Chemistry Reference
In-Depth Information
described in Chapter 11. It is proposed that DREAM remains bound to a downstream regulatory element (DRE)
which acts as a gene silencer when nuclear Ca
2
þ
is low. When the nuclear Ca
2
þ
levels rise, DREAM dissociates
from the DNA, causing de-repression of DRE, and activation of downstream genes such as that which codes for
dynorphins (which may act as an antidote to the pleasurable effects of cocaine) and attenuation of pain signalling
in vivo. Within seconds of Ca
2
þ
entry into the cytoplasm, through both N-methyl-D-aspartate (NMDA) receptors
and L-type voltage-gated Ca
2
þ
channels (VGCC), calmodulin (CaM) is activated and translocates to the nucleus
where it participates in the activation of Ca
2
þ
/cAMP responsive element-binding protein (CREB)-dependent gene
expression. Calmodulin also mediates CREB phosphorylation via the adenyl cyclase/phosphokinase A (AC/PKA)
and the MAP kinase (MAPK) pathways, which begin to exert their influence subsequently. Almost as rapidly,
CaM activates another target protein in the mammalian brain, calcineurin (CaN), a heterodimeric phosphatase,
which dephosphorylates a member of the nuclear factor of activated T-cells (NFAT) family of transcription factors,
NFATc4. The NFATc group of transcription factors play a key role in neuronal plasticity as well as vascular
development and muscular hypertrophy. NFATc4 is expressed in neurons of the hippocampus, the memory, and
learning centre of the brain. Upon dephosphorylation, NFATc4 undergoes translocation from the cytosol to the
nucleus.
Synaptotagmins are yet another family of Ca
2
þ
-binding proteins, localised on the membranes of synaptic
vesicles, where they seem to be involved in the release of neurotransmitters. While the mechanism by which they
are involved in Ca
2
þ
-mediated synaptic transmission is unclear, it seems likely that the neurotoxicity of heavy
metals, such as Pb, is due to a higher affinity of synaptotagmins for Pb
2
þ
than for Ca
2
þ
.
The Ca
2
þ
/calmodulin-dependent protein kinase CaMKII plays a central role in Ca
2
þ
signal transduction and is
highly enriched in brain tissue, accounting for about 2% of total hippocampal protein and around 0.25% of total
brain protein. It is the most abundant protein in the postsynaptic density, the region of the postsynaptic membrane
which is physically connected to the ion channels which mediate synaptic transmission. The structural modifi-
cation of synaptic proteins is thought to be the molecular event which is involved in the memory storage process.
The substrates phosphorylated by CaMKII are implicated in homeostatic regulation of the cell, as well as in
activity-dependent changes in neuronal function that appear to underlie complex cognitive and behavioural
responses, including learning and memory.
Astrocytes can exocytotically release the gliotransmitter glutamate from vesicular compartments. Increased
cytosolic Ca
2
þ
concentration is necessary and sufficient for this process. The predominant source of Ca
2
þ
for
exocytosis in astrocytes resides within the endoplasmic reticulum (ER). Inositol 1,4,5-trisphosphate and ryanodine
receptors of the ER provide a conduit for the release of Ca
2
þ
to the cytosol. The ER store is (re)filled by the store-
specific Ca
2
þ
-ATPase. Ultimately, the depleted ER is replenished by Ca
2
þ
which enters from the extracellular
space to the cytosol via store-operated Ca
2
þ
entry; the TRPC1 protein has been implicated in this part of the
astrocytic exocytotic process. Voltage-gated Ca
2
þ
channels and plasma membrane Na(
)/Ca
2
þ
exchangers are
additional means for cytosolic Ca
2
þ
entry. Cytosolic Ca
2
þ
levels can be modulated by mitochondria, which can
take up cytosolic Ca
2
þ
via the Ca
2
þ
uniporter and release Ca
2
þ
into cytosol via the mitochondrial Na(
þ
)/Ca
2
þ
exchanger, as well as by the formation of the mitochondrial permeability transition pore. The interplay between
various Ca
2
þ
sources generates cytosolic Ca
2
þ
dynamics that can drive Ca
2
þ
-dependent exocytotic release of
glutamate from astrocytes.
þ
ZINC, COPPER, AND IRON
The brain barrier systems, i.e., the blood
cerebrospinal fluid barriers, ensure that there are
adequate supplies of zinc, copper, and iron available for brain function and prevention of neurological diseases.
Too much or too little will be detrimental to brain function. Specific transporters present on the BBB will ensure
the passage of each of these metals across this barrier.
Another metal ion that has been implicated in brain function is Zn
2
þ
, the secondmost prevalent trace metal in the
body after iron. The brain barrier systems, i.e., the blood
brain and blood
e
e
brain and blood
cerebrospinal fluid barriers, ensure that
e
e
