Essential Cell Biology 5th edition

554 CHAPTER 16 Cell Signaling
by membrane-embedded Ca 2+ pumps that actively remove Ca 2+ from the
cytosol, sending it either into the ER or across the plasma membrane and
out of the cell. As a result, a steep electrochemical gradient of Ca 2+ exists
across both the ER membrane and the plasma membrane (discussed in
Chapter 12). When a signal transiently opens Ca 2+ channels in either of
these membranes, Ca 2+ rushes down its electrochemical gradient into the
cytosol, where it triggers changes in Ca 2+ -responsive proteins. The same
Ca 2+ pumps that normally operate to keep cytosolic Ca 2+ concentrations
low also help to terminate the Ca 2+ signal.
The effects of Ca 2+ in the cytosol are largely indirect, in that they are mediated
through the interaction of Ca 2+ with various kinds of Ca 2+ -responsive
proteins. The most widespread and common of these is calmodulin,
which is present in the cytosol of all eukaryotic cells that have been
examined, including those of plants, fungi, and protozoa. When Ca 2+
binds to calmodulin, the protein undergoes a conformational change
that enables it to interact with a wide range of target proteins in the cell,
altering their activities (Figure 16–25). One particularly important class
of targets for calmodulin is the Ca 2+ /calmodulin-dependent protein
kinases (CaM-kinases). When these kinases are activated by binding to
calmodulin complexed with Ca 2+ , they influence other processes in the
cell by phosphorylating selected proteins. In the mammalian brain, for
example, a neuron-specific CaM-kinase is abundant at synapses, where
it is thought to play an important part in some forms of learning and
memory. This CaM-kinase is activated by the pulses of Ca 2+ signals that
occur during neural activity, and mutant mice that lack the kinase show
a marked inability to remember where things are.
A GPCR Signaling Pathway Generates a Dissolved Gas
That Carries a Signal to Adjacent Cells
Second messengers like cyclic AMP and calcium are hydrophilic molecules
that generally act within the cell where they are produced. But
some molecules produced in response to GPCR activation are small
enough or hydrophobic enough to pass across the membrane and carry
a signal directly to nearby cells. An important example is the gas nitric
oxide (NO), which acts as a signaling molecule in many tissues. NO diffuses
readily from its site of synthesis and slips into neighboring cells.
The distance the gas diffuses is limited by its reaction with oxygen and
water in the extracellular environment, which converts NO into nitrates
and nitrites within seconds.
Figure 16–25 Calcium binding changes
the shape of the calmodulin protein.
(A) Calmodulin has a dumbbell shape,
with two globular ends connected by a
long α helix. Each of the globular ends
has two Ca 2+ -binding sites. (B) Simplified
representation of the structure, showing
the conformational changes that occur
when Ca 2+ -bound calmodulin interacts
with an isolated segment of a target
protein (red ). In this conformation, the
α helix jackknifes to surround the target
(Movie 16.6). (B, adapted from W.E.
Meador, A.R. Means, and F.A. Quiocho,
Science 257:1251–1255, 1992, and M. Ikura
et al., Science 256:632–638, 1992.)
(A)
2 nm
Ca 2+
NH 2
COOH
Ca 2+ H 2 N
(B)
COOH
HOOC
H 2 N
peptide portion
of target protein
e.g., CaM-kinase
COOH
NH 2