may be removed when the combination of ﬁ rst messenger and
receptor is taken into the cell by endocytosis. The processes
described here are physiologically controlled. For example,
in many cases the inhibitory phosphorylation of a receptor is
mediated by a protein kinase in the signal transduction path-
way triggered by ﬁ rst-messenger binding to that very receptor.
Thus, this receptor inactivation constitutes negative feedback.
This concludes our description of the basic principles of
signal transduction pathways. It is essential to recognize that
the pathways do not exist in isolation but may be active simul-
taneously in a single cell, undergoing complex interactions.
This is possible because a single ﬁ rst messenger may trigger
changes in the activity of more than one pathway and, much
more importantly, because many different ﬁ rst messengers—
often dozens—may simultaneously inﬂ uence a cell. Moreover,
a great deal of “cross-talk” can occur at one or more levels
among the various signal transduction pathways. For example,
active molecules generated in the cAMP pathway can alter
the ability of receptors that, themselves, function as protein
kinases to activate transcription factors.
Why should signal transduction pathways be so diverse
and complex? The only way a cell can achieve controlled dis-
tinct effects in the face of the barrage of multiple ﬁ rst mes-
sengers, each often having more than one ultimate effect, is
to have diverse pathways with branch points that may enhance
one pathway and reduce another.
The biochemistry and physiology of plasma membrane
signal transduction pathways are among the most rapidly
expanding ﬁ elds in biology. Most of this information, beyond
the basic principles we have presented, exceeds the scope of
this book. For example, the protein kinases we have identiﬁ ed
are those that are closest in the various sequences to the origi-
nal receptor activation. In fact, as noted earlier, there are often
cascades of protein kinases in the remaining portions of the
pathways. Moreover, a host of molecules other than protein
kinases play “helper” roles.
Finally, for reference purposes,
the biochemistry of the second messengers described in this
I. Receptors for chemical messengers are proteins or glycoproteins
located either inside the cell or, much more commonly, in the
plasma membrane. The binding of a messenger by a receptor
manifests speciﬁ city, saturation, and competition.
II. Receptors are subject to physiological regulation by their own
messengers. This includes down- and up-regulation.
III. Different cell types express different types of receptors; even a
single cell may express multiple receptor types.
Signal Transduction Pathways
I. Binding a chemical messenger activates a receptor, and this
initiates one or more signal transduction pathways leading to
the cell’s response.
II. Lipid-soluble messengers bind to receptors inside the
target cell. The activated receptor acts in the nucleus as a
transcription factor to alter the rate of transcription of speciﬁ c
genes, resulting in a change in the concentration or secretion
of the proteins the genes encode.
Reference Table of Important Second Messengers
Converted into eicosanoids by cytoplasmic enzymes
Eicosanoids exert paracrine and autocrine
effects, such as smooth muscle relaxation
Enters cell through plasma membrane ion channels
or is released from endoplasmic reticulum
Activates calmodulin and other calcium-
binding proteins; calcium-calmodulin
activates calmodulin-dependent protein
kinases. Also activates protein kinase C
Cyclic AMP (cAMP)
A G protein activates plasma membrane adenylyl
cyclase, which catalyzes the formation of cAMP from
Activates cAMP-dependent protein kinase
(protein kinase A)
Cyclic GMP (cGMP)
Generated from guanosine triphosphate in a reaction
catalyzed by a plasma membrane receptor with
guanylyl cyclase activity
Activates cGMP-dependent protein kinase
(protein kinase G)
A G protein activates plasma membrane
phospholipase C, which catalyzes the generation
of DAG and IP
from plasma membrane
phosphatidylinositol bisphosphate (PIP
Activates protein kinase C
Inositol trisphosphate (IP
See DAG above
Releases calcium from endoplasmic reticulum