Calcium Biochemistry
157
to be kept in a narrow concentration range
in the resting cell (i.e. 100–300 nM). On
the other hand, as indicated before, the
free Ca
2
+
concentration in the extracel-
lular milieu is 2 to 5 mM. This results
in a very steep concentration gradient
across the membrane, and thus small
changes in the free Ca
2
+
concentration
can influence the different signal trans-
duction pathways. Therefore, a number
of different transmembrane Ca
2
+
trans-
porting systems participate in controlling
the free Ca
2
+
concentration in the cell.
Most of these systems are either lo-
cated in the plasma membrane (Ca
2
+
channel, ATP-dependent transporting sys-
tem, Na
+
/Ca
2
+
exchanger), in the sarco
(endo)plasmic reticular system (ATPase,
Ca
2
+
-release channel), or in mitochondria
(an electrophoretic uptake system, a Na
+
-
dependent Ca
2
+
exchanger).
6.1
Calcium Transport Systems of the Plasma
Membrane
6.1.1
The Calcium Channel
Transient changes in the intracellular free
Ca
2
+
can be due to calcium deriving
either from intracellular stores (see be-
low) or from the extracellular fluid by
passing through speciFcally regulated (i.e.
gated) channels in the plasma mem-
brane down their electrochemical gradient.
Electrophysiological and pharmacological
properties have been used to characterize
different subtypes of the calcium channels.
To date, six different types of channels
have been identiFed: L, N, T, P, Q, and
R. On the basis of their electrophysiolog-
ical properties, using the well-established
patch-clamp technique, it can be shown
that these channels differ by their opening
kinetics and their conductance:
1. L-type:
long-lasting
inward current and
strong conductance (7–8 pS at 0.1 M
Ca
2
+
) antagonist: dihydropyridines
2. T-type:
transient
inward current and a
conductance of 5 to 10 pS at 0.1 M Ca
2
+
3. N-type: originally deFned as
neither
L-
nor
T-type channel (mainly found in
neurons
) with a characteristic activation
by strong depolarization and interme-
diate conductance (11–15 pS at 0.1 M
Ca
2
+
). Insensitive to dihydropyridines,
but blocked by
ω
-conotoxin-GVIA
4. P-type: high-voltage activated channel,
mainly found in cerebellar
Purkinje
cells, blocked by
ω
-Agatoxin-IVA but
not by
ω
-conotoxin-GVIA
Recently, two other types of channels
have been identiFed in Purkinje cells,
Q-type and R-type channels. Q-type chan-
nels are less sensitive to
ω
-Agatoxin-IVA,
whereas R-type channels are insensitive
to
ω
-Agatoxin-IVA and
ω
-conotoxin-GVIA
but sensitive to Ni
2
+
. All these channels
are characterized by their difference in
voltage dependence and their response
to pharmaca. A different type of classiF-
cation depending on the mechanism by
which the transition between the ‘‘open’’
and ‘‘closed’’ conformations are regulated
distinguishes between
1. voltage-operated channels (VOC) in
which the gating depends on voltage
as described above
2. receptor-operated channels (ROC) in
which gating depends on ligand bind-
ing
3. store-operated channels (SOC) in which
activation depends on the depletion
of Ca
2
+
stores of the endoplasmic
reticulum (ER) through a mechanism
known as capacitative calcium entry
(CCE).
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