Each Cell Is Programmed to Respond to Specific Combinations of Signaling

Molecules

Any given cell in a multicellular organism is exposed to many - perhaps hundreds - of different
signals from its environment. These signals can be soluble, or bound to the extracellular matrix,
or bound to the surface of a neighboring cell, and they can act in many millions of possible
combinations. The cell must respond to this babel selectively, according to its own specific
character, acquired through progressive cell specialization in the course of development. Thus a
cell may be programmed to respond to one set of signals by differentiating, to another set by
proliferating, and to yet another by carrying out some specialized function..

   Combinatorial signaling

Each cell type displays a set of receptors that enables it to respond to a corresponding set of
signaling molecules produced by other cells. These signaling molecules work in combinations to
regulate the behavior of the cell. As shown here, many cells require multiple signals ( green
arrows) to survive and additional signals ( red arrows) to proliferate; if deprived of all signals,
these cells undergo programmed cell death.

Most cells in higher animals, moreover, are programmed to depend on a specific set of signals
simply for survival: when deprived of the appropriate signals (in a culture dish, for example), a
cell will activate a suicide program and kill itself - a process called programmed cell death.

Different types of cells require different sets of survival signals and so are restricted to different
environments in the body. Because signaling molecules generally act in combinations, an animal
can control the behavior of its cells in highly specific ways using a limited diversity of such
molecules: hundreds of such signals can be used in millions of combinations.
Different Cells Can Respond Differently to the Same Chemical Signal

The same signaling molecule can induce different responses in different target cells

In some cases this is because the signaling molecule binds to different receptor proteins, as
illustrated in (A) and (B). In other cases the signaling molecule binds to identical receptor
proteins that activate different response pathways in different cells, as illustrated in (B) and (C).
In all of the cases shown the signaling molecule is acetylcholine (D).

The specific way a cell reacts to its environment varies, first, according to the set of receptor
proteins that the cell possesses through which it is tuned to detect a particular subset of the
available signals and, second, according to the intracellular machinery by which the cell
integrates and interprets the information that it receives. Thus a single signaling molecule often
has different effects on different target cells. The neurotransmitter acetylcholine, for example,
stimulates the contraction of skeletal muscle cells but decreases the rate and force of contraction
in heart muscle cells. This is because the acetylcholine receptor proteins on skeletal muscle cells
are different from those on heart muscle cells. But receptor differences are not always the
explanation for the different effects. In many cases the same signaling molecule binds to
identical receptor proteins and yet produces very different responses in different types of target
cells, reflecting differences in the internal machinery to which the receptors are coupled.

Nitric Oxide Gas Signals by Binding Directly to an Enzyme Inside the Target Cell

Although most extracellular signals are mediated by hydrophilic molecules that bind to receptors
on the surface of the target cell, some signaling molecules are hydrophobic enough and/or small
enough to pass readily across the target-cell plasma membrane; once inside, they directly
regulate the activity of specific intracellular proteins. A remarkable example is the gas nitric
oxide (NO), which only recently has been recognized to act as a signaling molecule in
vertebrates. When acetylcholine is released by autonomic nerves in the walls of a blood vessel,
for example, it causes smooth muscle cells in the vessel wall to relax. The acetylcholine acts
indirectly by inducing the endothelial cells to make and release NO, which then signals the
smooth muscle cells to relax. This effect of NO on blood vessels provides an explanation for the
mechanism of action of nitroglycerine, which has been used for almost 100 years to treat patients
with angina (pain due to inadequate blood flow to heart muscle). The nitroglycerine is converted
to NO, which relaxes blood vessels, thereby reducing the workload on the heart and, as a
consequence, the oxygen requirement of the heart muscle. NO is also produced as a local
mediator by activated macrophages and neutrophils to help them kill invading microorganisms.
In addition, it is used by many types of nerve cells to signal neighboring cells: NO released by
autonomic nerves in the penis, for example, causes the local blood vessel dilation that is
responsible for penile erection.

NO is made by the enzyme NO synthase by the deamination of the amino acid arginine. Because
it diffuses readily across membranes, the NO diffuses out of the cell where it is produced and
passes directly into neighboring cells. It acts only locally because it has a short half-life - about
5-10 seconds - in the extracellular space before it is converted to nitrates and nitrites by oxygen
and water. In many target cells, such as endothelial cells, NO reacts with iron in the active site of
the enzyme guanylyl cyclase, stimulating it to produce the intracellular mediator cyclic GMP,
which we discuss later. The effects of NO can be rapid, occurring within seconds, because the
rate of turnover of cyclic GMP is high: rapid production from GTP by guanylyl cyclase is
balanced by rapid degradation to GMP by a phosphodiesterase. There is recent evidence that
carbon monoxide (CO) is also used as an intercellular signal and can act in the same way as NO,
by stimulating guanylyl cyclase.

Gases such as NO and CO are not the only signaling molecules that can pass directly across the
target-cell plasma membrane. A group of small, hydrophobic, nongaseous hormones and local
mediators also enter target cells in this way, but instead of binding to enzymes, they bind to
intracellular receptor proteins that directly regulate gene transcription.
Steroid Hormones, Thyroid Hormones, Retinoids, and Vitamin D Bind to Intracellular
Receptors That Are Ligand-activated Gene Regulatory Proteins

The intracellular receptor superfamily

A model of an intracellular receptor protein. In its inactive state the receptor is bound to an
inhibitory protein complex that contains a heat-shock protein called Hsp90 (discussed in Chapter
5). The binding of ligand to the receptor causes the inhibitory complex to dissociate, thereby
activating the receptor by exposing its DNA-binding site. The model shown is based on the
receptor for cortisol, but all of the receptors in this superfamily have a related structure, as shown
in (B), where the short DNA-binding domain in each receptor is shown in green. Domain-swap
experiments suggest that many of the hormone-binding, transcription-activating, and DNA-
binding domains in these receptors can function as interchangeable modules. It is thought that all
of the intracellular receptor proteins bind to DNA as either homodimers or heterodimers.

Steroid hormones, thyroid hormones, retinoids,and vitamin Dare small hydrophobic molecules
that differ greatly from one another in both chemical structure and function. Nonetheless, they all
act by a similar mechanism. They diffuse directly across the plasma membrane of target cells and
bind to intracellular receptor proteins. Ligand binding activates the receptors, which then directly
regulate the transcription of specific genes. These receptors are structurally related and constitute
the intracellular receptor superfamily (or steroid-hormone receptor superfamily)
Steroid hormones, including cortisol, the steroid sex hormones, vitamin D (in vertebrates), and
the moulting hormone ecdysone (in insects), are all made from cholesterol. Cortisol is produced
in the cortex of the adrenal gland and influences the metabolism of many cell types. The steroid
sex hormones are made in the testis and ovary and are responsible for the secondary sex
characteristics that distinguish males from females. Vitamin D is synthesized in the skin in
response to sunlight; after it is converted to an active form in the liver or kidneys, it functions to
regulate Ca2+ metabolism, promoting Ca2+ uptake in the gut and reducing its excretion in the
kidney. The thyroid hormones, which are made from the amino acid tyrosine, act to increase
metabolism in a wide variety of cell types, while the retinoids, such as retinoic acid, which are
made from vitamin A, play important roles as local mediators in vertebrate development.
Although all of these signaling molecules are relatively insoluble in water, they are made soluble
for transport in the bloodstream and other extracellular fluids by binding to specific carrier
proteins, from which they dissociate before entering a target cell.

Besides the fundamental difference in the way they signal their target cells, most water-insoluble
signaling molecules differ from water-soluble ones in the length of time that they persist in the
bloodstream or tissue fluids. Most water-soluble hormones are removed and/or broken down
within minutes of entering the blood, and local mediators and neurotransmitters are removed
from the extracellular space even faster - within seconds or milliseconds. Steroid hormones, by
contrast, persist in the blood for hours and thyroid hormones for days. Consequently, water-
soluble signaling molecules usually mediate responses of short duration, whereas the water-
insoluble ones tend to mediate longer-lasting responses.