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 613<br />
and by lining the walls <strong>of</strong> the pore with appropriate<br />
hydrophilic residues. Receptor ion channels<br />
can, thus, provide a diffusion path for only<br />
cations or anions, or select among different ions.<br />
Ligand-gated ion channels provide the<br />
fastest signal transduction mechanism found in<br />
biology. Upon binding an agonist ligand, channels<br />
open within microseconds. At synapses,<br />
where neurotransmitters need to diffuse less<br />
than 0.1 micron, a signal in the postsynaptic<br />
<strong>cell</strong> can be generated in 100 microseconds. In<br />
contrast, receptor-stimulated G proteins require<br />
about 100 milliseconds to exchange GDP for<br />
GTP, and the action <strong>of</strong> receptor protein kinases<br />
is even slower. Ligand-gated ion channels are<br />
important receptors in many <strong>cell</strong>s in addition<br />
to neurons and muscle, and other ion channels<br />
play equally vital roles in <strong>signaling</strong> pathways<br />
triggered by other classes <strong>of</strong> ligands.<br />
Ion channel <strong>signaling</strong> differs from that <strong>of</strong><br />
the other receptors mentioned in this chapter<br />
in that there is no immediate protein target nor,<br />
in most cases, is there a specific second messenger<br />
involved. In most cases, channel-mediated<br />
ion flow acts to increase or decrease the <strong>cell</strong>’s<br />
membrane potential and, thus, modulates all<br />
transport processes for metabolites or ions that<br />
are electrically driven.<br />
Animal <strong>cell</strong>s maintain an inside-negative<br />
membrane potential by pumping out Na + ions<br />
and pumping in K + ions (for more on membrane<br />
potential see 2.4 Electrochemical gradients<br />
across the <strong>cell</strong> membrane generate the membrane potential).<br />
The opening <strong>of</strong> a channel selective for<br />
Na+ will thus depolarize <strong>cell</strong>s, and the opening<br />
<strong>of</strong> a channel for K + will hyperpolarize <strong>cell</strong>s.<br />
Similarly, because Cl - is primarily extra<strong>cell</strong>ular,<br />
opening Cl - channels will also cause hyperpolarization.<br />
These electrical effects convey information<br />
to effector proteins that are energetically<br />
coupled to the membrane potential, or to specific<br />
ion gradients, or that bind a specific ion<br />
(such as Ca2+) whose concentration changes<br />
upon channel opening.<br />
The nicotinic acetylcholine receptor is the prototypical<br />
receptor ion channel and was the first<br />
receptor that was shown to be a channel. It is a relatively<br />
unselective cation channel that causes depolarization<br />
<strong>of</strong> the target <strong>cell</strong> by allowing Na+<br />
influx. It is best known as the excitatory receptor<br />
at the neuromuscular synapse, where it triggers<br />
contraction, but alternative is<strong>of</strong>orms are also active<br />
in neurons and many other <strong>cell</strong>s. In muscles,<br />
nicotinic depolarization acts via a voltage-sensitive<br />
Ca2+ channel to allow Ca2+ release from the sarcoplasmic<br />
reticulum into the cytosol. Calcium acts<br />
Nicotinic acetylcholine receptor structure<br />
CLOSED<br />
CYTOSOL<br />
Pore<br />
OPEN<br />
Pore<br />
FIGURE 14.19 The nicotinic cholinergic receptor is a cation-selective channel<br />
that is composed <strong>of</strong> five homologous but usually nonidentical subunits that<br />
oligomerize to form a primarily -helical membrane-spanning core. The channel<br />
itself is created within this core, and its opening and closing are executed<br />
by cooperative changes in subunit arrangement. Structure generated from<br />
Protein Data Bank file 2BG9.<br />
as a second (or third) messenger to initiate contraction<br />
(see 2.13 Cardiac and skeletal muscles are activated<br />
by excitation-contraction coupling). Nicotinic<br />
receptors promote exocytosis in some secretory<br />
<strong>cell</strong>s by a similar mechanism, where Ca2+ triggers<br />
the exocytic event. In neurons, where nicotinic<br />
stimulation causes an action potential (depolarization<br />
that is rapidly propagated along the neuron),<br />
the initial depolarization is sensed by<br />
voltage-sensitive Na+ channels. Their opening<br />
(along with the action <strong>of</strong> other channels) propagates<br />
the action potential along the neuron.<br />
The nervous system is rich in receptor cation<br />
channels that respond to other neurotransmitters,<br />
the most common <strong>of</strong> which is the amino<br />
acid glutamate (Glu). The three different families<br />
<strong>of</strong> glutamate receptors share the property<br />
<strong>of</strong> cation conductance, but each family has its<br />
own spectrum <strong>of</strong> drug responses. All operate as<br />
neuronal activators, with one interesting twist:<br />
The NMDA family <strong>of</strong> receptors, named for their<br />
response to a selective drug, is permeant to Ca2+<br />
in addition to Na+. A significant component <strong>of</strong><br />
its activity is to permit the inward flow <strong>of</strong> Ca2+,<br />
which acts as a second messenger on a wide variety<br />
<strong>of</strong> targets. Persistant stimulation <strong>of</strong> NMDA<br />
channels by glutamate released during injury,<br />
or by drugs, can cause toxic amounts <strong>of</strong> Ca2+ to<br />
enter, resulting in neuronal death.<br />
A second functional group <strong>of</strong> receptor channels<br />
is selective for anions and, by allowing inward<br />
flux <strong>of</strong> Cl - , hyperpolarizes the target <strong>cell</strong>.<br />
Anion-selective receptors include those for γ-<br />
aminobutyric acid (GABA) and glycine (Gly). In<br />
neurons, hyperpolarization can inhibit the initiation<br />
<strong>of</strong> an action potential and/or neurotransmitter<br />
release.<br />
14.18 Signaling through ion channel receptors is very fast 613