Principles of cell signaling - UT Southwestern
Principles of cell signaling - UT Southwestern
Principles of cell signaling - UT Southwestern
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39057_ch14_<strong>cell</strong>bio.qxd 8/28/06 5:11 PM Page 593<br />
istic <strong>of</strong> the effector domain, usually correlates<br />
best with overall structure and sequence conservation.<br />
(Receptor families grouped by their<br />
functions are the organizational basis <strong>of</strong> the second<br />
half <strong>of</strong> this chapter.) However, classifying<br />
receptors pharmacologically, according to their<br />
specificity for ligands, is particularly useful for<br />
understanding the organization <strong>of</strong> endocrine<br />
and neuronal systems and for categorizing the<br />
multiple physiological responses to drugs.<br />
Expression <strong>of</strong> a receptor that is not normally<br />
expressed in a <strong>cell</strong> is <strong>of</strong>ten sufficient to<br />
confer responsiveness to that receptor’s ligand.<br />
This responsiveness <strong>of</strong>ten occurs because the<br />
<strong>cell</strong> expresses the other components necessary<br />
for propagating the intra<strong>cell</strong>ular signal from the<br />
receptor. The precise nature <strong>of</strong> the response will<br />
reflect the biology <strong>of</strong> the <strong>cell</strong>. Experimentally,<br />
responsiveness to a compound can be induced<br />
by introducing the cDNA that encodes the receptor.<br />
For example, mammalian receptors may<br />
be expressed in yeast, such that the yeast respond<br />
visibly to receptor ligands, thus providing<br />
a way to screen for new chemicals (drugs)<br />
that activate the receptor.<br />
Finally, it is possible to create chimeric receptors<br />
by fusing the ligand-binding domain<br />
from one receptor with the effector domain<br />
from a different receptor (Figure 14.2). Such<br />
chimeras can mediate novel responses to the<br />
ligand. With genetic modification <strong>of</strong> the ligandbinding<br />
domain, receptors can be reengineered<br />
to respond to novel ligands. Thus, scientists can<br />
manipulate <strong>cell</strong> functions with nonbiological<br />
compounds.<br />
14.4<br />
Receptors are catalysts<br />
and amplifiers<br />
Key concepts<br />
• Receptors act by increasing the rates <strong>of</strong> key<br />
regulatory reactions.<br />
• Receptors act as molecular amplifiers.<br />
Receptors act to accelerate intra<strong>cell</strong>ular functions<br />
and are, thus, functionally analogous to enzymes<br />
or other catalysts. Some receptors,<br />
including the protein kinases, protein phosphatases,<br />
and guanylate cyclases, are themselves<br />
enzymes and thus classical biochemical catalysts.<br />
More generally, however, receptors use<br />
the relatively small energy <strong>of</strong> ligand binding to<br />
accelerate reactions that are driven by alternative<br />
energy sources. For example, receptors that<br />
are ion channels catalyze the movement <strong>of</strong> ions<br />
across membranes, a process driven by the electrochemical<br />
potential developed by distinct ion<br />
pumps. G protein-coupled receptors and other<br />
guanine nucleotide exchange factors catalyze<br />
the exchange <strong>of</strong> GDP for GTP on the G protein,<br />
an energetically favored process dictated by the<br />
<strong>cell</strong>’s nucleotide energy balance. Transcription<br />
factors accelerate the formation <strong>of</strong> the transcriptional<br />
initiation complex, but transcription itself<br />
is energetically driven by multiple steps <strong>of</strong><br />
ATP and dNTP hydrolysis.<br />
As catalysts, receptors enhance the rates <strong>of</strong><br />
reactions. Most <strong>signaling</strong> involves kinetic rather<br />
than thermodynamic regulation; that is, <strong>signaling</strong><br />
events change reaction rates rather than<br />
their equilibria (see the next section). Thus, <strong>signaling</strong><br />
is similar to metabolic regulation, in<br />
which specific reactions are chosen according to<br />
their rates, with thermodynamic driving forces<br />
playing only a supportive role.<br />
In all <strong>signaling</strong> reactions, receptors use their<br />
catalytic activities to function as molecular amplifiers.<br />
Directly or indirectly, a receptor generates<br />
a chemical signal that is huge, both<br />
energetically and with respect to the number<br />
<strong>of</strong> molecules recruited by a single receptor.<br />
Molecular amplification is a hallmark <strong>of</strong> receptors<br />
and many other steps in <strong>cell</strong>ular <strong>signaling</strong><br />
pathways.<br />
14.5<br />
Ligand binding changes<br />
receptor conformation<br />
Key concepts<br />
• Receptors can exist in active or inactive<br />
conformations.<br />
• Ligand binding drives the receptor toward the<br />
active conformation.<br />
A central mechanistic question in receptor function<br />
is how the binding <strong>of</strong> a <strong>signaling</strong> molecule<br />
to the ligand-binding domain increases the activity<br />
<strong>of</strong> the effector domain. The key to this<br />
question is that receptors can exist in multiple<br />
molecular conformations, some active for <strong>signaling</strong><br />
and others inactive. Ligands shift the<br />
conformational equilibrium among these conformations.<br />
The structural changes that occur<br />
during the receptor’s inactive-active isomerization<br />
and how ligand binding drives these<br />
changes are exciting areas <strong>of</strong> biophysical research.<br />
However, the basic concept can be described<br />
simply in terms <strong>of</strong> coupling the<br />
conformational isomerizations <strong>of</strong> the ligandbinding<br />
and effector domains.<br />
14.5 Ligand binding changes receptor conformation 593