126
Chapter 5
Three notes on general terminology are essential for this
discussion. First, the intercellular chemical messengers that
reach the cell from the extracellular fl uid and bind to their spe-
cifi c plasma membrane receptors are often referred to as
rst
messengers.
Second messengers,
then, are substances that
enter or are generated in the cytoplasm as a result of receptor
activation by the fi rst messenger. The second messengers dif-
fuse throughout the cell to serve as chemical relays from the
plasma membrane to the biochemical machinery inside the cell.
The third essential general term is
protein kinase.
As
described in Chapter 3, protein kinase is the name for any
enzyme that phosphorylates other proteins by transferring a
phosphate group to them from ATP. Introduction of the phos-
phate group changes the conformation and/or activity of the
phosphorylated protein, often itself an enzyme. There are many
different protein kinases, and each type is able to phosphory-
late only certain proteins. The important point is that a variety
of protein kinases are involved in signal transduction pathways.
These pathways may involve a series of reactions in which a
particular inactive protein kinase is activated by phosphoryla-
tion and then catalyses the phosphorylation of another inactive
protein kinase, and so on. At the ends of these sequences, the
ultimate phosphorylation of key proteins, such as transport-
ers, metabolic enzymes, ion channels, and contractile proteins,
underlies the cell’s biochemical response to the fi rst messenger.
As described in Chapter 3, other enzymes do the reverse
of protein kinases; that is, they dephosphorylate proteins.
These enzymes, termed protein phosphatases, also participate
in signal transduction pathways, but their roles are much less
understood than those of the protein kinases and will not be
described further in this chapter.
Receptors That Are Ligand-Gated Ion Channels
In the fi
rst type of plasma membrane receptor listed in Table
5–2, the protein that acts as the receptor is also an ion chan-
nel. Activation of the receptor by a fi rst messenger (the ligand)
results in a conformational change of the receptor such that
it forms an open channel through the plasma membrane
(
Figure 5–5a
). Because the opening of ion channels has been
compared to the opening of a gate in a fence, these type of
channels are known as
ligand-gated ion channels.
They are
particularly prevalent in the plasma membranes of nerve cells,
as you will learn in Chapter 6.
The opening of ligand-gated ion channels in response to
binding of a fi rst messenger to its receptor results in an increase
in the net diffusion across the plasma membrane of one or
more types of ions specifi c to that channel. As you will see in
Chapter 6, such a change in ion diffusion is usually associated
with a change in the electrical charge, or membrane potential,
of a cell. This electrical signal is often the essential event in the
cell’s response to the messenger. In addition, when the channel
is a calcium channel, its opening results in an increase, by dif-
fusion, in cytosolic calcium concentration. Increasing cytosolic
calcium is another essential event in the transduction pathway
for many signaling systems.
Receptors That Function as Enzymes
The receptors in the second category of plasma membrane
receptors listed in Table 5–2
have intrinsic enzyme activity.
With one major exception (discussed soon), the many recep-
tors that possess intrinsic enzyme activity are all protein kinases
(
Figure 5–5b
). Of these, the great majority specifi cally phos-
phorylate the portions of proteins that contain the amino acid
tyrosine. Thus, these receptors are known as
receptor tyro-
sine kinases.
The typical sequence of events for receptors with intrinsic
tyrosine kinase activity is as follows. The binding of a specifi c
messenger to the receptor changes the conformation of the
receptor so that its enzymatic portion, located on the cytoplas-
mic side of the plasma membrane, is activated. This results in
autophosphorylation of the receptor; that is, the receptor phos-
phorylates its own tyrosine groups. The newly created phos-
photyrosines on the cytoplasmic portion of the receptor then
serve as docking sites for cytoplasmic proteins. The bound
docking proteins then bind and activate other proteins, which
in turn activate one or more signaling pathways within the cell.
The common denominator of these pathways is that they all
involve activation of cytoplasmic proteins by phosphorylation.
The number of kinases that mediate these phosphoryla-
tions can be very large, and their names constitute a veritable
alphabet soup—RAF, MEK, MAPKK, and many others. In
all this complexity, it is easy to lose track of the point that the
end result of all these pathways is the activation or synthesis
of molecules, usually proteins, that ultimately mediate the
response of the cell to the messenger. Most of the receptors
with intrinsic tyrosine kinase activity bind fi rst messengers
that typically infl uence cell proliferation and differentiation.
There is one major exception to the generalization that
p
l
a
sm
a
m
emb
r
an
e
r
e
c
ep
to
r
s
w
i
th
inh
e
r
en
t
enzym
e
a
c
t
i
v
-
ity function as protein kinases. In this exception, the recep-
tor functions both as a receptor and as a
guanylyl cyclase
to
catalyse the formation, in the cytoplasm, of a molecule known
as
cyclic GMP (cGMP).
In turn, cGMP functions as a second
messenger to activate a protein kinase called
cGMP-dependent
protein kinase.
This kinase phosphorylates specifi c proteins that
then mediate the cell’s response to the original messenger. As
described in Chapter 7, receptors that function both as ligand-
binding molecules and as guanylyl cyclases are present in high
amounts in the retina of the vertebrate eye, where they are impor-
tant for processing visual inputs. This signal transduction path-
way is used by only a small number of messengers and should not
be confused with the much more prevalent cAMP system to be
described in a later section. Also, in certain cells, guanylyl cyclase
enzymes are present in the cytoplasm. In these cases, a fi rst mes-
senger—nitric oxide—diffuses into the cell and combines with
the guanylyl cyclase there to trigger the formation of cGMP.
Receptors That Interact with
Cytoplasmic JAK Kinases
Recall that in the previous category, the receptor itself has intrin-
sic enzyme activity. In the next category of receptors (see Table
5–2 and
Figure 5–5c
), the enzymatic activity—again tyrosine
kinase activity—resides not in the receptor but in a family of
separate cytoplasmic
kinases, termed
JAK kinases,
which are
associated with the receptor. (The term
JAK
has several deriva-
tions, including “janus kinase.”) In these cases, the receptor and
its associated JAK kinase function as a unit. The binding of a
fi rst messenger to the receptor causes a conformational change in
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