Principles of cell signaling - UT Southwestern

39057_ch14_cellbio.qxd 8/28/06 5:11 PM Page 614
Perhaps the most diverse family of ligandgated
channels is that of the TRP and TRP-like
family, of which about 30 have been found in
mammals. Distinct forms are found in invertebrates.
The TRP channels are Ca2+-selective
channels that are formed by tetramers of identical
subunits that surround the central channel.
Each subunit is composed of a homologous
bundle of six membrane-spanning helices, but
the N and C termini contain a diverse collection
of regulatory and protein interaction domains,
including protein kinase domains (whose
substrates are currently unknown).
All TRP channels allow transmembrane flux
of Ca2+ to permit its action as a second messenger,
but different TRP isoforms serve numerous
physiological functions. The prototypical TRP,
found in invertebrate photoreceptors, gates Ca2+
flow from intracellular stores into the cytoplasm
to initiate visual signaling. Others admit Ca2+
from outside the cell, and still others allow Ca2+
to enter the endoplasmic reticulum virtually directly
from the extracellular space because they
form a bridge between the plasma membrane
and channels in the endoplasmic reticulum at
points where the membranes abut each other.
Regulation of TRP channels is perhaps even
more diverse. Various TRP channels respond to
heat, cold, painful stimuli, pressure, and high
or low osmolarity. Many TRPs are regulated either
positively or negatively by lipids, such as
eicosanoids, diacylglycerol, and PIP 2
. For example,
capsaicin, the hot compound in chilis, is
an agonist for some vanilloid receptors (TRPVs).
Still other TRP channels are mechanosensors
that allow cilia to sense fluid flow. The most famous
of these is the sensory channel of the hair
cell of the inner ear. This channel opens when
the apical cilia on the hair cell are bent in response
to sound-driven fluid flow.
14.19
Nuclear receptors
regulate transcription
Key concepts
• Nuclear receptors modulate transcription by
binding to distinct short sequences in
chromosomal DNA known as response elements.
• Receptor binding to other receptors, inhibitors, or
coactivators leads to complex transcriptional
control circuits.
• Signaling through nuclear receptors is relatively
slow, consistent with their roles in adaptive
responses.
Nuclear receptors are unique among cellular
receptors in that their ligands pass unaided
through the plasma membrane. These receptors,
when complexed with their ligands, enter
the nucleus and regulate gene transcription.
Ligands for nuclear receptors include sex steroids
(estrogen and testosterone) and other steroid
hormones, vitamins A and D, retinoids and
other fatty acids, oxysterols, and bile acids.
Nuclear receptors are structurally conserved.
They consist of a C-terminal ligand binding domain,
an N-terminal interaction region that recognizes
components of the transcriptional
machinery and acts as a transactivation domain,
a centrally located zinc finger domain that binds
DNA, and, often, another transactivation domain
nearer the C-terminus. In the absence of
ligand, these receptors are bound to corepressor
proteins that suppress their activity. Upon
hormone binding, corepressors dissociate and
the receptors are assembled in multiprotein
complexes with coactivators that modulate receptor
action and facilitate transcriptional regulation.
As illustrated in FIGURE 14.20, agonists
and antagonists bind to distinct receptor conformations
(see 14.5 Ligand binding changes receptor
conformation). Receptor agonists favor the binding
of receptors to coactivators and DNA, and
antagonists favor conformations that block coactivator-receptor
binding.
Nuclear receptors bind with high specificity
to hormone response elements in the 5’ untranscribed
region of regulated genes. Response
elements are typically short direct or inverted
repeat sequences, and a gene may contain response
elements for several different receptors
in addition to binding sites for other transcriptional
regulatory proteins.
The sex steroid estrogen can bind to two
different nuclear receptors, the estrogen receptors
ER and ER. Coactivator and corepressor
proteins differentially regulate ER and ER in
transcriptional complexes that are expressed in
specific cell types. Other ligands that bind to
these receptors include valuable therapeutic
agents. For example, 4 hydroxy-tamoxifen is
an estrogen receptor antagonist used in the therapy
of estrogen-receptor-positive breast cancer
to inhibit growth of residual cancer cells.
However, unlike its antagonistic effects on the
estrogen receptor in breast, 4 hydroxy-tamoxifen
displays weak partial agonist activity in
uterus. In the estrogen receptor system, partial
agonists are known as selective estrogen receptor
modulators (SERMs). Properties that contribute
to partial agonist activity include the
relative expression of the two estrogen recep-
614 CHAPTER 14 Principles of cell signaling