Calcium Biochemistry
161
PKC site is located within the CaM bind-
ing domain, and phosphorylation of this
site can be prevented by the presence
of CaM.
To date, four different genes of the
PMCA pump have been identiFed in
mammalian species. Additional variabil-
ity of this multigene family is produced
by alternative splicing within the phospho-
lipid and the calmodulin binding domains.
Splicing could give rise to differences in
tissue-speciFc expression as well as to
differences in afFnity to calmodulin, for ex-
ample, as documented for PMCA2, which
has the highest afFnity for calmodulin
of all the isoforms studied to date. ±our
genes have been localized on human chro-
mosomes: PMCA1 on chromosome 12,
PMCA2 on chromosome 3, PMCA3 on
chromosome X, and PMCA 4 on chromo-
some 1. PMCA1 and 4 are ubiquitously
distributed, whereas PMCA2 and 3 are
much more restricted in their tissue dis-
tribution, that is, the latter two are mainly
found in the brain.
6.1.3
Na
+
/Ca
2
+
Exchanger
Next
to
the
Ca
2
+
pump,
there
also
exists a Na
+
-dependent Ca
2
+
exchanger
in
the
plasma
membranes
of
many
cells, especially in excitable tissues. This
Na
+
/Ca
2
+
exchanger has a lower afFnity
for Ca
2
+
compared to the Ca
2
+
pump,
but a much higher transport capacity.
It is an electrogenic system; that is, it
transports three Na
+
for one Ca
2
+
,th
e
direction of the transport depending on
the ionic transmembrane gradients or
the transmembrane electrical potential,
that is, the exchanger can operate fully
reversible. Three homologous exchanger
gene products (
NCX1
,
2
,
3
) have been
identiFed; they are differently expressed
in the heart, the brain, and the kidney.
Hydropathy analysis has predicted 9 to 11
transmembrane domains, depending on
the model, with the consequence that N-
andC
-
t
e
rm
inu
sa
r
elo
c
a
t
edonoppo
s
i
t
e
sides of the membrane. The size of the
protein is between 110 and 120 kDa.
Expression of the different gene products
is controlled by tissue-speciFc promoters;
some can be modulated by Ca
2
+
,f
o
r
example, expression of
NCX2
in neurons
is under the control of calcineurin, the
CaM-dependent phosphatase.
6.2
Ca
2
+
Transport Systems of the Reticulum
Next to the Ca
2
+
transporting systems
located in the plasma membrane, there
are also intracellular organelles involved
in controlling the free Ca
2
+
ion concen-
tration of the cell. The reticular systems
have best been studied in skeletal, smooth,
and cardiac muscle cells, that is, the
sarcoplasmic reticulum, but also the re-
lated endoplasmic reticulum of other cells
gained importance owing to the knowl-
edge that the Ca
2
+
content of these stores
can be released into the cytosol by inositol-
1,4,5-phosphate (IP
3
). This latter second
messenger links plasma membrane re-
ceptor activation response to extracellular
hormonal stimuli to Ca
2
+
mobilization
from intracellular stores.
6.2.1
The IP
3
Receptor
IP
3
is
produced
by
receptor-activated
phospholipase C–dependent hydrolysis of
phosphatidyl inositol diphosphate (PIP
2
).
Subsequently, IP
3
binds to a speciFc
receptor located in the membranes of the
ER, thereby releasing calcium into the
cytosol through the Ca
2
+
-ion channel of
the receptor. The IP
3
receptor, which is
highly concentrated in the Purkinje cells
of the cerebellum, has been identiFed
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