128
Chapter 5
in this example known as G
s
(the subscript s denotes “stimula-
tory”). This causes G
s
to activate its effector protein, the mem-
brane enzyme called
adenylyl cyclase
(also known as adenylate
cyclase). The activated adenylyl cyclase, whose catalytic site is
located on the cytosolic surface of the plasma membrane,
catalyzes the conversion of cytosolic ATP molecules to cyclic
3´,5´-adenosine monophosphate, or
cyclic AMP (cAMP)
(
Figure 5–7
). Cyclic AMP then acts as a second messenger
(see Figure 5–6). It diffuses throughout the cell to trigger the
sequence of events leading to the cell’s ultimate response to the
fi rst messenger. The action of cAMP eventually terminates when
it is broken down to noncyclic AMP, a reaction catalyzed by the
enzyme
phosphodiesterase
(see Figure 5–7). This enzyme is
also subject to physiological control. Thus, the cellular concen-
tration of cAMP can be changed either by altering the rate of
its messenger-mediated generation or the rate of its phospho-
diesterase-mediated breakdown. Caffeine and theophylline, the
active ingredients of coffee and tea, are widely consumed stimu-
lants that work partly by inhibiting phosphodiesterase activity,
thus prolonging the actions of cAMP within a cell.
What does cAMP actually do inside the cell? It binds to
and activates an enzyme known as
cAMP-dependent protein
kinase,
also called protein kinase A (see Figure 5–6). Protein
kinases phosphorylate other proteins—often enzymes—by
transferring a phosphate group to them. The changes in the
activity of proteins phosphorylated by cAMP-dependent protein
kinase bring about the cell’s response (secretion, contraction,
and so on). Again, note that each of the various protein kinases
that participate in the multiple signal transduction pathways
described in this chapter has its own specifi c substrates.
In essence, then, the activation of adenylyl cyclase by
a G protein initiates an “amplifi cation cascade” of events that
converts proteins in sequence from inactive to active forms.
Figure 5–8
illustrates the benefi t of such a cascade. While it is
active, a single enzyme molecule is capable of transforming into
product not one but many substrate molecules, let us say 100.
Therefore, one active molecule of adenylyl cyclase may catalyze
the generation of 100 cAMP molecules. At each of the two
subsequent enzyme-activation steps in our example, another
100-fold amplifi cation occurs. Therefore, the end result is that
a single molecule of the fi rst messenger could, in this example,
cause the generation of 1 million product molecules. This helps
to explain how hormones and other messengers can be effective
at extremely low extracellular concentrations. To take an actual
example, one molecule of the hormone epinephrine can cause
the liver to generate
and release 10
8
molecules of glucose.
In addition, cAMP-activated protein kinase A can dif-
fuse into the cell nucleus, where it can phosphorylate a protein
that then binds to specifi c regulatory regions of certain genes.
Such genes are said to be cAMP-responsive. Thus, the effects
of cAMP can be rapid and independent of changes in gene
activity, as in the example of epinephrine and glucose pro-
duction, or slower and dependent upon the formation of new
gene products.
How can cAMP’s activation of a single molecule,
cAMP-dependent protein kinase, be common to the great
variety of biochemical sequences and cell responses initiated
by cAMP-generating fi rst messengers? The answer is that
cAMP-dependent protein kinase can phosphorylate a large
number of different proteins (
Figure 5–9
). Thus, activated
cAMP-dependent protein kinase can exert multiple actions
within a single cell and different actions in different cells. For
example, epinephrine acts via the cAMP pathway on fat cells to
stimulate the breakdown of triglyceride, a process that is medi-
ated by one particular phosphorylated enzyme. In the liver,
epinephrine acts via cAMP to stimulate both glycogenolysis
and gluconeogenesis, processes that are mediated by phos-
phorylated enzymes that differ from those in fat cells.
Note that whereas phosphorylation mediated by cAMP-
dependent protein kinase activates certain enzymes, it inhibits
others. For example, the enzyme catalyzing the rate-limiting
step in glycogen synthesis is inhibited by phosphorylation.
This explains how epinephrine inhibits glycogen synthesis at
the same time it stimulates glycogen breakdown by activating
the enzyme that catalyzes the latter response.
Not mentioned thus far is the fact that receptors for
some fi rst messengers, upon activation by their messengers,
inhibit
adenylyl cyclase. This inhibition results in less, rather
OH
HO
H
H
OH
O
P
O
P
O
P
O
OO
O
HH
OH
OH
OH
CH
2
Adenine
OH
H
H
OH
O
P
O
O
HO
HH
OH
CH
2
Adenine
OH
OH
H
H
O
O
O
O
HH
CH
2
P
Adenine
ATP
AMP
PP
cAMP
H
2
O
Phosphodiesterase
Adenylyl cyclase
Figure 5–7
Structure of ATP, cAMP, and AMP, the last resulting from
enzymatic inactivation of cAMP.
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