Control of Cells by Chemical Messengers
123
Competition is the ability of different messenger mol-
ecules that are very similar in structure to compete with each
other for a receptor. Competition occurs physiologically with
closely related messengers, and it also underlies the action of
many drugs. If researchers or physicians wish to interfere with
the action of a particular messenger, they can administer com-
peting molecules that are similar enough to the endogenous
messenger that they bind to the receptors for that messenger.
However, the competing molecules fail to activate the recep-
tor. This blocks the endogenous messenger from binding and
yet does not trigger the cell’s response. Such drugs are known
as
antagonists
with regard to the usual chemical messenger.
One example are the beta-blockers, used in the treatment of
high blood pressure and other diseases. These drugs antagonize
the ability of epinephrine and norepinephrine to bind to one of
their receptors—the beta-adrenergic receptor. Because epineph-
rine and norepinephrine normally act to raise blood pressure
(Chapter 12), beta-blockers tend to reduce blood pressure by
acting as antagonists. Antihistamines are another example, and
are useful in treating allergic symptoms brought on due to excess
histamine secretion from cells known as mast cells (Chapter 18).
Antihistamines are antagonists that block histamine from bind-
ing with cells and triggering an allergic response.
On the other hand, some drugs that bind to a partic-
ular receptor type do trigger the cell’s response exactly as if
the true (endogenous) chemical messenger had combined
with the receptor. Such drugs, known as
agonists,
are used
therapeutically to mimic the messenger’s action. For example,
the decongestant drugs phenylephrine, pseudoephedrine, and
oxymetazoline mimic the action of epinephrine on a different
class of receptors, called alpha-adrenergic receptors, in blood
vessels. When alpha-adrenergic receptors are activated, the
smooth muscles of blood vessels in the nose contract, resulting
in vasoconstriction in the nasal passages and fewer sniffl es.
Regulation of Receptors
Receptors are themselves subject to physiological regulation.
The number of receptors a cell has, or the affi nity of the recep-
tors for their specifi c messenger, can be increased or decreased in
certain systems. An important example of such regulation is the
phenomenon of
down-regulation.
When a high extracellular
concentration of a messenger is maintained for some time, the
total number of the target cell’s receptors for that messenger may
decrease—that is, down-regulate. Down-regulation has the effect
of reducing the target cells’ responsiveness to frequent or intense
stimulation by a messenger—that is, desensitizing them—and
thus represents a local negative feedback mechanism.
Change in the opposite direction, called
up-regulation,
also occurs. Cells exposed for a prolonged period to very low
concentrations of a messenger may come to have many more
receptors for that messenger, thereby developing increased sen-
sitivity
(supersensitivity)
to it. For example, when the nerves
to a muscle are cut, the delivery of neurotransmitters from
those nerves to the muscle is eliminated. Under these condi-
tions, the muscle will contract in response to a much smaller
amount of experimentally injected neurotransmitter than that
to which a normal muscle responds. This happens because the
receptors for the neurotransmitter have been up-regulated,
resulting in supersensitivity.
Up-regulation and down-regulation are possible because
there is a continuous degradation and synthesis of receptors.
The main cause of down-regulation of plasma-membrane
receptors is
internalization.
The binding of a messenger to
its receptor can stimulate the internalization of the complex;
that is, the messenger-receptor complex is taken into the cell
by receptor-mediated endocytosis. This increases the rate of
receptor degradation inside the cell. Thus, at high hormone
concentrations, the number of plasma-membrane receptors of
that type gradually decreases during down-regulation.
The opposite events also occur and contribute to up-
regulation. The cell may contain stores of receptors in the mem-
branes of intracellular vesicles. These are then inserted into the
plasma membrane via exocytosis during up-regulation.
Another important mechanism of up-regulation and
down-regulation is alteration of the expression of the genes
that code for the receptors.
Signal Transduction Pathways
What are the sequences of events by which the binding of a
chemical messenger (hormone, neurotransmitter, or paracrine/
autocrine agent) to a receptor causes the cell to respond?
The combination of messenger with receptor causes a
change in the conformation (three-dimensional shape) of the
receptor. This event, known as
receptor activation,
is always
the initial step leading to the cell’s responses to the messenger.
These responses can take the form of changes in: (1) the per-
meability, transport properties, or electrical state of the cell’s
plasma membrane; (2) the cell’s metabolism; (3) the cell’s
secretory activity; (4) the cell’s rate of proliferation and differ-
entiation; or (5) the cell’s contractile activity.
Despite the seeming variety of these fi ve types of ulti-
mate responses, there is a common denominator: They are all
directly due to alterations of particular cell proteins. Let us
examine a few examples of messenger-induced responses, all
of which are described more fully in subsequent chapters. The
neurotransmitter-induced generation of electrical signals in
nerve cells refl ects the altered conformation of membrane pro-
teins (ion channels) through which ions can diffuse between
Figure 5–3
Characteristics of receptor binding to messengers. The receptors with
high affi nity will have more bound messenger at a given messenger
concentration (e.g., concentration X). The presence of a competitor
will reduce the amount of messenger bound, until at very high
concentrations the receptors become saturated with messenger.
Free messenger concentration
Amount of messenger bound
High-affinity receptor
High-affinity receptor in
presence of competitor
Low-affinity receptor
X
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