Control of Cells by Chemical Messengers
127
cAMP
ATP
αα
β
γ
β
γ
Inactive
cAMP-dependent
protein kinase
Active
cAMP-dependent
protein kinase
+ ATP
Protein-PO
4
+ ADP
Receptor
G
s
protein
CELL’S RESPONSE
Extracellular fluid
Plasma membrane
Intracellular fluid
Protein
Begin
First
messenger
Second
messenger
Adenylyl
cyclase
Figure 5–6
Cyclic AMP second-
messenger system. Not
shown in the fi
gure is
the existence of another
regulatory protein, G
i
,
which certain receptors
can react with to cause
inhibition of adenylyl
cyclase.
the receptor that leads to activation of the JAK kinase. Different
receptors associate with different members of the JAK kinase
family, and the different JAK kinases phosphorylate different
target proteins, many of which act as transcription factors. The
result of these pathways is the synthesis of new proteins, which
mediate the cell’s response to the fi rst messenger. Signaling by
cytokines—proteins secreted by cells of the immune system that
play a critical role in immune defenses (Chapter 18)—occurs
primarily via receptors linked to JAK kinases.
G-Protein-Coupled Receptors
The fourth category of plasma membrane receptors in Table 5–2
is by far the largest, including hundreds of distinct receptors
(
Figure 5–5d
). Bound to the receptor is a protein complex
located on the cytosolic surface of the plasma membrane and
belonging to the family of heterotrimeric (containing three
different subunits) proteins known as
G proteins.
The bind-
ing of a fi rst messenger to the receptor changes the conforma-
tion of the receptor. This change increases the affi nity of the
alpha subunit of the G protein for GTP. When bound to GTP,
the alpha subunit dissociates from the remaining two (beta and
gamma) subunits of the trimeric G protein. This dissociation
allows the activated alpha subunit to link up with still another
plasma membrane protein, either an ion channel or an enzyme.
These ion channels and enzymes are termed plasma membrane
effector proteins because they mediate the next steps in the
sequence of events leading to the cell’s response.
In essence, then, a G protein serves as a switch to couple
a receptor to an ion channel or to an enzyme in the plasma
membrane. Thus, these receptors are known as
G-protein-
coupled receptors
. The G protein may cause the ion chan-
nel to open, with a resulting change in electrical signals or,
in the case of calcium channels, changes in the cytosolic cal-
cium concentration. Alternatively, the G protein may activate
or inhibit the membrane enzyme with which it interacts. Such
enzymes, when activated, cause the generation of second mes-
sengers inside the cell.
Once the alpha subunit of the G protein activates its
effector protein, a GTP-ase activity inherent in the alpha sub-
unit cleaves the GTP into GDP plus P
i
. This cleavage renders
the alpha subunit inactive, allowing it to recombine with its
beta and gamma subunits. The beta and gamma subunits help
anchor the alpha subunit in the membrane.
There are several subfamilies of plasma membrane G
proteins, each with multiple distinct members, and a single
receptor may be associated with more than one type of G
protein. Moreover, some G proteins may couple to more than
one type of plasma membrane effector protein. Thus, a fi rst-
messenger-activated receptor, via its G-protein couplings, can
call into action a variety of plasma membrane effector pro-
teins such as ion channels and enzymes. These molecules can,
in turn, induce a variety of cellular events.
To illustrate some of the major points concerning G pro-
teins, plasma membrane effector proteins, second messengers,
and protein kinases, the next two sections describe the two
most important effector protein enzymes regulated by G pro-
teins—adenylyl cyclase and phospholipase C. In addition, the
subsequent portions of the signal transduction pathways in
which they participate are described.
Adenylyl Cyclase and Cyclic AMP
In this pathway (
Figure 5–6
), activation of the receptor
by the
binding of the fi rst messenger (for example, the hormone epi-
nephrine) allows the receptor to activate its associated G protein,
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