140
Calcium Biochemistry
Marfan syndrome owing to mutations dis-
rupting the pair-wise interaction of cbEGF
domains in ±brillin-1.
3.2
The Extracellular Calcium Sensor
As stated before, calcium in the extracel-
lular fluid is tightly controlled because of
a strict regulation by different hormones
keeping the level of calcium concentration
within a narrow window (see Fig. 1). Re-
ceptors of the different hormones, such
as PTH, CT and Vitamin D
3
,in
v
o
l
v
e
d
in this regulation have been identi±ed,
but the molecular basis for sensing the
extracellular calcium level was poorly un-
derstood. On the basis of several obser-
vations, however, it was postulated that a
cell-surface Ca
2
+
-sensing receptor might
exist with functional similarities to the
G-protein–coupled receptors of the Ca
2
+
-
mobilizing hormones. In 1993, Brown
et al. reported the successful cloning and
characterization of a 500 kDa protein from
parathyroid glands with a large, extracel-
lular N-terminal region and a smaller,
cytosolic C-terminal domain that could be
activated by mM Ca
2
+
, corresponding to
the concentration of extracellular Ca
2
+
.
Since the predicted amino acid sequence of
the protein contained seven putative trans-
membrane domains, it was suggested that
this calcium receptor (CaR) functionally
belongs to the well-characterized group of
G protein-coupled receptors. The CaR is a
glycoprotein that shares some homologies
with glutamate receptors. The extracellular
domain contains low-af±nity Ca
2
+
binding
sites characterized by clusters of negatively
charged amino acid residues, typical for
extracellular, Ca
2
+
-sensing proteins. CaR
can be found in most cells throughout
the body, but especially in cells of those
organs that mainly control the level of
calcium in the extracellular fluid, that is,
in bone-forming and -resorbing cells, in
parathyroid glands, and in cells of kidney
and intestine. Long before the discovery
of CaR, clinical observations of inheritable
hypo- and hypercalcemic syndromes have
been described that could now be linked to
speci±c mutations of CaR, most of them in
the extracellular calcium-sensing domain.
4
Signal Transduction Principles
4.1
General Properties
Cell-surface receptors can recognize ex-
tracellular signals (‘‘primary messengers’’)
and multiply them into a cascade of intra-
cellular events using a limited number
of intracellular signal transducers, so-
called ‘‘second messengers.’’ The most
common intracellular signal multiplica-
tion system makes use of the phospho-
rylation/dephosphorylation of proteins or
enzymes by activating a bunch of different
kinases/phosphatases. To date, ±ve classes
of intracellular messengers are known:
1. cyclic
nucleotides
[cyclic
adenosine
3
0
–5
0
monophosphate (cyclic AMP);
cyclic guanosine 3
0
–5
0
monophosphate
(cyclic GMP); cyclic ADP-ribose];
2. derivatives of phosphatidylinositol [in-
ositolpolyphosphates,
e.g.
inositol-
1,4,5-triphosphate
(IP3),
inositol-
1,3,4,5-tetraphosphate (IP4), and dia-
cylglycerol (DAG), stemming from the
same precursor phosphatidylinositol-
4,5- diphosphate (PIP2);
3. free Ca
2
+
ions;
4
. gasessuchasn
itr
icox
ide(NO)
,proba
-
bly also carbon monoxide (CO);
5. nicotinic
acid
adenine
dinucleotide
phosphate (NAADP).
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