Control of Cells by Chemical Messengers
131
messenger leads to opening or closing of ion channels, causing
a change in membrane potential.
Calcium as a Second Messenger
The calcium ion (Ca
2+
) functions as a second messenger in a great
variety of cellular responses to stimuli, both chemical and elec-
trical. The physiology of calcium as a second messenger requires
an analysis of two broad questions: (1) How do stimuli cause
the cytosolic calcium concentration to increase? (2) How does
the increased calcium concentration elicit the cells’ responses?
Note that, for simplicity, our two questions are phrased in terms
of an
increase
in cytosolic concentration. There are, in fact, fi rst
messengers that elicit a
decrease
in cytosolic calcium concen-
tration and therefore a decrease in calcium’s second-messenger
effects. Now for the answer to the fi rst question.
By means of active-transport systems in the plasma mem-
brane and cell organelles, Ca
2+
is maintained at an extremely
low concentration in the cytosol. Consequently, there is always
a large electrochemical gradient favoring diffusion of calcium
into the cytosol via calcium channels in both the plasma mem-
brane and the endoplasmic reticulum. A stimulus to the cell
can alter this steady state by infl uencing the active-transport
systems and/or the ion channels, resulting in a change in
cytosolic calcium concentration.
The most common ways that receptor activation by a
fi rst messenger increases the cytosolic Ca
2+
concentration have
already been presented in this chapter and are summarized in
the top part of
Table 5–4
.
The previous paragraph dealt with receptor-initiated
sequences of events. This is a good place, however, to empha-
size that there are calcium channels in the plasma membrane
that are opened directly by an electrical stimulus to the mem-
brane. Calcium can act as a second messenger, therefore, in
response not only to chemical stimuli acting via receptors, but
to electrical stimuli acting via voltage-gated calcium channels
as well. Moreover, extracellular calcium entering the cell via
these channels can, in certain cells, bind to calcium-sensitive
channels in the endoplasmic reticulum and open them. In
this manner, a small amount of extracellular calcium entering
the cell can function as a second messenger to release a much
larger amount of calcium from the endoplasmic reticulum.
This phenomenon is called “calcium-induced calcium release.”
Thus, depending on the cell and the signal—fi rst messenger
or an electrical impulse—the major second messenger that
releases calcium from the endoplasmic reticulum can be either
IP
3
or calcium itself (see item 1b in the top of Table 5–4).
Now we turn to the question of how the increased cyto-
solic calcium concentration elicits the cells’ responses (see
bottom of Table 5–4). The common denominator of calci-
um’s actions is its ability to bind to various cytosolic proteins,
altering their conformation and thereby activating their func-
tion. One of the most important of these is a protein, found
in virtually all cells, known as
calmodulin
(
Figure 5–11
).
On binding with calcium, calmodulin changes shape, and this
allows calcium-calmodulin to activate or inhibit a large variety
of enzymes and other proteins, many of them protein kinases.
Activation or inhibition of
calmodulin-dependent protein
kinases
leads, via phosphorylation, to activation or inhibition
of proteins involved in the cell’s ultimate responses to the fi rst
messenger.
Calmodulin is not, however, the only intracellular pro-
tein infl uenced by calcium binding. For example, you will learn
in Chapter 9 how calcium binds to a protein called troponin in
certain types of muscle to initiate contraction.
Arachidonic Acid and Eicosanoids
The
eicosanoids
are a family of molecules produced from
the polyunsaturated fatty acid
arachidonic acid,
which is
present in plasma membrane phospholipids. The eicosanoids
include the
cyclic endoperoxides,
the
prostaglandins,
the
thromboxanes,
and the
leukotrienes
(
Figure 5–12
). They
Table 5–3
Summary of Mechanisms by Which
Receptor Activation Infl uences Ion
Channels
1. The ion channel is part of the receptor.
2. A G protein directly gates the channel.
3. A G protein gates the channel indirectly via a second
messenger.
Table 5–4
Calcium as a Second Messenger
Common Mechanisms By Which Stimulation of a Cell
Leads to an Increase in Cytosolic Ca
2+
Concentration:
1. Receptor activation
a. Plasma-membrane calcium channels open in response
to a fi rst messenger; the receptor itself may contain the
channel, or the receptor may activate a G protein that
opens the channel via a second messenger.
b. Calcium is released from the endoplasmic reticulum; this
is mediated by second messengers, particularly IP
3
and
calcium entering from the extracellular fl
uid.
c. Active calcium transport out of the cell is inhibited by a
second messenger.
2. Opening of voltage-gated calcium channels.
Major Mechanisms By Which an Increase in Cytosolic Ca
2+
Concentration Induces the Cell’s Responses:
1. Calcium binds to calmodulin. On binding calcium, the
calmodulin changes shape, which allows it to activate or
inhibit a large variety of enzymes and other proteins. Many
of these enzymes are protein kinases.
2. Calcium combines with calcium-binding intermediary
proteins other than calmodulin. These proteins then act in a
manner analogous to calmodulin.
3. Calcium combines with and alters response proteins directly,
without the intermediation of any specifi c calcium-binding
protein.
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