136
Calcium Biochemistry
being 2
×
10
9
years (blue–green algae).
In minerals as well as in solution, cal-
cium occurs predominantly in a complex
form, mostly as calcium phosphate (e.g.
hydroxyapatite [Ca
10
(PO
4
)
6
(OH)
2
]), which
makes up 60% of the weight of human
skeleton, that is, the skeleton of a man
contains 1.0 to 1.3 kg of calcium, that of a
woman 0.8 to 0.9 kg, comprising 99% of
the total calcium of a human body. Com-
pared to this amount, the calcium found
in the extracellular fluid and intracellu-
larly in the cytosol or in other intracellular
compartments is almost negligible. In the
ECF or in the lumen of intracellular retic-
ular systems, the calcium concentration
is millimolar (2–5 mM, of which about
50% is unbound, i.e. corresponds to free
Ca
2
+
concentration), whereas the cytoso-
lic free Ca
2
+
concentration of a resting cell
is about 100 to 300 nM. This results in
a steep concentration gradient of ionized
Ca
2
+
across cellular membranes, which is
regulated by a variety of channels, pumps,
and other transporting systems controlling
the fluxes of Ca
2
+
into and out of the cell
and between the various intracellular com-
partments. On the other hand, calcium
homeostasis of the ECF is maintained
through a highly integrated and complex
endocrine system. This involves the inter-
play between a receptor sensing the level
of Ca
2
+
in ECF (see below) and two antag-
onistic polypeptide hormones, parathyroid
hormone (PTH) and calcitonin (CT), and a
Vitamin D metabolite, 1,25 (OH)
2
D
3
(see
Fig. 1). They measure the level of calcium
in the ECF and regulate its flow into and
out of the ECF by acting on target cells of
the intestine, kidney, and bone. Normally,
PTH prevents calcium of the ECF from
falling below a threshold level, whereas
CT prevents abnormal increases of serum
calcium. PTH is also responsible for the
formation of 1,25 (OH)
2
D
3
,wh
i
cha
c
t
s
on speci±c receptors in the intestine to
promote absorption of Ca
2
+
.
At the end of the nineteenth century, the
English physiologist Sidney Ringer discov-
ered that calcium plays an essential role
in regulating the contraction of the heart,
but for decades, calcium was considered
to be a speci±c factor merely important for
muscle contraction. Evidently, the general
implication of Ringer’s observation came
ahead of its time. It needed the formulation
of the ‘‘second messenger’’ concept, which
was developed by Earl Sutherland on the
basis of the discovery of cyclic AMP as
an intracellular regulatory constituent. It
was supported by the work of Ebashi et al.
who showed how Ca
2
+
works in skeletal
muscle, and identi±ed troponin C as the
±rst member of the EF-hand type calcium
binding proteins. However, it was not un-
til the discovery of calmodulin by Cheung
and Kakiuchi in the sixties of the twentieth
century to realize the pivotal role of Ca
2
+
as a general regulator of cellular functions.
This is made possible due to the tightly
controlled steep concentration gradient of
ionized Ca
2
+
across cellular membranes.
If a cell becomes activated because of an
external signal, this often results in up to a
100-fold rise in the intracellular free Ca
2
+
concentration owing to the uptake of extra-
cellular Ca
2
+
and/or the release of Ca
2
+
from intracellular stores. These changes
inthefreeCa
2
+
concentration can cause
signi±cant oscillations of Ca
2
+
in the cy-
tosol providing the possibility of signal
transduction for a number of different
cellular activities (e.g. muscle contrac-
tion; glycogen metabolism; fertilization;
cell growth, division, and apoptosis; exci-
tation–contraction and stimulus-secretion
coupling; mineralization). Many of these
functions are accomplished through the
interaction of Ca
2
+
with speci±c pro-
teins, resulting in speci±c modulations of
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