Biomedical Engineering Reference
In-Depth Information
6.6.4
Zinc Ion and Its Partners
Zinc serves as a structural constituent of proteins, among which thousands of
enzymes involved in cell signaling and transcription factors. On the other hand,
reactive free Zn
2
+
ion localizes in the nucleus (30%) and in the cytosol and
organelles (50%, the remainder being bound to proteins). Free Zn
2
+
ion amount
depends on the redox state and the level of reactive oxygen species in cells [
638
].
Zinc is cytotoxic. Excess Zn
2
+
cation in cells is buffered by binding to cysteine,
histidine, or glutamate residues of metalloproteins.
In cardiomyocytes at rest, the cytosolic Zn
2
+
concentration is low (
1nmol;
i.e., 100-fold less than [Ca
2
+
]
i
). Oxidants cause approximately a 30-fold increase in
[Zn
2
+
]
i
, but only 2-fold in [Ca
2
+
]
i
in cardiomyocytes.
Zinc sparks
and
transients
result mostly from an increased cytosolic Ca
2
+
concentration [
638
]. In neurons, Ca
2
+
-dependent Zn
2
+
release originates from
mitochondria.
In mastocytes,
Zinc wave
that corresponds to Zn
2
+
release from the endoplasmic
reticulum and/or the surrounding area after cross-linking of the high-affinity
immunoglobulin-E receptor also depends on Ca
2
+
influx, without contribution of
extracellular Zn
2
+
ion [
638
].
Calsequestrin is a Zn
2
+
-binding protein of the endoplasmic reticulum that can
bind up to 200 mol Zn
2
+
/mol as well as 50 mol Ca
2
+
/mol [
638
].
Zinc homeostasis in the cell results from a balance between uptake, excretion,
and intracellular storage [
638
]. Zinc enters the cardiomyocyte through SLC39
transporter and different channels such as Ca
V
1.2 channel. Zinc efflux is carried out
by SLC30 transporter (or ZnT). Furthermore, Na
+
-Zn
2
+
exchanger enables Zn
2
+
extrusion. A Zn
2
+
-H
+
antiporter may contribute to Zn
2
+
accumulation in cellular
organelles.
Zinc provokes autophosphorylation of Ca
2
+
-calmodulin-dependent protein
kinase camK2 and inhibition of protein Tyr phosphatases and voltage-gated Ca
2
+
channels [
638
].
Soluble cytosolic Zn
2
+
-binding proteins comprise anti-oxidant metallothionein.
Zinc ion can be released after metallothionein nitrosylation [
638
]. In cardiomy-
ocytes, mitochondria, which occupy 30 to 40% of the cell volume, constitute the
major source of intracellular reactive oxygen species. Reactive oxygen species
cause changes in metal-binding properties of metallothioneins and other redox-
active proteins. Reactive oxygen species stimulate inducible nitric oxide synthase
NOS2 that, in turn, supports the release of Zn
2
+
from Zn
2
+
-metallothioneins.
In cardiomyocytes, nitric oxide mobilizes intracellular Zn
2
+
via the cGMP-
PKG pathway and mitochondrial ATP-sensitive K
+
channel [
638
]. Mitochondrial
NO production rises with increasing Ca
2
+
concentration that can result from Ca
2
+
uptake by Ca
2
+
uniporter.
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