142
Calcium Biochemistry
key assumption of the model proposed
by Berridge et al. is the existence of two
independent cytosolic Ca
2
+
stores: one
that influences the cytosolic Ca
2
+
level
owing to the IP
3
-induced Ca
2
+
release,
and the other that contains the Ca
2
+
-
induced Ca
2
+
release channel. In this
model, receptor activation leads to the
formation of IP
3
, which releases Ca
2
+
from IP
3
-sensitive Ca
2
+
stores for induc-
ing a constant efflux of calcium. The latter
triggers Ca
2
+
from Ca
2
+
-sensitive stores,
leading to an autocatalytic process in which
the spiking characteristics depend on the
frequency of the depletion and reFlling of
the Ca
2
+
-sensitive Ca
2
+
stores. Owing to
the distribution of the storage systems over
much of the cellular volume, calcium spik-
ing leads to calcium waves (propagation
rate 10–100
µ
ms
1
) as observed for many
cells. Since the diffusion rate of IP
3
is 100
times faster than that of Ca
2
+
,c
a
l
c
ium
stores have to be much closer in space for
the CICR model as compared to the ICC
model to generate efFcient calcium waves
across the cell.
4.3
Calcium and the Cell Cycle
Calcium is one of the control elements of
the cell division cycle (cdc) during prolif-
eration of cells. Usually, there are three
control points in a cell cycle: START, mito-
sis ENTRY, and mitosis EXIT. At all three
points, a transient rise in the intracellular
Ca
2
+
can be observed. The probable me-
diator of these Ca
2
+
-dependent cell cycle
controls is calmodulin, a multifunctional
intracellular calcium binding protein, as
described later. It has been shown that
overexpression of calmodulin leads to a
reduction of the G1-phase in the cell cy-
cle, whereas reduced calmodulin synthesis
leads to arrest in G1 and mitosis EXIT.
Of special interest is the observation that
CaM-kinase activity is required for entry
into mitosis. The relevant target for CaM
kinase is a tyrosine phosphatase, known
as cdc25 in yeast. This enzyme is acti-
vated because of phosphorylation by CaM
kinase that enables it to dephosphorylate
pp34
cdc2
, a kinase involved in nuclear en-
velope breakdown, one of the key events
during the cell cycle.
The essential role of calmodulin during
cell cycle progression was demonstrated
by Davis et al. for yeast. Evidence was
provided that calmodulin was required
for chromosome segregation and the po-
larized growth of bud formation. Inter-
estingly, Davis identiFed two calmodulin
targets that are important for chromoso-
mal segregation, the spindle pole body
protein SPC110 and the nonconventional
myosin Myo2P. A mammalian homolog
of SPC110 has recently been identiFed as
a calmodulin target, supporting the earlier
Fndings that calmodulin is associated with
centrosomes during mitosis.
4.4
Calcium and Apoptosis
Apoptosis, or programmed cell death
(PCD), is a process during which cells
shrink and dissociate from their sur-
rounding neighbors, their organelles re-
tain in size, and in the nucleus chro-
matin forms dense aggregates on the
nuclear
membrane.
Eventually,
chro-
matin undergoes fragmentation, and the
formation of membrane-enclosed struc-
tures termed
apoptotic bodies
that are
extruded into the extracellular environ-
ment can be observed. On the other
hand, necrotic cells swell, their mito-
chondria enlarge, the plasma membranes
disrupture, but the nuclear changes are
marginal.
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