Calcium Biochemistry
169
role in biological systems, controlling
a myriad of key cell processes. It can
fulFll a static function, in stabilizing
structures, or a dynamic function, par-
ticipating in signal transduction path-
ways as a second messenger.
2. Calcium homeostasis in an organism is
carefully controlled, involving a variety
of systems in the skeleton, in the
EC±, and inside cells. Depending on
its function, calcium can be complexed
in different forms: by hydroxyapatite
in the skeleton; by acidic, low-afFnity
proteins in the EC±; by the high-afFnity
E±-hand proteins inside cells.
3. Extracellular and intracellular concen-
trations of calcium differ by several or-
ders of magnitude. Therefore, cells are
exposed to a steep Ca
2
+
gradient across
the membranes, which makes it pos-
sible for even small changes in mem-
brane permeability to lead to substantial
changes in intracellular free Ca
2
+
con-
centration. Signals can be converted
from an extracellular analog to an intra-
cellular digital form. The control of cel-
lular calcium is maintained by an elab-
orate system of channels, exchangers,
and pumps located in the plasma mem-
brane and in intracellular membranes.
4. The E±-hand proteins play a pivotal role
in permitting Ca
2
+
to function as a sec-
ond messenger. These proteins bind
Ca
2
+
with high afFnity, selectivity, and
cooperativity, thereby permitting inter-
action with targets. More than 600 E±-
hand proteins have been identiFed to
date, which fulFll the different tasks of
calcium-dependent mechanisms (e.g.
glycogen metabolism, muscle contrac-
tion, excitation–secretion coupling, cell
cycle control, gene expression, mineral-
ization).
5. Solving the structure of several key com-
ponents of calcium-controlled pathways
helped understand their mechanism of
action.
See also
Bioinorganic Chemistry;
Cellular Interactions.
Bibliography
Books and Reviews
Carafoli, E., Klee, C. (1999)
Calcium as a Cellular
Regulator
, Oxford University Press, New York.
Carafoli, E., Krebs, J. (2000)
Calcium Homeosta-
sis
, Topics in Biological Inorganic Chemistry,
Vol. 3, Springer, Berlin.
Carafoli, E., Santella, L., Branca, D., Brini, M.
(2001)
Generation, control, and processing of
cellular calcium signals
,
Crit. Rev. Biochem. Mol.
Biol.
36
, 107–260.
Krebs, J.
(1991)
Calcium,
Biochemistry,
in:
Dulbecco, R. (Ed.)
Encyclopedia of Human
Biology
,Vo
l
.2
,A
c
ad
em
i
cP
r
e
s
s
,S
anD
i
ego
,
pp. 89–99.
Krebs, J., Guerini, D. (1996) The Calcium Pump
of Plasma Membranes, in: Lee, A.G. (Ed.)
Biomembranes
, Vol. 5, Jai Press, Greenwich,
pp. 101–131.
Krebs, J. (1998) The role of calcium in apoptosis,
BioMetals
11
, 375–382.
Pochet, R. (2000)
Calcium. The Molecular Basis of
Calcium Action in Biology and Medicine
,Kluwer
Academic Publishers, Dordrecht.
Primary Literature
Babu, Y.S., Sack, J.S., Greenhough, T.J., Bugg,
C.E., Means, A.R., Cook, W.J. (1985) Three-
dimensional structure of calmodulin,
Nature
315
, 37–40.
Brown, E.M.,
Gamba, G.,
Riccardi, D.,
Lom-
bardi, M.,
Butters, R.,
Kifor, O.,
Sun, A.,
Hediger, M.A., Lytton, J., Hebert, S.C. (1993)
Cloning and characterization of an extracel-
lular Ca(2
+
)-sensing receptor from bovine
parathyroid,
Nature
366
, 575–580.
Elshorst,
B.,
Hennig,
M.,
±orsterling,
H.,
Diener, A.,
Maurer,
M.,
Schulte,
P.,
Schwalbe, H.,
Griesinger,
C.,
Krebs,
J.,
Schmid, H., Vorherr, T., Carafoli, E. (1999)
NMR solution structure of a complex of
