Calcium Biochemistry
141
The
primary
event
in
all
signal-
transducing pathways is the reception of
an external signal by a speciFc receptor in
the cellular membrane, activating a chain
of reactions that will Fnally result in an
intracellular response, that is, the cellular
or plasma membrane is the main informa-
tion barrier.
Ca
2
+
performs its second messenger
function owing to changes in the distri-
bution at the two sides of the membrane,
which modulates its messenger function,
in contrast to the metabolic synthesis and
degradation of the other second messenger
molecules. If the intracellular Ca
2
+
rises
owing to the opening of Ca
2
+
channels
upon receiving an extracellular signal, the
ion will bind to speciFc proteins. This event
will result in a conformational change en-
abling the triggering device to multiply the
incoming signal. The occurrence of such
Ca
2
+
binding regulatory proteins was Frst
described in muscle tissues (i.e. troponin
C) as mentioned before. The concept was
later corroborated because of the detection
of a variety of homologous proteins, as
described in detail in Sect. 5.
The different second messengers are
central components of intracellular control
mechanisms. They are connected in their
action through a complex network of
feedback mechanisms. In addition, the
interaction of polypeptide growth factors
with their receptors is connected with
signal transduction pathways. Thus, one
of the earliest responses upon binding
of growth factors to their receptors is
a rapid increase in cytosolic free Ca
2
+
owing to receptor-activated, membrane-
bound phospholipase C. This enzyme
speciFcally cleaves phosphatidylinositol-
4,5-diphosphate (PIP2) to release IP
3
and
DAG, the former releasing Ca
2
+
from
intracellular stores, whereas DAG activates
the Ca
2
+
- and phospholipid-dependent
protein kinase C.
4.2
Calcium Oscillations in the Cell
In 1986, Cobbold et al. made a striking ob-
servation: by monitoring the cytosolic cal-
cium level of individual hepatocytes, they
noticed that upon addition of vasopressin,
a hormone known to mobilize intracellular
calcium, the intracellular Ca
2
+
did not rise
to a sustained level, but instead increased
and decreased repetitively with a certain
f
requency(ca
lc
iumsp
ikes
)
.Theyfu
r
the
r
observed that it was the frequency and not
the amplitude of spiking that increased
proportional to the rise in concentration
of the added hormone, that is, an extra-
cellular
analog
signal was converted into
an intracellular
digital
signal. This sem-
inal observation was soon conFrmed in
other laboratories on a variety of differ-
ent cells indicating that calcium ‘‘spikes’’
and, in addition, calcium ‘‘waves,’’ the spa-
tial counterpart of calcium spiking, are
fundamentally important processes in sig-
nal transduction pathways. Two models
describing these phenomena have been
recently developed:
1. The
IP
3
–Ca
2
+
crosscoupling
(ICC)
model by Meyer & Stryer
2. The calcium-induced calcium-release
(CICR) model by Berridge
Pivotal to both systems are positive
feedback, cooperativity, deactivation, and
reactivation of the process. The key ele-
ment of the model described by Meyer
& Stryer is the mutual reinforcement
of the IP
3
-induced Ca
2
+
release and the
Ca
2
+
-stimulated IP
3
formation leading to
a crosscoupling of two oscillating sec-
ond messenger systems. By contrast, the
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