Chemistry Reference
In-Depth Information
Multiple mechanisms by which such extracellular zinc could modulate fast excitatory glutamantergic receptors
have been (
Paoletti et al., 2009
)
suggested. Both ionotrophic glutamate receptors and glutamate transporters are
sensitive to zinc. Zinc selectively inhibits NMDA receptor-mediated responses in cultured hippocampal neurons, by
producing a voltage-dependent noncompetitive inhibition, resulting in a decrease in channel opening. Certain
NMDA receptor subtypes (those containing the NR2A subunit) appear particularly interesting because they contain
allosteric sites which are exquisitely sensitive to extracellular zinc.
Glutamate receptors, which will clear glutamate from the synaptic cleft, are also modulated by zinc. Inhibition
of glutamate uptake may be damaging to such activated neurons, although, since zinc will also inhibit the release
of glutamate no real change may occur within the synaptic cleft. In addition, high voltage-activated calcium
channels that mediate calcium-dependent neurotransmitter release at the central synapses are also inhibited by
M
concentrations of zinc. Overall, it can be clearly observed that zinc could act as a critical neural messenger in both
health and disease via its ability to regulate NMDA receptor activity. Excessive synaptic release of zinc followed
by entry into vulnerable neurons contributes to severe neuronal cell death.
Mutations that cause reduced expression of the full-length Survival Motor Neuron (SMN) protein are a major
cause of spinal muscular atrophy (SMA), a disease characterised by the degeneration of the
m
-motor neurons in the
anterior horn of the spinal cord. The severity of SMA may be influenced by the actions of modifier genes. One
potential modifier gene is ZPR1, an essential protein with two zinc fingers, present in the nucleus of growing cells
which relocates to the cytoplasm in starved cells. ZPR1 p is downregulated in patients with SMA and interacts
with complexes formed by SMN. The expression of ZPR1 is suppressed in humans with severe SMA, although the
mechanism of its suppression remains unknown.
a
Copper
Genetic and nutritional studies have illustrated the essential nature of copper for normal brain function. Deficiency
of copper during the foetal or neonatal period will have adverse effects both on the formation and the maintenance of
myelin (
Kuo et al., 2001; Lee et al., 2001; Sun et al., 2007; Takeda and Tamana, 2010
). In addition, various brain
lesions will occur in many brain regions, including the cerebral cortex, olfactory bulb, and corpus striatum. Vascular
changes have also been observed. It is also of paramount importance that excessive amounts of copper do not occur
in cells, due to redox mediated reactions such that its level within cells must be carefully controlled by regulated
transport mechanisms. Copper serves as an essential cofactor for a variety of proteins involved in neurotransmitter
synthesis, e.g. dopamine
-hydroxylase, which transforms dopamine to nor-adrenaline, as well as in neuro-
protection via the Cu/Zn superoxide dismutase present in the cytosol. Excess “free” copper is however deleterious
for cell metabolism, and therefore intracellular copper concentration is maintained at very low levels, perhaps as
low as 10
18
M. Brain copper homeostasis is still not well understood.
The major route of copper entry into neuronal cells is via the Cu
þ
transporter Ctr1, although a second transporter
Ctr2 may also be involved. DMT1 may also contribute to the transport of copper across membranes although its
exact role is unknown. Ctr1 is also highly expressed in the choroid plexus. Copper transport to various cuproen-
zymes from Ctr1 is mediated via metallochaperone pathways which were outlined in Chapter 8. Interestingly, the
amyloid precursor protein possesses an N-terminal copper-binding domain which could reduce Cu
2
þ
to Cu
þ
.The
CSF contains non-ceruloplasmin bound copper, although the ligand to which it is bound is not yet identified.
The copper transporters ATP7A and ATP7B transport Cu
þ
using energy from ATP hydrolysis to catalyse the
transport of copper across membranes. It is thought that such copper is subsequently transported into intracellular
vesicles, which then fuse with the plasma membrane and release the copper from the cell. Copper export can be
stimulated in response to Ca
2
þ
channel activation. ATP7A expression in mouse brain in early postnatal devel-
opment is in the hippocampus, olfactory bulb, cerebellum, and choroid plexus. This alters with ageing with the
highest ATP7A expression found in CA2 hippocampal pyramid cells, cerebellar Purkinje neurons, and choroid
plexus. Low levels of ATP7A expression are found in astrocytes, microglia, myelinating oligodentrocytes, and
endothelial cells. Copper can be released from synaptic vesicles into the synaptic cleft of glutamatergic synapses
b
