Calcium Biochemistry
165
membranes, which is an autoinhibitory
domain.
Three different genes have been identiFed
to date to encode the SERCA pump.
SERCA1 is mainly found in the fast-
twitch skeletal muscle, whereas SERCA2
is the major form of cardiac, smooth,
and
nonmuscle
tissues.
SERCA3
has
been cloned from a kidney library and
is prominently present in platelets. ±or
SERCA1 and 2, several spliced isoforms
also have been described.
6.3
The Mitochondrial Calcium Transporting
Systems
Like the
reticular systems,
mitochon-
dria also provide intracellular calcium-
transporting systems sequestering Ca
2
+
by means of energy-dependent processes.
The mitochondrial calcium transporters,
that is, a Ca
2
+
uniporter and a Na
+
/Ca
2
+
exchanger, were thought, for a long time,
to play a minor role in the constant regu-
lation of the cytosolic Ca
2
+
concentration
since the mitochondrial Ca
2
+
uptake rate
is about 10-fold slower than that of the
SR, and the
K
M
v
a
l
u
ef
o
rt
h
et
r
a
n
s
-
porter is 10-fold higher than that of the
reticular systems. Using Ca
2
+
-speciFc in-
dicators targeted to different organelles, it
became clear that mitochondria were very
important for sensing Ca
2
+
changes in
‘‘microdomains’’ of the cell, rather than
in the bulk cytosol; that is, increase of
cytosolic Ca
2
+
induced by IP
3
was paral-
leled by a rapid increase of mitochondrial
Ca
2
+
. It soon became clear that the acti-
vation of mitochondrial Ca
2
+
uptake was
the result of the proximity of the mito-
chondria and the ER, and the release of
large amounts of Ca
2
+
by the latter could
create microdomains of local high Ca
2
+
concentrations, sufFcient to activate the
low-afFnity mitochondrial Ca
2
+
uniporter.
In spite of concentrated studies, however,
the molecular nature of this mitochondrial
Ca
2
+
transporting system could not be
identiFed to date.
6.4
Calcium in the Nucleus
The nucleus is separated from the cytosol
by the nuclear envelope consisting of two
concentric membranes, of which the outer
membrane is continuous with the ER. The
nuclear envelope is not a completely closed
system but is interrupted by the nuclear
pores, large multicomponent protein com-
plexes that regulate the transport into and
out of the nucleus. Whether Ca
2
+
can
freely diffuse through these pores like
most small molecules or whether it is
gated is still controversial, but it is clear
that there are important Ca
2
+
-dependent
processes occurring in the nucleus, in-
cluding Ca
2
+
-dependent gene expression.
A key factor of Ca
2
+
-dependent gene ex-
pression (including a number of Ca
2
+
transporting systems) is the transcription
factor CREB, originally identiFed as the
protein recognizing cAMP-responsive el-
ements. Thus, CREB can be activated
by phosphorylation of a serine residue,
Ser133, either by cAMP-dependent PKA
or by a CaM-dependent protein kinase,
CaMKII or IV. In this respect, a recent
Fnding is of particular interest, showing
that the mode of entry of Ca
2
+
into cells,
that is, via the voltage-dependent calcium
L-channel or through other means, speci-
Fes the response to Ca
2
+
-dependent gene
transcription.
Another pathway of Ca
2
+
-dependent
gene transcription recently attracted much
attention, that is, the transcription factor
N±AT that has originally been described as
being important in T cells and that is under
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