than more, generation of cAMP. This occurs because these
receptors are associated with a different G protein known as G
(the subscript i denotes “inhibitory’’). Activation of G
the inhibition of adenylyl cyclase. The result is to decrease the
concentration of cAMP in the cell and thereby the phosphor-
ylation of key proteins inside the cell.
Phospholipase C, Diacylglycerol, and
In this system, a G protein called G
gets activated by a receptor
that has bound a ﬁ rst messenger. Activated G
then activates a
plasma membrane effector enzyme called
This enzyme catalyzes the breakdown of a plasma membrane
phospholipid known as phosphatidylinositol bisphosphate,
). Both DAG and IP
function as second messengers but in very different ways.
DAG activates a class of protein kinases known collec-
protein kinase C,
which then phosphorylate a large
number of other proteins, leading to the cell’s response.
, in contrast to DAG, does not exert its second mes-
senger role by directly activating a protein kinase. Rather, IP
after entering the cytosol, binds to receptors located on the
endoplasmic reticulum. These receptors are ligand-gated Ca
channels. When bonded to IP
, the channels open. Because
the concentration of calcium is much higher in the endo-
plasmic reticulum than in the cytosol, calcium diffuses out
of this organelle into the cytosol, signiﬁ cantly increasing
cytosolic calcium concentration. This increased calcium con-
Mechanism by which an activated receptor stimulates the enzymatically-mediated breakdown of PIP
to yield IP
and DAG. IP
then causes the
release of calcium ions from the endoplasmic reticulum, which together with DAG activate protein kinase C.
centration then continues the sequence of events leading to
the cell’s response to the ﬁ rst messenger. We will pick up this
thread in more detail in a later section. However, it is worth
noting that one of the actions of Ca
is to help activate some
forms of protein kinase C (which is how this kinase got its
name—“C” for calcium).
Control of Ion Channels by G Proteins
A comparison of Figures 5–5d and 5–9 emphasizes one more
important feature of G-protein function—its ability to both
directly and indirectly gate ion channels. As shown in Figure
5–5d and described earlier, an ion channel can be the effec-
tor protein for a G protein. This situation is known as direct
G-protein gating of plasma membrane ion channels because
the G protein interacts directly with the channel. All the
events occur in the plasma membrane and are independent
of second messengers. Now look at Figure 5–9, and you will
see that cAMP-dependent protein kinase can phosphorylate
a plasma membrane ion channel, thereby causing it to open.
As we have seen, the sequence of events leading to the activa-
tion of cAMP-dependent protein kinase proceeds through a
G protein, so it should be clear that the opening of this chan-
nel is indirectly dependent on that G protein. To generalize,
indirect G-protein gating
of ion channels utilizes a second-
messenger pathway for the opening or closing of the channel.
Not just cAMP-dependent protein kinase, but protein kinases
involved in other signal transduction pathways can participate
in reactions leading to such indirect gating.
marizes the three ways by which receptor activation by a ﬁ rst