168
Calcium Biochemistry
kinase revealed an overlapping with CaM
kinase II and protein kinase C. Together
with the ubiquitous distribution of CDPK
in plants, this observation suggests a multi-
functional kinase property for this enzyme,
but speciFc endogenous substrates still
have to be identiFed to characterize the
role of CDPK in calcium signal transduc-
tion pathways in plants.
8
Calcium and Disease
Sustained raise of cellular Ca
2
+
into
the micromolar range leads to deleteri-
ous effects upon Ca
2
+
signaling, which
could eventually lead to cell death. Muta-
tions of the intracellular Ca
2
+
-dependent
protease, calpain, the activity of which
normally is tightly controlled – like dis-
ruption of the gene responsible for a
muscle isoform – cause muscular dystro-
phy type 2A, whereas mutations of another
isoform lacking the C-terminal Ca
2
+
bind-
ing domain favor the onset of type 2
diabetes.
As indicated before, bone formation and
bone resorption is a highly integrated pro-
cess that, in cases of misbalance, leads to
severe diseases (e.g. osteopetrosis, osteo-
porosis, Paget’s disease) and thereby influ-
ences calcium homeostasis. The reason for
these malfunctions can be manifold and
will not be discussed here, but recently
two examples became known in which
disturbance of calcium homeostasis could
be traced to mutations of single proteins
involved in Ca
2
+
regulation.
Malignant hyperthermia is manifested
in humans and swine as an acute hyper-
thermic reaction accompanied by skeletal
muscle contracture and high fever, indi-
cating a lack of regulation of Ca
2
+
within
muscle cells. This could be due to either
an enhanced or chronic release of Ca
2
+
into the cell or due to a defective reuptake
of Ca
2
+
. Detailed studies by MacLennan
and his laboratory implicated a defect in
the Ca
2
+
release mechanism that could be
traced to a number of mutations within
the gene of the ryanodine-sensitive Ca
2
+
-
release channel in the sarcoplasmic reticu-
lum of skeletal muscle. To date, more than
20 different mutations linked to this defect
have been described in the
RyR1
gene.
Defects in the genes of the two brain-
speciFc isoforms of the plasma membrane
Ca
2
+
pump, PMCA2 and 3, have also
been described. Of special note is PMCA2
that is abundant in the outer hair cells
of the organ of Corti. Recent Fndings in
mice with hearing defects localized genetic
mutations within PMCA2, which could be
used as a model for investigating hearing
defects in humans.
Vitamin D–resistant rickets is an auto-
somal recessive disorder resulting from an
inability to regulate Ca
2
+
,wh
ichleadsto
bone demineralization, loss of hair, and
increased levels of the active vitamin D
metabolite 1,25 (OH)
2
D
3
.A
ssh
ownb
y
Hughes et al., the reason for these defects
lies in a number of inherited mutations
of the vitamin D receptor, a member
of the steroid/thyroid family of hormone-
sensitive transcription factors. The muta-
tions identiFed so far fall either into the
DNA binding or into the hormone binding
domain.
9
Conclusions
In summary, several general points can
be made:
1. Calcium, as one of the oldest com-
ponents of organisms, plays a central
previous page 842 Encyclopedia of Molecular Cell Biology and Molecular Medicine read online next page 844 Encyclopedia of Molecular Cell Biology and Molecular Medicine read online Home Toggle text on/off