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Figure legends
Figure 1. Subcellular localization of ZNT and ZIP proteins. A. Most ZIPs function to
transport extracellular Zn2+ into the cytosol, whereas most ZNTs function to mobilize cytosolic
Zn2+ into the lumen of intracellular compartments, including the endoplasmic reticulum (ER),
Golgi apparatus, trans-Golgi network (TGN), and endosomes, as well as synaptic vesicles,
secretory vesicles, and insulin granules in specialized cells. ZNT10 is not shown because it
functions as a Mn2+ transporter. B. ZNTs transport Zn2+ in a rocker-switch manner, whereas
ZIPs use an elevator-type mechanism.
Figure 2. ZNT5-6 and ZNT7 contribute to the stabilization and metalation of Zn2+
enzymes in the early secretory pathway. ZNT5-6 and ZNT7 function to transport Zn2+ into
the lumen of the early secretory pathway compartments (ER and Golgi) to supply Zn2+ to apoenzymes. Apo-enzymes are thus converted into holo-enzymes. This conversion is required for
the activation and stabilization of a number of enzymes (listed in Table 1).
Figure 3. Proposed labile Zn2+ concentrations in subcellular compartments in cells. The
labile Zn2+ concentration is maintained at a very low level within cells, although it may vary
among different cell types and fluctuate in response to various stimuli. The measured
concentrations, determined using a FRET-based sensor (eZinCh-2, highlighted in light
green)83,84 and a fluorescent type probe (ZnDA, highlighted in light yellow)36,85, are indicated
15
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as representative examples. Notably, vesicular Zn2+ concentrations, such as those found in
synaptic vesicles and insulin granules (refer to Figure 1), known to accumulate high amounts
of labile Zn2+, are not shown. The omission is due to the ongoing need for further investigation
to accurately determine their concentrations.
Figure 4. Phenotypes of medaka fish (Oryzias latipes) with disrupted Znt5 and/or Znt7. A.
Abnormal tactile phenotype in medaka fish. A mechanosensory stimulation induced swimming
away in WT, Znt5+/−;Znt7+/−, and Znt5+/−;Znt7−/− (three upper rows), but not in Znt5−/−;Znt7+/−
medaka. Znt5−/−;Znt7+/− medaka did not respond to touch (for 0–3 s). The figure shown in this
panel was taken from reference (48). B. Znt5-6 and Znt7 are required for melanogenesis in
medaka fish. Lateral views of Znt5−/−;Znt7−/− embryos at 8–9 days post-fertilization (left) and
of Znt5+/−;Znt7−/− (right) embryos before hatching (upper panels). Melanin content was
decreased in Znt5−/−;Znt7−/−medaka compared to that in Znt5+/−;Znt7−/− littermates (lower
panel). The images in these panels were taken from reference (60).
Figure 5. Zn2+ enzymes involved in extracellular adenine nucleotide metabolism. ATP
released extracellularly is hydrolyzed to ADP, AMP, and adenosine by several enzymes. Among
them, TNAP, CD73/NT5E, and ENPPs (ENPP1 and ENPP3) are Zn2+ enzymes. Extracellular
ATP and ADP bind to ionotropic P2X and metabotropic P2Y receptors and adenosine binds to
P1 receptors to transmit signals that have opposing effects (inflammation vs. antiinflammation).
16
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ZNT1
ZIP1-6, ZIP8, ZIP10, ZIP12, ZIP14
ZNT4, ZNT5-ZNT6, ZNT7
Golgi
ZIP9, ZIP13
ZNT3
Synaptic vesicle
ZIP7
Insulin granule
ZNT
Extracellular/Lumen
Zn
ZNT2
Secretory vesicle
ZNT8
ER
ZNT4
Endosome
Zn
Cytosol
ZIP
Extracellular/Lumen
Zn
ZNT9
ZIP11
Nucleus
Mitochondria
Zn
Cytosol
Fig. 1
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Stabilization
Activation
Zn
Zn
Holo
ZNT6
Metalation
Zn
Golgi
ZNT5
ZNT7
Zn
Apo
ER
Fig. 2
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Cytosol
0.83 nM
0.87 nM
0.22 nM
Nucleus
0.13 nM
0.11 nM
0.2 nM
0.8 nM
Golgi
Mitochondria
0.17 nM
ER
3.3 pM
trans:
14 pM
∼80 nM
∼60 nM
cis: ∼80 nM
pre-cis: ∼100 nM
60 pM
medial:
Fig. 3
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Znt5+/-;Znt7-/-
Znt5-/-;Znt7+/Melanin (µg) / Protein (µg)
Znt5-/-;Znt7-/- Znt5+/-;Znt7-/-
WT
Znt5+/-;Znt7+/1.0 mm
0s
1s
2s
3s
0.025
0.020
**
0.020
0.010
0.005
Znt5+/-;Znt7-/- Znt5-/-;Znt7-/-
Fig. 4
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Zn
ENPP1, ENPP3
ATP
Zn
TNAP
P2X
Zn
Zn
ADP
TNAP
Inflammation
Zn
AMP
CD73
TNAP
Zn
Adenosine
P2Y
P1
Cytosol
anti-Inflammation
Fig. 5
...
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