Molecular Biology of the Cell by Bruce Alberts, Alexander Johnson, Julian Lewis, David Morgan, Martin Raff, Keith Roberts, Peter Walter by by Bruce Alberts, Alexander Johnson, Julian Lewis, David Morg

SIGNALING THROUGH G-PROTEIN-COUPLED RECEPTORS
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CaM-kinase II activity
every 20 sec
0 20 40 60 80 sec
0 20 40 60 80 sec
(discussed in Chapter 11). When CaM-kinase II is exposed to both a protein phosphatase
and repetitive pulses of Ca 2+ /calmodulin at different frequencies that
mimic those observed in stimulated cells, the enzyme’s activity increases steeply
as a function of pulse frequency (Figure 15–35).
MBoC6 m15.45/15.35
Some G Proteins Directly Regulate Ion Channels
G proteins do not act exclusively by regulating the activity of membrane-bound
enzymes that alter the concentration of cyclic AMP or Ca 2+ in the cytosol. The
α subunit of one type of G protein (called G 12 ), for example, activates a guanine
nucleotide exchange factor (GEF) that activates a monomeric GTPase of the Rho
family (discussed later and in Chapter 16), which regulates the actin cytoskeleton.
In some other cases, G proteins directly activate or inactivate ion channels in
the plasma membrane of the target cell, thereby altering the ion permeability—
and hence the electrical excitability—of the membrane. As an example, acetylcholine
released by the vagus nerve reduces the heart rate (see Figure 15–5B). This
effect is mediated by a special class of acetylcholine receptors that activate the
G i protein discussed earlier. Once activated, the α subunit of G i inhibits adenylyl
cyclase (as described previously), while the βγ subunits bind to K + channels in
the heart muscle cell plasma membrane and open them. The opening of these
K + channels makes it harder to depolarize the cell and thereby contributes to the
inhibitory effect of acetylcholine on the heart. (These acetylcholine receptors,
which can be activated by the fungal alkaloid muscarine, are called muscarinic
acetylcholine receptors to distinguish them from the very different nicotinic acetylcholine
receptors, which are ion-channel-coupled receptors on skeletal muscle
and nerve cells that can be activated by the binding of nicotine, as well as by acetylcholine.)
Other G proteins regulate the activity of ion channels less directly, either by
stimulating channel phosphorylation (by PKA, PKC, or CaM-kinase, for example)
or by causing the production or destruction of cyclic nucleotides that directly activate
or inactivate ion channels. These cyclic-nucleotide-gated ion channels have a
crucial role in both smell (olfaction) and vision, as we now discuss.
CaM-kinase II activity
every 2 sec
(A) low-frequency Ca 2+ oscillations (B) high-frequency Ca 2+ oscillations
Figure 15–35 CaM-kinase II as a
frequency decoder of Ca 2+ oscillations.
(A) At low frequencies of Ca 2+ spikes, the
enzyme becomes inactive after each spike,
as the autophosphorylation induced by
Ca 2+ /calmodulin binding does not maintain
the enzyme’s activity long enough for the
enzyme to remain active until the next
Ca 2+ spike arrives. (B) At higher spike
frequencies, however, the enzyme fails to
inactivate completely between Ca 2+ spikes,
so its activity ratchets up with each spike.
If the spike frequency is high enough,
this progressive increase in enzyme
activity will continue until the enzyme is
autophosphorylated on all subunits and is
therefore maximally activated. Although not
shown, once enough of its subunits are
autophosphorylated, the enzyme can be
maintained in a highly active state even with
a relatively low frequency of Ca 2+ spikes (a
form of cell memory). The binding of Ca 2+ /
calmodulin to the enzyme is enhanced by
the CaM-kinase II autophosphorylation
(an additional form of positive feedback),
helping to generate a more switchlike
response to repeated Ca 2+ spikes. (From
P.I. Hanson, T. Meyer, L. Stryer, and
H. Schulman, Neuron 12:943–956, 1994.
With permission from Elsevier.)
Smell and Vision Depend on GPCRs That Regulate Ion Channels
Humans can distinguish more than 10,000 distinct smells, which they detect using
specialized olfactory receptor neurons in the lining of the nose. These cells use
specific GPCRs called olfactory receptors to recognize odors; the receptors are
displayed on the surface of the modified cilia that extend from each cell (Figure
15–36). The receptors act through cAMP. When stimulated by odorant binding,