166
Calcium Biochemistry
the control of the CaM-dependent phos-
phatase calcineurin. Similar Fndings have
recently been reported for neurons, where
calcineurin regulates the gene expression
of some of the Ca
2
+
transporters. This is
especially true for the cerebellum, where
calcineurin mediates the rapid transcrip-
tional downregulation of speciFc isoforms
of the PMCA pumps and of the NCXs.
Ca
2
+
can also regulate transcription
directly through the recently identiFed
transcription factor DREAM (
d
ownstream
r
egulatory
e
lement
a
ntagonist
m
odulator),
which is an E±-hand-type protein. Ca
2
+
-
free DREAM binds to the regulatory
element DRE, thereby silencing the gene
that is released owing to the binding of
Ca
2
+
to DREAM.
7
Role of Calcium in Specialized Tissues
7.1
Calcium and Fertilization
Interaction of sperm with the egg upon
fertilization results in a sharp increase
in Ca
2
+
concentration, thereby depolariz-
ing the plasma membrane. Subsequently,
phospholipase C is activated and phospho-
inositide lipid turnover is induced leading
to IP
3
generation, a prerequisite to release
Ca
2
+
from intracellular stores. Also, cyclic
ADP-ribose/RyR channels and NAADP-
sensitive Ca
2
+
stores contribute to Ca
2
+
mobilization. Several mechanisms are dis-
cussed to be responsible for the elevation
of Ca
2
+
during fertilization; the most likely
candidate is of proteinaceous nature. Nev-
ertheless, irrespective of the mechanism,
theimmediateconsequenceofCa
2
+
rise is
the exocytosis of cortical granules respon-
sible for the elevation of the fertilization
envelope to prevent polyspermy.
7.2
Calcium in Calcifying Tissues
Bone is formed by osteoblasts of mes-
enchymal origin and resorbed by osteo-
clasts of hematopoietic stem cell origin.
In this highly integrated process, it is im-
portant to maintain a balance between the
formation and resorption of bone. If one
part dominates over the other, leading
either to osteopetrosis, that is, increase
of bone formation, or to osteoporosis,
that is, increase of bone resorption, one
of the consequences is the imbalance of
the calcium homeostasis. Therefore, it is
important for a variety of cells to sense
changes in the extracellular Ca
2
+
levels
to be able to modify their functions ac-
cordingly. The existence of such calcium
sensors has Frst been demonstrated for
the parafollicular cell of the thyroid gland
(C-cell) and for the parathyroid cell, which
through the secretion of parathyroid hor-
mone regulate the level of serum calcium,
that is, responding to changes in PTH
secretion inversely related to the ambi-
ent ionized calcium concentration. These
cells can recognize small changes in the
extracellular Ca
2
+
concentration through a
‘‘Ca
2
+
receptor,’’ presumably a cell-surface
receptor protein, which in the case of
cytotrophoblast cells of the human pla-
centa has been identiFed as a protein of
500 kDa. In the case of osteoclasts that
can locally be exposed up to 30 mM Ca
2
+
during bone resorption, increase in extra-
cellular Ca
2
+
concentration leads to an
increase in intracellular Ca
2
+
resulting
mainly from influx of extracellular Ca
2
+
through voltage-insensitive channels. This
in turn leads to a modiFcation of the
cytoskeletal arrangement of these highly
polarized cells, to a reduction of speciFc
adhesion structures responsible for the
attachment to bone, and, Fnally, to an
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