extracellular and intracellular ﬂ
uid. Similarly, changes in the
rate of glucose secretion by the liver induced by the hormone
epinephrine reﬂ ect the altered activity and concentration
of enzymes in the metabolic pathways for glucose synthesis.
Finally, muscle contraction induced by the neurotransmitter
acetylcholine results from the altered conformation of con-
Thus, receptor activation by a messenger is only the ﬁ rst
step leading to the cell’s ultimate response (contraction, secre-
tion, and so on). The diverse sequences of events between
receptor activation and cellular responses are termed
The “signal” is the receptor activa-
tion, and “transduction” denotes the process by which a stim-
ulus is transformed into a response. The important question
is: How does receptor activation inﬂ uence the cell’s internal
proteins, which are usually critical for the response but may be
located far from the receptor?
Signal transduction pathways differ between lipid-soluble
and water-soluble messengers. As described earlier, the recep-
tors for these two broad chemical classes of messenger are in
different locations—the former inside the cell and the latter in
the plasma membrane of the cell. The rest of this chapter elu-
cidates the general principles of the signal transduction path-
ways that these two broad categories of receptors initiate.
Pathways Initiated by Lipid-Soluble Messengers
Lipid-soluble messengers generally act on cells by binding
to intracellular receptor proteins. Lipid-soluble messengers
include steroid hormones, the thyroid hormones, and the ste-
roid derivative, 1,25-dihydroxy vitamin D. Structurally these
hormones are all lipophilic, and their receptors constitute the
steroid-hormone receptor superfamily.
membrane receptors for a few of these messengers have been
identiﬁ ed, most of the receptors in this superfamily are intra-
cellular. When not bound to a messenger, the receptors are
inactive. In a few cases, the inactive receptors are located in the
cytosol and move into the nucleus after binding their hormone.
Most of the inactive receptors in the steroid hormone super-
family, however, already reside in the cell nucleus, where they
bind to and are activated by their respective ligands. Receptor
activation leads to altered rates of gene transcription.
The messenger diffuses out of capillaries from plasma to
the interstitial ﬂ
uid. From there, the messenger diffuses across
the cell’s plasma membrane and nuclear membrane to enter
the nucleus and bind to the receptor there
receptor, activated by the binding of hormone to it, then
functions in the nucleus as a
as any regulatory protein that directly inﬂ uences gene tran-
scription. The hormone-receptor complex binds to a speciﬁ c
sequence near a gene in DNA called a response element, an
event that increases the rate of that gene’s transcription into
mRNA. The mRNA molecules move out of the nucleus to
direct the synthesis, on ribosomes, of the protein the gene
encodes. The result is an increase in the cellular concen-
tration of the protein and/or its rate of secretion, and this
accounts for the cell’s ultimate response to the messen-
ger. For example, if the protein encoded by the gene is an
enzyme, the cell’s response is an increase in the rate of the
reaction catalyzed by that enzyme.
Two other points are important. First, more than one
gene may be subject to control by a single receptor type. For
example, the glucocorticoid hormone cortisol (Chapter 11)
acts via one type of intracellular receptor to activate numer-
ous genes involved in cellular metabolism and energy balance.
Second, in some cases the transcription of a gene or genes may
rather than increased by the activated receptor.
Cortisol, for example, inhibits transcription of several genes
whose protein products mediate inﬂ ammatory responses that
occur following injury or infection (Chapter 18).
Pathways Initiated by Water-Soluble Messengers
Water-soluble messengers exert their actions on cells by
binding to receptor proteins on the extracellular surface of
the plasma membrane. Water-soluble messengers include most
hormones, neurotransmitters, and paracrine/autocrine com-
pounds. On the basis of the signal transduction pathways they
initiate, plasma membrane receptors can be classiﬁ ed into the
types listed in
and illustrated in
Mechanism of action of lipid-soluble messengers. This ﬁ
the receptor for these messengers in the nucleus. In some cases, the
unbound receptor is in the cytosol rather than the nucleus, in which
case the binding occurs there, and the messenger-receptor complex
moves into the nucleus. For simplicity, a single messenger is shown
binding to a single receptor. In many cases, however, two messenger/
receptor complexes must bind together in order to activate a gene.