEXPHEXGD
motif in TM helix V. The PrP-like domain is
also found in some ZIP transporters (ZIP5,
ZIP6, and ZIP10). The arrow indicates the
predicted processing site around the CPALLY
motif in some ZIP transporters (ZIP4, ZIP6,
and ZIP10). The long extracellular amino-terminal portion of most LIV-1 subfamily members is generally highly glycosylated (90,
127, 285, 402, 430, 431). The image is
simplified and does not reflect the relative
sizes of each ZIP transporter. The actual protein length of each transporter is shown in
FIGURE 1B. B: the sequences of TM helices
IV and V of human ZIP transporters are
aligned. The conserved hydrophilic residues
in multiple alignments are highlighted, in
which two conserved histidines indicated by
arrowheads are speculated to be involved in
an intramembranous zinc-binding site.
DD-HD changes zinc-specific transport to zinc and cadmium transport in ZnT transporters (158). An asparagine is
present in ZnT10 (that is ND-HD), which can function as a
manganese transporter (see sect. IVI) (341, 417) (FIGURE
5C). The DD-HD motif is found in YiiP, which transports
both zinc and cadmium, but not manganese (158), while the
DD-DD is found in plant ZnT homologs that transport
manganese (137, 286). In yeast and plant ZnT homologs,
many amino acids other than HD-HD have been shown to
affect metal specificity (202, 242), and some of them are
conserved in ZnT transporters. Therefore, further clarifying the relationship between the motif and metal specificity
is required.
mission of entry of zinc to the HD-HD in the four-helix
bundle (202, 203, 391). In several ZnT transporters, another conserved short histidine-rich sequence found in the
cytosolic NH2-terminal portion may also contribute to
sensing and translocating of zinc to the HD-HD site (12).
The cytosolic histidine-rich loop between TM helices IV
and V is another characteristic of ZnT transporters (FIGURE
1). Deletion and mutational analyses suggest that the histidine-rich loop may be functional as a sensor of cytosolic
zinc levels (202, 325), and be involved in controlling per-
ZIP transporters function by replenishing cytosolic zinc
from the extracellular space and the lumens of intracellular
compartments (184, 189, 239) (FIGURES 4 AND 6A). Most
ZIP transporters are localized to the plasma membrane, and
their cell-surface localization, except for ZIP5, increases
758
Generally, CDF transporters are classified into three groups
(with 13 clusters), namely, Zn-CDF, Zn/Fe-CDF, and MnCDF. Unlike bacteria and plants, all ZnT transporters belong to the Zn-CDF group (286).
B. ZIP Transporters
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ROLE OF ZINC TRANSPORTERS IN ZINC HOMEOSTASIS AND METABOLISM
under zinc-deficient conditions (56, 85, 116, 161, 207, 241,
246, 249, 402, 431). Rapid internalization and degradation
occurs to these transporters in response to excess zinc (168,
261, 437). There are no three-dimensional structures of ZIP
transporters and their homologs. Hydrophobicity plots
suggest that these transporters have eight TM helices with
extracellular/luminal NH2 and COOH termini (184, 189,
239). ZIP transporters and their homologs form homodimers for zinc transport activity (32, 243), and their
apparent Km values range from hundreds of nanomolar to
⬃20 ␮M when overexpressed in the cells (10, 78, 84, 116,
117, 246, 323, 431), although ZIP12 has a much lower Km
(56). Currently, the zinc transport mechanism of ZIP transporters has not been well defined. A bicarbonate/zinc symport mechanism is suggested in several ZIP transporters
(116, 127, 152). However, a nonsaturable and electrogenic
zinc transport fashion was revealed in a purified bacterial
ZIP homolog when reconstituted into proteoliposomes
(243). The channel-like zinc transport fashion is also supported by evidence that phosphorylation can trigger zinc
transport by a ZIP transporter (401).
The zinc substrate specificity for ZIP transporters is not
strict, and they are involved in iron, manganese, copper,
and cadmium transport. The determinants of metal specificity of ZIP transporters have not been completely defined,
but a conserved histidine residue in TM helix V may play a
crucial role, which is speculated to be involved in an intramembranous zinc-binding site (FIGURE 6B), if it operates
as a “transporter.” The histidine is replaced by glutamic
acid in ZIP8 and ZIP14 (FIGURE 6B), both of which are
known to have broad metal specificity (107, 127, 183).
How ZIP transporters determine their selectivity to zinc or
other metals has been of interest.
ZIP transporters are classified into subfamilies I, II, LIV-1,
and gufA, according to their sequence similarities (115,
399, 405) (see sect. V). ZIP I and guf-A include a single
member, respectively. ZIPII consists of three ZIP transporters, and thus the LIV-1 subfamily is the most populous
subfamily (405). The sequence diversity of LIV-1 subfamily
transporters mirrors their wide range of biological functions. Nonetheless, some features are common, in particular,
a potential metalloprotease-like motif (CHEXPHEXGD) in TM
helix V and an extracellular CPALLY motif located before
the first TM helix (FIGURES 1 AND 6). The functional significance of the CHEXPHEXGD motif has not been elucidated, but may be involved in regulating zinc transport by
closing the pore through the formation of a disulfide bond
between its first cysteine, which is highly conserved among
LIV-1 members localized to the plasma membrane, and that
of the CPALLY motif (404). The NH2-terminal portion
containing the CPALLY motif is cleaved in some LIV-1
subfamily transporters (ZIP4, ZIP6, and ZIP10) (referred
to as “processing”) (90, 159, 192), and thus processing may
operate to open the pore to facilitate uptake of zinc into
cells. Moreover, processing is likely to be important for
regulating their cellular trafficking (159). Intriguingly, an
evolutionary link has been proposed in the extracellular
portion between some LIV-1 subfamily transporters (ZIP5,
ZIP6, and ZIP10) and the prion proteins, in which the PrPlike amino acid sequence is found (89, 90, 324, 363). These
results suggest that particular ZIP transporters may be involved in the etiology of prion diseases.
IV. CELLULAR AND PHYSIOLOGICAL
FUNCTIONS OF EACH ZnT
TRANSPORTER
A. ZnT1
ZnT1 is the only ZnT transporter that is localized mainly to
the plasma membrane and functions by exporting cytosolic
zinc into the extracellular space (309). Thus ZnT1 protects
cells from excess zinc influx under pathological conditions,
such as transient forebrain ischemia (414). Upregulated
ZnT1 mRNA due to increases in cellular zinc levels, which
is mediated by MREs in its promoter in a fashion similar to
MT (229), probably contributes to the protection function
of ZnT1 (see sect. IID).
In polarized epithelial cells, ZnT1 is localized to the basolateral membrane. Thus ZnT1 facilitates the absorption of
zinc by exporting it into the portal blood in enterocytes
(280) and similarly the reabsorption of zinc in kidney epithelial cells (239). In contrast, ZnT1 is localized to the apical membrane in pancreatic acinar cells and is implicated in
pancreatic secretion of zinc (69). ZnT1 also localizes to
intracellular vesicles in some cell types (87, 106) and to the
ER in keratinocytes by forming hetero-complexes with
EVER proteins, which are responsible for Epidermodysplasia verruciformis (EV), a rare autosomal recessive skin disease (OMIM 226400) (232). The molecular mechanism underlying the specific localization of ZnT1 is not well understood, except for ER localization.
ZnT1 interacts with various intracellular proteins, which
contributes to its roles in cellular signaling. ZnT1 binds to
the NH2-terminal regulatory region of Raf-1, a signal transducer of the Ras-ERK pathway, which promotes Raf-1 activation. This activation is likely to occur through lowering
the cytosolic zinc level, which inhibits their interaction, possibly releasing zinc from the cysteine-rich domain of Raf-1
(186). The regulation of Raf-1 activity by ZnT1 contributes
to the protection of cells from ischemia reperfusion (21).
ZnT1, which forms a hetero-complex with EVER proteins,
downregulates the transcription factors stimulated by
MTF-1, c-Jun, and Elk. ZnT1 also interacts with the regulatory ␤-subunit of the L-type calcium channel (LTCC),
which reduces the capacity of the ␤-subunit to chaperone
the pore-forming ␣1-subunit of LTCC to the cell surface
(236). ZnT1 enhances the activity and surface expression of
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KAMBE ET AL.
the T-type calcium channel, which is regulated via activation of Ras-ERK signaling (287). Upregulation of ZnT1 in
response to lipopolysaccharide (LPS) stimulation is involved in TLR signaling by decreasing intracellular zinc
levels in dendritic cells (215). ZnT1 is essential during embryonic development, because deletion of the Znt1 gene in
mice results in embryonic lethal (9) (TABLE 2).
B. ZnT2
ZnT2 is a zinc transporter that confers cells with zinc resistance by transporting surplus cytosolic zinc into the lumen
of vesicular compartments, including endosomes/lyso-
somes, to which it is localized (100, 180, 307). ZnT2 is also
localized to the ER in breast cancer cells (38), the zymogen
granules in pancreatic acinar cells (134, 249), and the inner
mitochondrial membrane of mammary cells (370). The alternative splicing variant of ZnT2 locates to the plasma
membrane (253). Abundant ZnT2 mRNA expression is observed in mammary glands, prostate, pancreas, small intestine, kidney, and retina (235, 248, 308), which is upregulated by high zinc levels via the MRE located downstream
from the ZnT2 transcription start site (134). Upregulation
of ZnT2 transcription also occurs via a glucocorticoid receptor and STAT5 interaction in pancreatic acinar cells
(134), or via the prolactin-induced JAK2/STAT5 signaling
Table 2. Phenotypes of KO or mutant mice of ZnT transporters
Official
Symbol
Name
Slc30a1
Slc30a2
Slc30a3
Znt1
Znt2
Znt3
Slc30a4
Slc30a5
Znt4
Znt5
Slc30a6
Slc30a7
Znt6
Znt7
Slc30a8
Znt8
Slc30a10
Znt10
Phenotypes of KO or Mutant Mice
KO: embryonic lethal
⫺
KO: slightly higher thresholds to seizures, deficits in learning and memory
in the aged, reduction in hypoglycemia-induced progenitor cell
proliferation and neuroblast production, alternation of protein and gene
expression levels that are important in neurotransmission
Mutation: low zinc in breast milk (lethal milk mouse)
KO: growth retardation, muscle weakness, osteopenia, male-specific
sudden cardiac death, reduction of delayed-type allergic response
mediated by mast cells
⫺
KO: growth retardation, low body zinc accumulation, low fat accumulation,
impaired glucose tolerance and insulin resistance in male mice, possible
involvement in the early onset of prostate tumors
KO: loss of the dense core of zinc-insulin crystals (reduction of zinc content
in islets)
Impairment of glucose-stimulated insulin secretion from isolated islets
Impairment of glucose-stimulated insulin secretion from isolated islets in
high-fat diet feeding
Enhancement of glucose-stimulated insulin secretion from isolated islets
in high-fat diet feeding
Slight enhancement of glucose-stimulated insulin secretion from isolated
islets but reduced plasma insulin levels
Increase in the body weight in high-fat diet feeding
Decrease in the body weight in high-fat diet feeding
Glucose intolerance and diabetic in high-fat diet feeding
␤-Cell specific KO: loss of the dense core of zinc-insulin crystals (reduction
of zinc content in islets)
Glucose intolerance and impairment of glucose-stimulated insulin
secretion
Glucose intolerance, impairment of glucose-stimulated insulin secretion
from isolated islets, and decrease in the body weight in high-fat diet
feeding
Enhancement of glucose-stimulated insulin secretion from isolated islets,
but reduced blood insulin levels, mild glucose intolerance,
enhancement of hepatic insulin clearance
␣-Cell specific KO: no observable changes in plasma glucagon and glucose
homeostasis
⫺
Reference Nos.
9
1, 59, 269, 294, 377,
389
167
177, 299
170, 173, 407
150, 234, 297, 327,
328
327
234
150
297
150, 234, 297
328
150, 234, 297
150, 396, 447
447
150
396
447
Phenotypes of each Znt8 KO mice are shown, because general consensus is lacking among mouse colonies.
KO, knockout; ⫺, no report.
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ROLE OF ZINC TRANSPORTERS IN ZINC HOMEOSTASIS AND METABOLISM
pathway in mammary epithelial cells (334). ZnT2 mRNA
expression is ⬃20-fold higher in the ventral prostate of aged
rats when compared with levels in young rats (176).
ZnT2 is indispensable for zinc mobilization to breast milk
in humans. Mothers with mutations in the ZnT2 gene produce zinc-deficient milk (75–90% reduction), and thus infants exclusively breast-fed by mothers carrying this mutation experience transient neonatal zinc deficiency (TNZD;
OMIM 608118) (57, 180, 231, 283) (see sect. VIB). ZnT2mediated zinc secretion is posttranslationally regulated by
prolactin; prolactin stimulates ZnT2 ubiquitination, which
targets ZnT2 to exocytic vesicles to transiently enhance zinc
secretion, after which ZnT2 is degraded by the ubiquitin
proteasome pathway (369). Overexpression of ZnT2 decreases invasive phenotypes of breast cancer cells (38).
C. ZnT3
ZnT3 is a critical transporter of zinc into synaptic vesicles
of a subset of glutamatergic neurons in the hippocampus
and neocortex (60). The synaptically released zinc from
presynaptic vesicles plays pivotal roles in modulating neuronal transmission and plasticity. This is achieved through
zinc binding to multiple neuronal ligand- and voltage-gated
ion channels, transporters, and receptors of neurotransmitters on postsynaptic neurons (104, 157, 300, 367, 368, 394,
424). ZnT3 probably contributes to the prevention of aging-related cognitive loss, because ZnT3 expression levels
fall with age (1) and in patients with Alzheimer’s disease (1,
34) or Parkinson’s disease dementia (446). Consistent with
these results, aged Znt3-KO mice exhibit deficits in learning
and memory (1, 269, 377). However, young Znt3-KO mice
were first reported to show almost no obvious phenotypes
without slightly higher thresholds to seizures than wild-type
mice, despite the observation that synaptic zinc is essentially
absent (59). Currently, it is reported that Znt3-KO mice
show a reduction in hypoglycemia-induced progenitor cell
proliferation and neuroblast production (389). The fundamental changes in expression of proteins and genes important in neurotransmission are also reported in Znt3-KO
mice (1, 294). Zinc accumulated in synaptic vesicles by
ZnT3 has been shown to play an essential role in presynaptic Erk1/2 signaling during hippocampus-dependent learning (377). In addition, the importance of the synaptic zinc
mediated by ZnT3 has also been revealed in several
knock-in mice studies, where mutations are introduced in
zinc-binding sites of receptors of neurotransmitters (157,
300). Synaptic zinc may contribute to amyloid deposition in
an age-dependent manner (233). Thus proper handling of
zinc into synaptic vesicles by ZnT3 should be critical for
preventing the onset of Alzheimer’s disease.
A brain-specific adaptor protein, AP-3, conducts the trafficking of ZnT3 to the synaptic vesicles through interacting
with the COOH-terminal portion of ZnT3 (355). There-
fore, mocha mice expressing a mutant form of AP-3 show
disturbed localization or loss of ZnT3 and synaptic zinc
(201). Zinc transport activity by ZnT3 in neuronal cells is
potentiated by a chloride channel (354) and a vesicular
glutamate transporter (352).
In addition to the brain, ZnT3 expression is detected in
pancreatic ␤ cells where it is involved in the regulation of
insulin production (379). ZnT3 mRNA is also abundantly
expressed in the testis; however, the ZnT3 protein is not
expressed (308).
D. ZnT4
Znt4 is known as a responsible gene for a spontaneous
mutant lethal milk (lm) mouse (167), which is characterized
by reduced milk zinc levels. Pups die before weaning because of a deficiency in zinc when nursed by affected lm/lm
dams (321). There is no evidence of mutations in the ZnT4
gene of women who produce low milk zinc levels (194,
281), suggesting that zinc supply into breast milk is controlled by species-specific mechanisms. The lm mice can
grow if foster nursed by normal dams, but show congenital
defect of otolith (calcium carbonate crystals in the inner ear)
with delayed righting, “tail-spinning,” and abnormal swimming (98). The lm mice also exhibit extensive hair loss,
dermatitis, and skin lesions over 8 mo of age (98), which are
typical features of zinc deficiency. Thus ZnT4 may be involved in a zinc absorption process in adults.
ZnT4 is found in the endosomes/lysosomes, cytoplasmic
vesicles, Golgi apparatus, and trans-Golgi network (TGN),
which changes during differentiation and high zinc conditions (169, 224, 248, 282, 343). In polarized cells, vesicles
where ZnT4 locates are concentrated to both the apical and
the basal sides, and this localization is dependent on the cell
type (207, 248, 343). ZnT4 plays a role in the maintenance
of cytosolic zinc homeostasis by controlling zinc translocation to the lysosomes, cooperatively with a lysosomal zinc
leak channel, the transient receptor potential mucolipin 1
(TRPML1) (224). Zinc translocated by ZnT4 into TGN is
likely to be supplied to zinc-requiring enzymes, such as
carbonic anhydrase VI (278).
ZnT4 mRNA is ubiquitously expressed, but expression is
relatively higher in the brain and digestive tract (167). In the
villus of the small intestine, ZnT4 expression is dramatically increased during differentiation (16). Upregulation of
ZnT4 mRNA expression, along with ZnT7 mRNA by GMCSF in macrophages, may contribute to the phagocyte antimicrobial effector function by shuttling zinc away from
phagosomes through the mobilization of zinc into the Golgi
apparatus (388). ZnT4 expression decreases in the progression from benign to invasive prostate cancer (153).
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KAMBE ET AL.
E. ZnT5
ZnT5 is localized to the early secretory pathway including
COPII-coated vesicles and the Golgi apparatus (195, 390).
ZnT5 uniquely forms heterodimer complexes with ZnT6
(114, 230, 391), which is conserved in ZnT5 orthologs (94,
101). ZnT5-ZnT6 heterodimers and ZnT7 (see below) have
important biosynthetic functions by delivering zinc into the
early secretory pathway, which is required for the activation of zinc-requiring enzymes such as alkaline phosphatases (ALPs) (113, 390). The activation of ALPs occurs in a
two-step mechanism through stabilizing the enzyme, and
then the conversion of the enzyme from the apo- to the
holo-form with zinc loading (113, 390). ZnT5 contributes
to the homeostatic maintenance of the secretory pathway
functions by supplying zinc into the lumen during zinc deficiency, which induces the unfolded protein response
(UPR) (95, 163, 179). ZnT5 is implicated in the regulation
of cellular signaling, e.g., translocation of PKC to the
plasma membrane (299). The splicing variant of ZnT5 (referred to as hZTL1 or ZnT5B) mediates zinc transport in
the opposite or bidirectional directions at the plasma membrane, which may be because this variant has an extra TM
helix next to the cation efflux domain (71, 419).
ZnT5 mRNA expression is significantly increased by the
UPR inducer through the conserved UPR element (179),
which is a probable feedback regulation mechanism that
maintains homeostasis of the secretory pathway. ZnT5
mRNA is relatively highly expressed in the pancreas, and
the ZnT5 protein is associated with insulin granules in pancreatic ␤-cells (195, 373). However, its contribution to insulin crystallization is minor (190). Meanwhile, ZnT5 may
play an important role in regulating GH secretion (318).
Zinc-induced transcriptional repression of ZnT5 is shown
to be under the control of the zinc transcriptional regulatory
element (ZTRE) (63). The disruption of Znt5 gene in mice
causes poor growth, osteopenia, and male-specific sudden
cardiac death because of the bradyarrhythmia (177), and
also impairs the mast cell-mediated, delayed-type allergic
reaction (299).
F. ZnT6
ZnT6 is a zinc transporter localized to the Golgi apparatus
and TGN (169). However, ZnT6 itself lacks zinc transport
activity, because two histidine residues of the intramembranous zinc-binding site in the four-helix bundle are substituted with leucine and phenylalanine (114, 189) (FIGURE
5C). A serine residue of the cytosolic COOH-terminal portion of ZnT6 is identified as a potential phosphorylation
site (160), which may indicate that ZnT6 is a modulator
subunit of zinc transport activity of ZnT5-ZnT6 heterodimers (114). ZnT6 mRNA expression is less ubiquitous
than ZnT5 mRNA expression (169, 195, 371), and the
subcellular localization of ZnT6 is somewhat distinct from
762
that of ZnT5 (169, 390), e.g., its subcellular localization is
altered under high zinc conditions (169). Therefore, ZnT6
may have specific biological functions in some cell types
that do not involve the formation of the ZnT5-ZnT6 complex.
G. ZnT7
ZnT7 is localized mainly to the early secretory pathway,
including the Golgi apparatus (214). ZnT7 is homologous
to ZnT5 in the cation efflux domain, but ZnT7 cannot
interact with ZnT6, which is attributed to the lower homology in the cytosolic COOH-terminal region between ZnT7
and ZnT5 (114, 189). ZnT7 is involved in the activation of
ALPs (113, 188, 391) and contributes to homeostatic control in the early secretory pathway, cooperatively with
ZnT5-ZnT6 heterodimers (179). ZnT7 is also involved in
cellular signaling, e.g., overexpression of ZnT7 increases
Irs2 and Akt phosphorylation in skeletal muscle cells (170).
The disruption of the Znt7 gene in mice causes poor
growth, decreased adiposity, and reduced absorption of dietary zinc, indicating the involvement of ZnT7 in dietary
zinc absorption and in the regulation of body adiposity.
However, dermatitis and hair abnormality, typical symptoms of zinc deficiency, are not observed (173). Male Znt7deficient mice fed with a high-fat diet are more susceptible
to diet-induced glucose intolerance and insulin resistance
(170). The absence of ZnT7 may promote the early onset of
prostate tumors (407).
H. ZnT8
ZnT8 was identified as a pancreatic ␤-cell-specific zinc
transporter, which enhances glucose-stimulated insulin secretion in a high glucose challenge (53, 54), and afterward
was shown to be expressed in ␣-cells (139). ZnT8 transcription in ␤-cells is regulated by the ␤-cell-enriched transcription factor Pdx-1 through an intronic enhancer (326). ZnT8
plays an indispensable role in supplying zinc to insulin granules in ␤-cells to form insulin-zinc crystals. In a line of
Znt8-KO mice, the dense core of zinc-insulin crystals is lost
because of a reduction in zinc content in ␤-cells (234, 297,
327, 396, 447).
Nonsynonymous single nucleotide polymorphism [SNP;
rs13266634 (R325W)] of the ZnT8 gene is associated with
a high risk of type 2 diabetes mellitus (OMIM 125853)
(359, 365, 378, 458) (see sect. VIC). The ZnT8 variant of
the elevated risk reduces the zinc transport activity of ZnT8
(297). In the evaluation of quantitative traits, the risk allele
(R325) carriers have abnormalities in both glucose-stimulated insulin secretion (GSIS) and insulin processing (35,
385).
In addition to loss of zinc-insulin crystals, Znt8-KO mice
show the effect of ZnT8 abnormalities on glucose-stimu-
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ROLE OF ZINC TRANSPORTERS IN ZINC HOMEOSTASIS AND METABOLISM
lated insulin secretion, glucose tolerance, and body weight,
often when fed a high-fat diet (150, 234, 297, 327, 328,
396, 447), although the observed effects have been highly
variable among mouse colonies (302) (TABLE 2). Some effects are influenced by sex and genetic background (328),
and probably age. Zinc, which is accumulated by ZnT8 in
insulin granules, can reduce insulin secretion from ␤-cells and
suppress hepatic insulin clearance, when being cosecreted with
insulin following glucose stimuli (396). Thus ZnT8 is an
essential component of ␤-cell functions, and dysfunctional
ZnT8 in ␤-cells leads to an increase in the risk of type 2 diabetes. Additionally, non-␤-cell-specific effects of ZnT8 may
contribute to the risk of developing type 2 diabetes (150).
However, contrary to the above evidence, a rare variant association study has shown that haploinsufficiency of ZnT8 is
protective against type 2 diabetes (102). This controversial
relationship between pathogenesis of type 2 diabetes and
ZnT8 function requires further investigation.
ZnT8 is also targeted by autoantibodies in 60 – 80% of
new-onset type 1 diabetes (442). The R risk allele is shown
to be to a key determinant in humoral autoreactivity to
ZnT8 (443) (see sect. VIC).
V. CELLULAR AND PHYSIOLOGICAL
FUNCTIONS OF EACH ZIP
TRANSPORTER
A. ZIP1 (ZIPII Subfamily)
ZIP1 functions as an importer of zinc at the plasma membrane (84, 117). Zinc taken up by ZIP1 contributes to the
activation of microglia by inducing ATP release and autocrine/paracrine activation of P2X7 receptors (154). The
overexpressed ZIP1 on the cell surface is endocytosed,
thereby decreasing in response to excess zinc (429), which is
mediated through the dileucine motif in the cytosolic loop
between TM helices III and IV (168). ZIP1 expression, however, is not zinc responsive in vivo (437). Expression of
ZIP1 is significantly reduced in prostate cancer and carcinoma cells, and parallel decreases in zinc levels are observed
(66, 465), suggesting that ZIP1 expression is indispensable
for normal prostate metabolism. Zip1-KO mice are more
likely to develop abnormally during pregnancy than wildtype mice, when dietary zinc was limited (82) (TABLE 3).
B. ZIP2 (ZIPII Subfamily)
I. ZnT10
ZnT10 is a zinc transporter localized to early/recycling endosomes or the Golgi apparatus (37, 312), which is altered
to the plasma membrane at higher extracellular zinc concentrations (37). Expression of ZnT10 is downregulated by
IL-6 (108) and is suggested to be under the control of
ZTRE, as in ZnT5 (63). The downregulation of ZnT10
along with ZnT3 by angiotensin II may be associated with
cellular senescence in vascular smooth muscle cells (312).
Homozygous mutations of the ZnT10 gene cause Parkinsonism and dystonia with hypermanganesemia, polycythemia, and hepatic cirrhosis (OMIM 613280) (341, 417). In
these patients, not zinc, but systemic and cellular manganese homeostasis was disturbed (341, 417), suggesting that
the primary function of ZnT10 is manganese transport (see
sect. IIIA). The ability of ZnT10 to transport manganese
has been shown recently at the molecular level (237).
ZnT10 mRNA expression is high in the liver and brain,
which is consistent with high manganese accumulation in
these tissues for patients with ZnT10 mutations (341, 417).
ZnT9 was classified to ZnT transporter members, based on
its low sequence similarity to cation efflux domains of ZnT
transporters. However, ZnT9 is thought to have no zinc
transport functions, because it lacks an essential histidine constituting the intramembranous zinc-binding site, and has not
been shown to interact with other ZnT transporters, unlike
ZnT6. Moreover, ZnT9 is predominantly localized in the cytoplasm, and its cell membrane localization was ruled out
(376). ZnT9 acts as nuclear receptor coactivator and is renamed as GAC63 (GRIP1-associated coactivator 63) (51).
ZIP2 imports zinc from the extracellular space (116). Zinc
uptake by ZIP2 is necessary for the differentiation of keratinocytes and for the turnover of the epidermis (178). ZIP2
mRNA expression is relatively low in limited tissues (84,
116), but is significantly induced by zinc deprivation in
monocytes (68) and by GM-CSF in macrophages (388), as
well as during keratinocyte differentiation (178). In the
prostate, ZIP2 expression decreases in carcinomas (79).
Similarly to Zip1-KO mice, Zip2-KO mice are sensitive to
dietary zinc deficiency during pregnancy (317).
C. ZIP3 (ZIPII Subfamily)
ZIP3 imports zinc from the extracellular space. The plasma
membrane localization of ZIP3 changes to intracellular
compartments following zinc treatment (207). The apical
membrane localization of ZIP3 in lactating mammary
glands suggests its role in zinc reuptake from the alveolar
lumen (208). ZIP3 expression increases during differentiation to a secretory phenotype in mammary epithelial cells in
response to prolactin (206).
Zip3-KO mice are more likely to develop abnormally in
zinc-deficient pregnancy (81). Moreover, Zip1- and Zip3double or Zip1-, Zip2-, and Zip3-triple KO mice show
zinc-sensitive phenotypes during pregnancy, which is similar to the corresponding single KO mice (82, 193), indicating that each has unique cell-specific functions for adaptation to a zinc deficiency during development. The involvement of ZIP1 and ZIP3 in zinc entry-induced neural
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KAMBE ET AL.
Table 3. Phenotypes of KO or mutant mice of ZIP transporters
Official
Symbol
Slc39a1
Slc39a2
Slc39a3
Name
Zip1
Zip2
Zip3
Slc39a4
Zip4
Slc39a5
Zip5
Slc39a6
Slc39a7
Slc39a8
Zip6
Zip7
Zip8
Slc39a9
Slc39a10
Zip9
Zip10
Slc39a11
Slc39a12
Slc39a13
Slc39a14
Zip11
Zip12
Zip13
Zip14
Reference
Nos.
Phenotypes of KO or Mutant Mice
KO: abnormal embryonic development in zinc-limited conditions
KO: abnormal embryonic development in zinc-limited conditions
KO: abnormal embryonic development and thymic pre-T cells depletion in zinc-limited
condition
Zip1 and Zip3-double KO: abnormal embryonic development in zinc-limited condition,
attenuation of seizure-induced neural degeneration
Zip1, Zip2, and Zip3-triple KO: abnormal embryonic development in zinc-limited
condition
KO: embryonic lethal
Intestinal conditional KO: disruption of the intestinal integrity
KO: impairment of hepatic zinc excretion in zinc-adequate condition and pancreatic
zinc excretion in zinc-excess conditions
Intestine-specific KO: impairment of pancreatic zinc excretion in zinc-adequate
conditions
Pancreas-specific KO: modest impairment of pancreatic zinc retention in zincadequate conditions
⫺
⫺
Hypomorphic: neonatal lethal (hypoplasia of multiple organs and defects in
hematopoiesis)
Chondrocyte-specific conditional KO: suppression of surgically induced osteoarthritis
pathogenesis
⫺
B cell-specific KO: splenoatrophy with diminished numbers of peripheral B cells and
immunoglobulin levels, poor growth of mature B cells, attenuation of T-celldependent- and -independent-immune responses
⫺
⫺
KO: growth retardation, abnormal development of skeletal and connective tissue
KO: growth retardation, dwarfism, impaired skeletogenesis, impaired
gluconeogenesis, increased body fat, insulin levels and liver glucose,
hypoglycemia, and impairment of hepatocyte proliferation
82
317
81
82, 333
193
86
123
122
122
122
118
212
162, 285
109
15, 22, 161
KO, knockout; ⫺, no report. Phenotypes of Zip1 and Zip3-double KO and Zip1, Zip2 and Zip3-triple KO are
summarized in the row of Zip3-KO.
degeneration has been shown using Zip1- and Zip3-double
KO mice (333).
ZIP1, ZIP2, and ZIP3 expression is often regulated in a
synchronized manner, e.g., their mRNA expression is decreased in lymphocytes in older people when compared
with their expression in young people (126). Moreover,
protein expression of these three transporters decreases in
prostate carcinomas (79), suggesting their potential roles as
tumor suppressors in the prostate. ZIP1 and ZIP3 mRNA
expression significantly increases in allergic airway inflammation (228).
D. ZIP4 (LIV-1 Subfamily)
The ZIP4 gene is responsible for inherited zinc deficiency,
acrodermatitis enteropathica (AE; OMIM 201100) (225,
432). ZIP4 is essential in dietary zinc absorption in mam-
764
mals, which was confirmed by enterocyte-specific deletion
of Zip4 (123). ZIP4 also plays a pivotal role in intestinal
integrity (123). ZIP4 mRNA is highly expressed in the small
intestine, including the duodenum and jejunum (85). ZIP4
expression is strictly regulated by zinc levels and multiple
posttranscriptional mechanisms; ZIP4 mRNA is stabilized
and ZIP4 accumulates on the apical membrane of the small
intestine during zinc deficiency (83, 85, 249, 261, 430,
437). ZIP4 is rapidly endocytosed and then degraded in
ubiquitin-proteasomal and lysosomal degradation pathways in response to high zinc levels (261, 437). ZIP4 undergoes processing (the proteolytic cleavage of the extracellular NH2-terminal portion, see sect. IIIB) during prolonged
zinc deficiency (192). AE-causing mutations in ZIP4 result
in reduced expression, trafficking defects to the plasma
membrane, decreased zinc uptake activity (97, 430), and
inhibition of processing (192). Complete Zip4-KO mice are
embryonic lethal by E8-E9. The heterozygosity of the Zip4
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ROLE OF ZINC TRANSPORTERS IN ZINC HOMEOSTASIS AND METABOLISM
gene in mice is teratogenic and embryotoxic and reveals
pleiotropic phenotypes (86), indicating its essential role
during development.
In other tissues, ZIP4 expression may be involved in diseases. Aberrant expression of ZIP4 is associated with
pathogenesis and progression in cancer and carcinomas
(238, 244, 438). In the case of pancreatic cancer, ZIP4
enhances CREB activity by the uptake of zinc, which transcriptionally increases miR-373 expression, leading to silencing of molecules with tumor suppressor activity (459).
High ZIP4 expression was associated with higher grade of
gliomas and shorter overall survival (244). Conversely, in
prostate carcinoma, ZIP4 expression is downregulated and
thus ZIP4 may act as a tumor suppressor (50).
E. ZIP5 (LIV-1 Subfamily)
ZIP5 is functional as a zinc importer. ZIP5 has moderate
sequence similarity to ZIP4 (36% similarity), particularly in
the COOH-terminal half (49% similarity). However, their
expression in response to zinc and subcellular localization
are reciprocally regulated (83, 437). ZIP5 expression is not
increased but decreased in zinc-depleted environments. In
polarized cells, ZIP5 is localized to the basolateral membrane (83, 431, 437). ZIP5 expression is not regulated at
the transcriptional level, but at the translational level (437).
ZIP5 translation is enhanced, when zinc is available, which
is mediated by a conserved stem-loop and two overlapping
miRNA seed sites in the 3’-untranslated region (435). ZIP5
is abundantly expressed in the small intestine and pancreas
(83). ZIP5 is also expressed during the whole process of eye
development, mainly in the sclera and retina (133). Zinc
mediated by ZIP5 is likely to be involved in the regulation of
Smad protein expression (133). Complete disruption of the
Zip5 gene in mice, and intestine- or pancreas-specific disruption of the Zip5 gene in mice, clearly indicates that ZIP5
participates in the control of zinc excretion. Pancreas-specific Zip5-KO mice revealed that ZIP5 in pancreatic acinar
cells likely functions in zinc accumulation/retention and
protects cells from zinc-induced acute pancreatitis (122).
ZIP5 has the PrP-like ectodomain (see sect. IIIB). Intriguingly, ZIP5 can be colocalized with the cellular prion protein (PrPC) at the plasma membrane and in Rab5 immunoreactive endosomes in neuroblastoma cells (324).
F. ZIP6 (LIV-1 Subfamily)
ZIP6 is localized to the plasma membrane and functional as
zinc transporter (218, 402). ZIP6 can be a growth factorelicited signaling molecule through its zinc influx functions
from the extracellular space, and thereby enhanced zinc
influx mediated by altered ZIP6 expression has been shown
to be closely associated with invasive and metastatic ability
and cancer progression (374, 462). Elevated expression of
ZIP6 is involved in epithelial-mesenchymal transition
(EMT) of breast cancer cells (159), in pancreatic carcinoma
(418), and in prostate cancer cells (256). In particular, the
intimate association of ZIP6 with breast cancer is supported
by a number of studies. Zinc influx mediated by ZIP6 inactivates glycogen synthase kinase 3␤ (GSK-3␤), resulting in
activation of Snail and leading to anoikis resistance (159).
Expression of ZIP6 is associated with estrogen receptor ␣
status (259, 413) and positively correlated with lymph node
involvement (260). Importantly, the ZIP6 gene is a downstream target of STAT3 (159, 452) that is constitutively
activated in many human malignancies (358). These results
indicate that ZIP6 is a new target for the prediction of
clinical cancer spread and also an attractive therapeutic
target for improving metastatic tumors in breast and other
tissues (159, 400). ZIP6 also plays a role in immune functions, e.g., ZIP6 contributes to dendritic cell maturation by
negatively regulating LPS-induced cell surface MHC class II
expression (215), or to tuning the TCR activation threshold
in T cells (455) through increasing zinc influx.
ZIP6 often plays a role in conjunction with its close homolog ZIP10. ZIP6 and ZIP10 promote cell motility of
breast cancer cells by high glucose stimulation (393). Maternally derived ZIP6 and ZIP10 import zinc into the mammalian oocyte for proper meiotic progression, in which
ZIP6 and ZIP10 transcripts are upregulated in a synchronized manner (218).
The trafficking of ZIP6 to the plasma membrane is regulated by processing on the ER (159). Thus the extracellular
NH2-terminal portion containing the PrP-like domain is
missing on the cell surface ZIP6.
G. ZIP7 (LIV-1 Subfamily)
ZIP7 is localized to the early secretory pathway including
the ER and Golgi apparatus (171, 403). Zinc transport
activity of ZIP7 is regulated by phosphorylation by casein
kinase 2 (CK2) protein kinase (401), and its regulated zinc
release from the intracellular stores promotes the activation
of tyrosine kinases, AKT and ERKs, both of which are
involved in regulating cell proliferation and migration
(401). ZIP7 expression levels inversely correlate with phosphorylated GSK3 levels and cellular zinc levels (130), although the molecular mechanism underlying their regulatory relationships is unknown. ZIP7 is implicated in glycemic control in skeletal muscle (292). Glucose-induced ZIP7
expression may facilitate the processing and storage of insulin in pancreatic ␤-cells (24).
Disturbed zinc homeostasis caused by aberrant ZIP7 expression is thought to contribute to growth and invasion,
leading to a more aggressive phenotype in breast cancers
(406). ZIP7 is among 10% of genes consistently overex-
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KAMBE ET AL.
pressed in many breast cancers with poor prognosis (160).
Moreover, ZIP7 expression has been shown to be progressively lost in the occipital lobe of neuronal ceroid lipofuscinosis (CLN6 disease) affected sheep, which suggests that
ZIP7 contributes to deregulation of subcellular zinc homeostasis in the disease (130).
H. ZIP8 (LIV-1 Subfamily)
ZIP8 is localized to the plasma membrane and to the apical
surface in polarized cells (152, 245), and is also localized to
the lysosome (14, 20). In both cases, ZIP8 activity increases
the cytosolic zinc status. ZIP8 mRNA expression is induced
significantly by the stimulus of BCG in monocytes (20).
Increased mRNA expression of ZIP8, with accompanying
lower plasma zinc levels, is reported in sepsis patients (27).
ZIP8 mRNA expression is a transcriptional target of NF␬B, and ZIP8 negatively regulates proinflammatory responses through zinc-mediated downmodulation of I␬B kinase (IKK) activity, thereby inhibiting NF-␬B activity (245).
Thus ZIP8 plays pivotal roles in a negative-feedback loop
that directly regulates the innate immune function (245).
The lysosome-located ZIP8 has functions in TCR-mediated T-cell activation by releasing zinc from the lysosomal lumen (14).
Higher ZIP8 expression is found in the cartilage of patients
with osteoarthritis (212), whose serum zinc levels have been
shown to be higher in clinical studies (306). The higher
expression of ZIP8 in chondrocytes mediates greater zinc
influx into the cells, which activates MTF1, thereby enhancing the expression of matrix-degrading enzymes such as
MMPs that induce cartilage breakdown, and thus is implicated in the pathogenesis of osteoarthritis (212). Ectopic
expression of ZIP8 in cartilage tissue causes cartilage destruction, while surgically induced osteoarthritis pathogenesis is suppressed in chondrocyte-specific conditional
Zip8-KO mice (212). MiR-488 has been shown to regulate
ZIP8 expression during pathogenesis of osteoarthritis
(381). ZIP8 plays indispensable roles in both multiple-organ organogenesis and hematopoiesis during early embryogenesis, because hypomorphic Zip8 mice show hypoplasia
of multiple organs, such as the spleen, liver, kidney, and
lung, and defects in hematopoiesis (118).
The ZIP8 gene was also identified as being responsible for
conferring cadmium-induced testicular toxicity in some inbred mouse strains (76). Multiple biochemical studies have
revealed that ZIP8 can transport cadmium, manganese, and
iron (107, 127, 183, 246). The involvement of ZIP8 in
enhancing the risk of cadmium-mediated toxicity in lung
tissue by cigarette smoke is suggested, because ZIP8 mRNA
expression is enhanced by cadmium in an NF-␬B-dependent
manner and is higher in the lungs of chronic smokers (295).
766
I. ZIP9 (ZIPI Subfamily)
ZIP9 is the only member belonging to the ZIPI subfamily
in mammals (115, 196). ZIP9 is localized to the Golgi
apparatus and the cell surface (274, 409). The Golgilocated ZIP9 plays a crucial role in B-cell receptor (BCR)
signaling through regulation of Akt and ERK activity by
translocating zinc from the Golgi lumen (397). The cell
surface ZIP9 can function as a membrane androgen receptor and contributes to testosterone-induced prostate
and breast cancer apoptosis through both zinc transporter functions and androgen signaling (25, 409). The
increased ZIP9 expression is reported in malignant breast
and prostate biopsies (409).
J. ZIP10 (LIV-1 Subfamily)
ZIP10 functions as a cell surface zinc importer (241). ZIP10
is indispensable for B-cell development in early and mature
stages (162, 285). The genetic ablation of ZIP10 in the early
B-cell stage causes splenoatrophy with diminished numbers
of peripheral B cells and immunoglobulin levels (285). Zinc
uptake through ZIP10 is important for anti-apoptotic signaling by inhibiting caspase activity and thus is essential for
early B-cell survival (285). ZIP10 is also essential in mature
B-cell functions for proper humoral immune responses following BCR activation (162). The mature B cells in B-cellspecific Zip10-KO mice grow poorly because of dysregulated BCR signaling. The Zip10 deficiency in mature B cells
attenuates both T-cell-dependent and -independent immune responses (162). ZIP10 mRNA is highly expressed in
follicular B lymphoma (285), and higher ZIP10 mRNA
expression is correlated with lymph node metastasis in clinical breast cancers (187). Thus ZIP10 is involved in invasive
behavior of cancer cells (187), as observed for ZIP6 (see
sect. VF).
ZIP10 transcription is regulated by cytokine signaling via
the JAK/STAT pathway, which is under the control of two
STAT-binding sites in the promoter (285). Moreover,
ZIP10 transcription is upregulated in zinc-depleted cells
(351) and attenuated in zinc excess conditions. The zincregulated transcription is mediated by pausing Pol II transcription by MTF-1 (241) (see sect. ID).
ZIP10 is processed by zinc starvation as observed for ZIP4
(192) (see sect. IIIB), and a similar cleavage of the extracellular NH2-terminal portion results when starved of manganese (90). The portion of ZIP10, which has a PrP-like domain, is also cleaved in prion-infected mouse brain. Intriguingly, the shedding of the NH2-terminal domain occurs in
PrP in zinc-deficient conditions (90). The processing regulation of ZIP10 by the status of zinc may represent significant meaning in the spread of the prion disease.
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ROLE OF ZINC TRANSPORTERS IN ZINC HOMEOSTASIS AND METABOLISM
K. ZIP11 (gufA Subfamily)
ZIP11 is the sole member assigned to the gufA subfamily in
mammals (115, 196). ZIP11 is localized to the nucleus or
Golgi apparatus (210, 270), and its mRNA is abundantly
expressed in testes and the digestive system (270, 456).
The presence of multiple MREs upstream of the first exon
of the ZIP11 gene suggests its zinc-dependent expression,
but the expression is not significantly upregulated by
excess zinc, compared with that of MT (270, 456). The
physiological and cellular functions of ZIP11 have not
been well defined.
L. ZIP12 (LIV-1 Subfamily)
ZIP12 is localized to the plasma membrane and imports
extracellular zinc into the cytosol (56). ZIP12 probably has
a higher affinity to zinc than other ZIP members because the
apparent Km of ZIP12 is ⬍10 nM (56) (see sect. IIIB).
ZIP12 mRNA is specifically expressed in the central nervous system (56, 198, 293). ZIP12 has critical functions in
neuronal differentiation, such as tubulin polymerization
and neurite extension, by facilitating zinc uptake into the
cytosol, which mediates CREB activation via phosphorylation (56).
M. ZIP13 (LIV-1 Subfamily)
ZIP13 is localized to the Golgi apparatus and cytoplasmic
vesicles (32, 109, 185). ZIP13 mobilizes zinc from the lumen of these compartments and plays pivotal roles in cellular signaling, such as the BMP/TGF-␤ signaling pathway
through regulating the nuclear translocation of Smad proteins (109) and in ER homeostatic maintenance (185).
The ZIP13 gene is responsible for spondylodysplastic
Ehlers-Danlos syndrome (SCD-EDS; OMIM 612350),
which is characterized by a variety of symptoms, including
skeletal and connective tissue abnormalities (109, 128) (see
sect. VIB). Zip13-deficient mice show phenotypes reminiscent of those of SCD-EDS patients (109). ZIP13 mRNA
expression is relatively high in these affected tissues (109).
Mutant ZIP13 proteins, which cause SCD-EDS, are subject
to more rapid degradation via the Valosin-containing protein-linked ubiquitin proteasome pathway (33).
thase (iNOS) (240). ZIP14 expression is also induced by the
UPR stimulated by zinc deficiency via ATF6 binding to
the ER stress response element (ERSE) upstream of the
translational start site (163). The extreme upregulation
of ZIP14 by IL-6 in the liver contributes to hypozincemia
of the acute-phase response through facilitating zinc uptake (251).
ZIP14 is important for regulating systemic growth;
Zip14-KO mice exhibit dwarf body sizes and impaired skeletogenesis, because ZIP14 modulates G protein-coupled receptor (GPCR)-mediated cAMP-CREB signaling through
suppression of the basal PDE activity (161). The Zip14deficient mice also have more body fat and are hypoglycemic and hyperinsulinemic, showing enhanced insulin receptor phosphorylation and higher levels of liver glucose (22).
In Zip14-KO mice, hepatocyte proliferation, following partial hepatectomy, is impaired, which indicates the importance of ZIP14 in liver regeneration (15).
Similarly to ZIP8, ZIP14 can mobilize various divalent cations, including iron, manganese, and cadmium (107, 323).
The ability of ZIP14 to transport a transferrin unbound
iron transport (NTBI) is thought to physiologically contribute to iron homeostasis (22), because hereditary hemochromatosis protein HFE inhibits iron uptake via downregulation of ZIP14 (120). Iron deficiency promotes ZIP14 degradation through proteasomes (463).
VI. ZnT AND ZIP TRANSPORTERS IN
INTEGRATIVE PHYSIOLOGY AND
DISEASE PATHOGENESIS
Growing evidence has illustrated the involvement of ZnT
and ZIP transporters in the pathophysiology and pathogenesis of multifarious diseases. The elected aspects of these
diseases are herein overviewed and discussed concisely.
Moreover, mutations of ZnT and ZIP transporter genes,
which are implicated in inherited diseases (194, 436), are
also summarized. In addition, a discussion about the associations between SNPs of ZnT and ZIP transporter genes
and disease traits, which have been revealed by genomewide association studies, are presented.
A. Involvement of ZnT and ZIP Transporters
in Pathophysiology
N. ZIP14 (LIV-1 Subfamily)
ZIP14 has two alternative splicing isoforms, ZIP14A and
ZIP14B. Both isoforms are localized to the plasma membrane and import zinc (127, 161, 251). ZIP14A and
ZIP14B show exclusive apical surface localization in polarized cells (127). Cell surface ZIP14 expression is upregulated significantly by cytokines and LPS (251), which is
mediated by NO production by inducible nitric oxide syn-
Both ZnT and ZIP transporters play a variety of pivotal
roles in immune cell functions by controlling zinc signaling,
and thus dysfunction of both transporters and dysregulation of their expression results in abnormal immune functions (144, 146, 156, 290). Moreover, recent literature has
revealed that ZnT and ZIP transporters are involved in
novel functions of zinc in immunity, “nutritional immunity” (384, 388), as in the case of transporters of other
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KAMBE ET AL.
nutritional metals such as iron (360). Here, the microbial
pathogen is starved of micronutrients through spatial isolation (164). Intoxication of zinc has also been suggested to
be involved in another operation of the immune system by
inhibiting the growth of phagocytosed microorganisms (39,
428), where ZnT and ZIP transporters may play a role, as
observed for copper transporters (445). The involvement of
zinc at the host-pathogen interface is complex (271) and
represents a topic that requires greater focus in the future
(145).
Chronic perturbations of brain zinc homeostasis have been
suggested to be closely related to the development of neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis (ALS) (73,
104, 392). The zinc levels (and other divalent cations) in the
cerebrospinal fluid or in the brain of the patients are significantly altered (73, 166, 345, 392). Free zinc (Zn2⫹) at a
high concentration is a potent killer of neurons (217, 440).
Conversely, zinc deficiency has been shown to induce the
SOD1 protein to be an ALS-linked pathogenic mutant conformation (163). A number of ZnT and ZIP transporters
show altered expressions at both the mRNA and protein
levels in the brains of patients with neurodegenerative dis-
eases (1, 29, 30, 36, 200, 380, 392). Thus how the alteration of their expression is involved in these diseases should
be extensively investigated.
Abnormal zinc metabolism is associated with the risk of cancer pathogenesis in breast and prostate cancers (65, 74). The
altered or ectopic expression of ZnT and ZIP transporters is
thought to be associated with cancer progression and invasive
and metastatic phenotypes in many carcinomas and cancers,
and thus both transporters have received significant attention
in terms of new targets for cancer therapy. Such information is
briefly described in each transporter section.
B. Genetic Diseases of Zinc Transporters
and Therapeutic Approaches
ZIP4/SLC39A4 gene mutations cause AE (8, 362)
(TABLE 4), characterized by eczematous dermatitis, alopecia, and diarrhea (288) at an estimated frequency of ⬃1 in
500,000 (275). The molecular basis underlying the severe
dermatitis in AE patients was recently shown (204). In this
study, irritant contact dermatitis through loss of Langerhans cells is revealed to cause dysregulation of ATP-
Table 4. Mutations of zinc transporters causing inherited diseases
Mutated Gene
Disease
Chr.
Localization
MIM No.
Clinical Features
Erosive dermatitis around the
mouth, genital region,
neck, and fingers. Diarrhea
and alopecia. Ameliorated
with zinc supplementation
during nursing. Mutations
are found in mothers.
Dysarthria, fine tremor,
hypertonia, bradykinesia,
and spastic
paraparesis.Blood
manganese levels and
clinical symptoms are
improved by metal
chelation therapy.
Eczematous dermatitis on
the perioral, perianal, and
acral areas, diarrhea,
alopecia and growth
retardation. Ameliorated
with zinc supplementation
(1–3 mg·kg⫺1·day⫺1)
Refractive error, tigroid and
focal atrophy of choroid.
Growth retardation, skeletal
and connective tissue
abnormalities, tapering
fingers, articular
hypermobility, and
protruding eyes with bluish
sclera.
ZnT2/SLC30A2
Transient neonatal zinc
deficiency
1p36.11
608118
ZnT10/SLC30A10
Syndrome of hepatic cirrhosis,
dystonia, polycythemia, and
hypermanganesemia
1q41
613280
ZIP4/SLC39A4
Acrodermatitis enteropathica
8q24.3
201100
ZIP5/SLC39A5
Nonsymptomatic high myopia
12q13.3
615946
ZIP13/SLC39A13
Spondylocheiro dysplastic
Ehlers–Danlos syndrome
11p11.2
612350
Chr., chromosomal.
768
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Reference Nos.
57, 180, 231,
283
341, 417
8, 225, 275, 362,
432
133
109, 128
ROLE OF ZINC TRANSPORTERS IN ZINC HOMEOSTASIS AND METABOLISM
mediated inflammatory signals (204). Zinc-deficient phenotypes in AE patients can be ameliorated with a simple, daily
oral zinc supplementation (1–3 mg·kg⫺1·day⫺1) (362).
ZIP4 is now the only zinc transporter indispensable for the
uptake of zinc from the intestinal lumen, but some AE mutations, which are not linked to the chromosomal region of
the ZIP4/SLC39A4 gene by homozygous mapping, are
present (362, 432). Thus another ZIP transporter may operate as a second zinc uptake route in the digestive tract.
TNZD is caused by low zinc levels in breast milk. The
symptoms, similar to AE, only develop during breast-feeding, and do not reoccur after weaning, so termed TNZD.
TNZD can be alleviated by a zinc supplement to the infant,
but not to the mother, who secretes low levels of zinc in breast
milk because of ZnT2/SLC30A2 gene mutations (57, 180,
231, 283). Because zinc levels in breast milk are considerably
high, particularly in colostrum (47, 252), ZnT2 function is
required for the secretion of large amounts of zinc (1–3 mg
zinc/day) into breast milk during lactation (209).
SCD-EDS is attributed to homozygous loss-of-function mutations of the ZIP13/SLC39A13 gene (109, 128). The patient displays a variety of symptoms, including postnatal
growth retardation, skeletal and connective tissue abnormalities, and hyperelastic and easily bruised skin, but these
zinc deficiency-related symptoms are not alleviated by zinc
supplementation, unlike the two inherited diseases described above. The accelerated degradation of SCD-EDScausing ZIP13 mutants is associated with the disease pathogenesis, and therefore, rescue of ZIP13 protein expression
by inhibiting its degradation may potentially improve the
symptoms of SCD-EDS (33).
Nonsense and missense mutations of ZIP5/SLC39A5 have
recently been shown to be associated with nonsyndromic
high myopia (133), which may be caused in an autosomal
dominant or haploinsufficient manner.
Homozygous loss-of-function mutations of the ZnT10/
SLC30A10 gene cause Parkinsonism and dystonia with hypermanganesemia, which are ameliorated by metal chelation therapy (341, 417).
C. Single Nucleotide Polymorphism and
Gene Dosage Effects of ZnT and ZIP
Transporters Related to Human Disease
Pathogenesis
The SNP rs13266634 of the ZnT8/SLC30A8 gene results in
R325W substitution in ZnT8 (TABLE 5). The R allele increases the risk of type 2 diabetes (359, 365, 378, 458)
because of lower zinc transport activity (297), whereas single-nucleotide variants, which cause truncation of ZnT8,
decrease the risk in heterozygous individuals (102). This
discrepancy requires further investigation. The SNP rs13266634
is implicated as a key determinant in humoral autoreactivity
to ZnT8 (443) and is also related to a favorable cardiometabolic lipid profile in human immunodeficiency virus (HIV)/
hepatitis C virus-coinfected patients (322) and skeletal muscle strength and size (383).
The SNP rs13107325 of the ZIP8/SLC39A8 gene causes an
A391T substitution in ZIP8, and the T allele (8% frequency) is revealed to be associated with relatively lower
circulation of high-density lipoprotein cholesterol (434).
The same SNP (rs13107325) is associated with body mass
index/obesity (382) and blood pressure (88) as well as and
the risk of schizophrenia (46).
The SNP rs4806874 of the ZIP3/SLC39A3 gene has been
shown to be associated with bipolar disorder (19). The SNP
rs1871534 in the ZIP4/SLC39A4 gene results in a L372V
substitution in ZIP4, and the V variant may be advantageous in Sub-Saharan Africa, because certain pathogens
would be starved of zinc (97).
Much attention and interest has been paid to the SNPs of
ZnT3/SLC30A3 in terms of brain functions and neurological disorders. The SNPs rs6547521, rs11126936,
rs2083363, and rs11126931 of the ZnT3/SLC30A3 are
shown to be associated with a gender-specific association
with schizophrenia (315). The SNP rs11126936 is suggested to be associated with memory deficits (75). A rare
copy number variant (duplication) of the ZnT3/SLC30A3
gene may be involved in monogenic determination of autosomal dominant, early-onset Alzheimer’s disease (350).
However, this is in contrast to reports describing decreased ZnT3 expression in patients with Alzheimer’s
disease (1, 34). Moreover, a rare copy number variation
(deletion) of the ZIP12/SLC39A12 gene is a plausible
candidate gene of the autism spectrum disorder (121).
Possible genetic links to the autism spectrum are described
in the SNPs of several ZnT and ZIP transporter genes (268).
VII. ZnT AND ZIP TRANSPORTER
FUNCTIONS FOUND IN
NONMAMMALIAN MODEL
ORGANISMS
Investigations using nonmammalian model organisms aid
our efforts to understand the functions of ZnT and ZIP
transporters. In particular, important evidence has been reported in Drosophila, zebrafish, and nematode, which are
briefly described here. Evolutionary trees among ZnT or
ZIP transporters of human and mouse, and their homologs
in Drosophila, zebrafish, and nematode, are shown to clarify their relationships (FIGURE 7).
In Drosophila, many ZnT and ZIP homologs have been
extensively characterized. Both dZip1 (dZip42C.1) and
dZip2 on the cell surface are responsible for importing zinc
Physiol Rev • VOL 95 • JULY 2015 • www.prv.org
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KAMBE ET AL.
Table 5. SNPs or gene dosage effects of zinc transporters that have been shown to be related with diseases
Genes
ZnT3/
SLC30A3
ZnT8/
SLC30A8
ZIP3/
SLC39A3
ZIP4/
SLC39A4
ZIP8/
SLC39A8
SNP No. or Gene
Dosage Effects
rs6547521
rs2083363
rs11126931
rs11126936
Chr.
No.
Nucleotide
Change
Effect on
Protein
Comments
Reference Nos.
Intron
variants
NA
NA
Gender-specific association
with schizophrenia
315
Intron variant
NA
NA
75, 315
Entire
duplication
Exon 2
NA
NA
c.101_107del
K34SfsX50
rs200185429
Exon 3
c.412C⬎T
R138X
rs13266634
Exon 8
c.973C⬎T
R325W
Intron variant
NA
NA
Memory deficits, genderspecific association with
schizophrenia
Early-onset of Alzheimer’s
disease
Reduction of risk of type 2
diabetes in heterozygous
individuals
Reduction of the risk of
type 2 diabetes in
heterozygous individuals
Increase in the risk of type
2 diabetes,
cardiometabolic lipid
profile, skeletal muscle
strength and size,
humoral autoreactivity to
ZnT8
Bipolar disorder
Advantageous in SubSaharan Africa
Risk of schizophrenia,
blood pressure, body
mass index/obesity,
lower circulation of highdensity lipoprotein
cholesterol
Autism spectrum
disorders
97
Copy number
variant
NA
2
Region
8
rs4806874
19
rs1871534
8
Exon 6
c.1114C⬎G
L372V
rs13107325
4
Exon 8
c.1171G⬎A
A391T
ZIP12/
Copy number
SLC39A12
variant
10
Deletion of all
exons
except for
exon 12
NA
NA
350
102
102
322, 359, 365,
378, 383,
443, 458
19
46, 88, 382,
434
121
Chr. No., chromosomal number; NA, not available.
from the lumen into the enterocyte (257, 336), and the
imported zinc is released into circulation by dZnt1
(dZnT63C) and ZnT77C (CG5130, no vertebrate ZnT homologs) on the basolateral membrane (257, 336). Gut-specific silencing of dZnt1 increases lethality under zinc-deficient conditions, which indicates importance of dZnt1
function on zinc absorption (433). Zinc repletion suppresses dZip1 and dZip2 mRNA expression and also suppresses dZnt1 protein expression (336). Expression of
dZnt1 (dZnT63C) and dZnT35C (possibly a ZnT2 homolog) is regulated by dMTF1 (454). FOI (273), a dZip6
and dZip10 ortholog, is essential for normal cell migration
(320) and gonad morphogenesis through posttranscriptional
control of DE-cadherin expression (272, 422). A Catsup mutant, in which dZip7 is defective, shows abnormally high levels
of catecholamines and is probably semi-dominant lethal (386).
The mutant also exhibits defects in membrane protein trafficking and elevated ER stress (129). In contrast to mammalian
ZIP13, dZip13 is identified as an iron exporter to supply iron
into the secretory pathway (450). Phenotypes of knockdowns
770
or overexpression of Drosophila ZnT and ZIP transporters,
and genetic interactions between them have been extensively
investigated and summarized (257, 258).
In zebrafish, zZip1 is a cell surface, zinc uptake transporter
(339, 340). Zebrafish Zip6 (zLiv1) is essential for gastrulation by controlling EMT under STAT3 activation (452),
indicating the conserved importance of ZIP6 in organ and
tissue remodeling and cancer metastasis. Zebrafish Zip7 is
required for eye, brain, and skeleton formation during early
embryonic development (453). Expression of zZnt1 is upregulated in the presence of excess zinc and downregulated
by zinc deprivation, and zZip10 is negatively regulated
through MREs (464), both of which are conserved responses in mammals. In puffer fish, pZip1 and pZip2 facilitate zinc uptake from the extracellular site as high- and
low-affinity zinc transporters, respectively (339, 340). In
Xenopus, xZip12 plays an important role in nervous system
development, including neurulation and neuronal differentiation (56).
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ROLE OF ZINC TRANSPORTERS IN ZINC HOMEOSTASIS AND METABOLISM
A
ZnT transporters
B
ZIP transporters
FIGURE 7. Phylogenetic relationships among human, mouse, Drosophila, zebrafish, and nematode of ZnT
(A) and ZIP (B) transporters. The neighbor-joining phylogenetic tree based on the protein alignment was
created with ClustalW. The protein names are represented with different colors. Human, red; mouse, orange;
Drosophila, purple; zebrafish, blue; and nematode, green. Homologs of ZIP transporter in pufferfish or
Xenopus, which are described in the text, are shown in B. Puffer fish, light blue; Xenopus, pink. The scale bar
indicates an evolutionary distance of 0.1 amino acid substitution per site.
In the nematode, the ZnT1 ortholog CDF1 is essential for
conferring zinc resistance in conditions with high levels of
zinc (44, 182). CDF1 positively regulates Ras-ERK signal
transduction by reducing the concentration of cytosolic zinc
through its zinc efflux functions (44). This evidence confirms the conserved function of ZnT1 in the regulation of
the Ras-ERK pathway. The regulatory function similar to
CDF1 is conducted by SUR-7 (no vertebrate ZnT homologs), which is probably localized to the ER. In homeostatic control, CDF2 (a ZnT2 homolog) or TTM-1 (no vertebrate ZnT homologs) also plays a crucial role by transporting zinc into gut granules (lysosome-related organelles)
or excreting zinc from the apical plasma membrane in intestinal cells, respectively (348, 349).
VIII. CONCLUSIONS AND FUTURE
PERSPECTIVES
The progressive understanding of ZnT and ZIP transporters has facilitated our understanding of the physiological,
biochemical, and molecular roles of zinc. Concurrently, this
knowledge base clearly illustrates that ZnT and ZIP transporters are relevant in many clinical fields, and understanding the function of these transporters should help in the
prevention and treatment of zinc-related pathological conditions. Nonetheless, questions remain in our effort to un-
derstand the molecular mechanisms and specific activities
of zinc transporters. Detailed three-dimensional structures,
mechanisms of zinc transport, and regulation of zinc transport activity following specific stimuli require further investigation. Furthermore, physiological and pathological interactions with other membrane proteins require further analysis, because increasing evidence indicates that these
interactions contribute to zinc metabolism and diseases relating to the dysfunction of zinc homeostasis (40, 91, 104,
194, 415). The answers to the above questions will lead to
a comprehensive understanding of the temporal-spatial regulation of zinc dynamics in physiology, and the indispensable roles of zinc as structural, catalytic, and signaling components in specific proteins and reactions. Additionally, the
involvement of ZnT and ZIP transporters in disease pathogenesis, including a variety of neurodegenerative diseases,
clearly suggests that future discoveries will pave the way for
the design of specific small compounds that can modulate
zinc transport activity by ZnT and ZIP transporters, which
should be of significant therapeutic benefit.
ACKNOWLEDGMENTS
We thank Shigeyuki Fujimoto and members of the Kambe
laboratory for assistance with manuscript preparation. T.
Tsuji, A. Hashimoto, and N. Itsumura are research fellows
(DC2) of the Japan Society for the Promotion of Science.
Physiol Rev • VOL 95 • JULY 2015 • www.prv.org
771
KAMBE ET AL.
We also thank the reviewers for their detailed comments
and suggestions related to zinc functions.
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phosphorylation and hepatocyte proliferation during liver regeneration in mice. Gastroenterology 142: 1536 –1546, 2012.
Address for reprint requests and other correspondence: T.
Kambe, Div. of Integrated Life Science, Graduate School of
Biostudies, Kyoto University, Kitashirakawa-Oiwake-cho,
Sakyo-ku, Kyoto 606 – 8502, Japan (e-mail: kambe1@kais.
kyoto-u.ac.jp).
16. Barila D, Murgia C, Nobili F, Gaetani S, Perozzi G. Subtractive hybridization cloning of
novel genes differentially expressed during intestinal development. Eur J Biochem 223:
701–709, 1994.
17. Barnett JP, Blindauer CA, Kassaar O, Khazaipoul S, Martin EM, Sadler PJ, Stewart AJ.
Allosteric modulation of zinc speciation by fatty acids. Biochim Biophys Acta 1830:
5456 –5464, 2013.
18. Bateman A, Birney E, Durbin R, Eddy SR, Howe KL, Sonnhammer EL. The Pfam
protein families database. Nucleic Acids Res 28: 263–266, 2000.
GRANTS
This work was supported by Grants-in-Aid for Challenging
Exploratory Reserch from the Japan Society for the Promotion of Science (KAKENHI, Grant No. 26660086).
DISCLOSURES
No conflicts of interest, financial or otherwise, are declared
by the authors.
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