Principles of cell signaling - UT Southwestern

39057_ch14_cellbio.qxd 8/28/06 5:11 PM Page 604
Alternatively, feedback control can initiate
downstream from multiple receptors in a convergent
pathway and thus regulate both the
initiating receptor and the others. Such heterologous
adaptation regulates all the possible
inputs to a given control point. A common
example is the phosphorylation of G proteincoupled
receptors by either protein kinase A or
protein kinase C, which are activated by downstream
signals cAMP or Ca2+ plus the lipid diacylglycerol,
respectively. Like GRK, these kinases
both attenuate receptor activity and promote
arrestin binding.
Cells also alter their responses to incoming
signals for homeostatic reasons. These considerations
include phase of the cell cycle, metabolic
status, or other aspects of cellular activity.
Again, all these adaptive processes may be displayed
to a greater or lesser extent in different
cells, different pathways within a cell or different
situations during the cell’s lifetime.
14.11
Signaling proteins are
frequently expressed as
multiple species
Key concepts
• Distinct species (isoforms) of similar signaling
proteins expand the regulatory mechanisms
possible in signaling pathways.
• Isoforms may differ in function, susceptibility to
regulation or expression.
• Cells may express one or several isoforms to fulfill
their signaling needs.
Cells increase the richness, adaptability, and
regulation of their signaling pathways by expressing
multiple species of individual signaling
proteins that display distinct biochemical
properties. These species may be encoded by
multiple genes or by multiple mRNAs derived
from a single gene by alternative splicing or
mRNA editing. The numerical complexity implicit
in these choices is impressive. Consider
the neurotransmitter serotonin: In mammals,
there are thirteen serotonin receptors, each of
which stimulates a distinct spectrum of G proteins
of the G i
, G s
, and G q
families. (A fourteenth
serotonin receptor is an ion channel.)
FIGURE 14.12 shows the relationship of serotonin
receptors to these G protein families.
There is also tremendous diversity among
the G proteins and adenylyl cyclases. There are
three genes for Gα i
and one each for the closely
related Gα z
and Gα o
. Furthermore, the Gα o
mRNA is multiply spliced. There are four G q
members. In addition, there are five genes for
Gβ and twelve for Gγ, and most of the possible
Gβγ dimers are expressed naturally. There are
ten genes for adenylyl cyclases, which are direct
targets of G s
and either direct or indirect targets
of the other G proteins. While all nine membrane-bound
adenylyl cyclase isoforms are stimulated
by Gα s
, they display diverse stimulatory
and inhibitory responses to Gβγ, Gα i
, Ca2+,
calmodulin, and several protein kinases, as illustrated
in FIGURE 14.13. Thus, stimulation by
serotonin can lead to diverse responses depending
upon the various forms of the proteins that
are engaged at a particular time and location.
FIGURE 14.12 Receptors for serotonin have
evolved in mammals as a family of 13 genes that
regulate three of the four major classes of G proteins.
While all respond to the natural ligand
serotonin, the binding sites have evolved sufficient
differences that drugs have been developed
that specifically target one or more
isoforms. The type 3 serotonin receptors, not
shown here, are ligand-gated ion channels and
are not obviously related to the others.
Evolutionary relationship of serotonin receptor isoforms
Isoforms G protein
1B
1D
1E G i
1F
1A
5A
7
5B
G s
4
2A
2C
G q
6
2B
G s
120 100 80 60 40 20 0
Nucleotide substitution distance
604 CHAPTER 14 Principles of cell signaling