Control of Cells by Chemical Messengers
133
ond messenger. Unlike the other second messengers discussed
in this chapter, though, arachidonic acid also serves as a sub-
strate to be converted into other products.
Finally, a word about drugs that infl uence the eicosanoid
pathway, which are perhaps the most commonly used drugs
in the world today. At the top of the list must come
aspi-
rin,
which inhibits cyclooxygenase and, therefore, blocks the
synthesis of the endoperoxides, prostaglandins, and throm-
boxanes. It and the new drugs that also block cyclooxygen-
ase are collectively termed
nonsteroidal anti-infl
ammatory
drugs (NSAIDs)
.
Their major uses are to reduce pain, fever,
and infl ammation. The term
nonsteroidal
distinguishes them
from the adrenal steroids that are used in large doses as anti-
infl ammatory drugs; these steroids inhibit phospholipase A
2
and thus block the production of all eicosanoids.
Plasma Membrane Receptors and Gene
Transcription
As described earlier in this chapter, the receptors for lipid-solu-
ble messengers, once activated by hormone binding, act in the
nucleus as transcription factors to increase or decrease the rate
of gene transcription. We now emphasize that there are many
other transcription factors inside cells and that the signal trans-
duction pathways initiated by
plasma membrane
receptors often
activate, by phosphorylation, these transcription factors. Thus,
many fi rst messengers that bind to plasma membrane receptors
can also alter gene transcription via second messengers. For
example, at least three of the proteins that cAMP-dependent
protein kinase phosphorylates function as transcription factors.
Some of the genes infl uenced by transcription factors
that are activated in response to fi rst messengers are known
collectively as
primary response genes,
or
PRGs
(also
termed
immed
ia
te-ear
ly
genes)
.
In
many
cases
,
espec
ia
l
ly
those involving fi rst messengers that infl uence the prolifera-
tion or differentiation of their target cells, the story does not
stop with a PRG and the protein it encodes. In these cases,
the protein the PRG encodes is itself a transcription factor for
other genes (
Figure 5–13
). Thus, an initial transcription fac-
tor activated in the signal transduction pathway causes the syn-
thesis of a different transcription factor, which in turn causes
the synthesis of additional proteins, ones particularly impor-
tant for the long-term biochemical events required for cellu-
lar proliferation and differentiation. A great deal of research is
being done on the transcription factors PRGs encode because
of their relevance to the abnormal growth and differentiation
that is typical of cancer.
Cessation of Activity in Signal Transduction
Pathways
Once initiated, signal transduction pathways are eventually
shut off because chronic overstimulation of a cell can in some
cases be detrimental. The key event is usually the cessation
of receptor activation. Because organic second messengers are
rapidly inactivated or broken down intracellularly (for example,
cAMP by phosphodiesterase), and because calcium is continu-
ously being pumped out of the cell or back into the endoplas-
mic reticulum, increases in the cytosolic concentrations of all
these components are transient events. Such changes persist
for only a brief time once the receptor is no longer being acti-
vated by a fi rst messenger.
A major way that receptor activation ceases is by a decrease
in the concentration of fi rst messenger molecules in the region
of the receptor. This occurs as enzymes in the vicinity metab-
olize the fi rst messenger, as the fi rst messenger is taken up by
adjacent cells, or as it simply diffuses away.
In addition, receptors can be inactivated in at least three
other ways: (1) the receptor becomes chemically altered (usu-
ally by phosphorylation), which may lower its affi nity for a
fi rst messenger, and so the messenger is released; (2) phos-
phorylation of the receptor may prevent further G-protein
binding to the receptor; and (3) plasma membrane receptors
Figure 5–13
Role of multiple transcription factors and primary response genes
(PRGs) in mediating protein synthesis in response to a fi rst messenger
binding to a plasma membrane receptor. The initial components of
the signal transduction pathway are omitted for simplicity.
Receptor
First part of
signal transduction
pathway
Primary response
genes
Other
genes
Synthesis of
different
transcription
factors
Synthesis of
proteins that mediate
the cell’s response to the
first messenger
(for example, proliferation
and differentiation)
Activation of proteins
that function as
transcription factors
Extracellular fluid
Plasma
membrane
Intracellular fluid
Nucleus
mRNA
mRNA
Begin
First
messenger
previous page 161 Vander's Human Physiology The Mechanisms of Body Function read online next page 163 Vander's Human Physiology The Mechanisms of Body Function read online Home Toggle text on/off