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Cooper GM. The Cell: A Molecular Approach. 2nd edition. Sunderland (MA): Sinauer Associates; 2000.

The Cell: A Molecular Approach. 2nd edition.

Signaling Molecules and Their Receptors

Many different kinds of molecules transmit information between the cells of multicellular organisms. Although all these molecules act as ligands that bind to receptors expressed by their target cells, there is considerable variation in the structure and function of the different types of molecules that serve as signal transmitters. Structurally, the signaling molecules used by plants and animals range in complexity from simple gases to proteins. Some of these molecules carry signals over long distances, whereas others act locally to convey information between neighboring cells. In addition, signaling molecules differ in their mode of action on their target cells. Some signaling molecules are able to cross the plasma membrane and bind to intracellular receptors in the cytoplasm or nucleus, whereas most bind to receptors expressed on the target cell surface. The sections that follow discuss the major types of signaling molecules and the receptors with which they interact. Subsequent discussion in this chapter focuses on the mechanisms by which cell surface receptors then function to regulate cell behavior.

Modes of Cell-Cell Signaling

Cell signaling can result either from the direct interaction of a cell with its neighbor or from the action of secreted signaling molecules (Figure 13.1). Signaling by direct cell-cell (or cell-matrix) interactions plays a critical role in regulating the behavior of cells in animal tissues. For example, the integrins and cadherins (which were discussed in the previous chapter) function not only as cell adhesion molecules but also as signaling molecules that regulate cell proliferation and survival in response to cell-cell and cell-matrix contacts. In addition, cells express a variety of cell surface receptors that interact with signaling molecules on the surface of neighboring cells. Signaling via such direct cell-cell interactions plays a critical role in regulating the many interactions between different types of cells that take place during embryonic development, as well as in the maintenance of adult tissues.

Figure 13.1

Modes of cell-cell signaling. Cell signaling can take place either through direct cell-cell contacts or through the action of secreted signaling molecules. (A) In endocrine signaling, hormones are carried through the circulatory system to act on distant (more. )

The multiple varieties of signaling by secreted molecules are frequently divided into three general categories based on the distance over which signals are transmitted. In endocrine signaling, the signaling molecules (hormones) are secreted by specialized endocrine cells and carried through the circulation to act on target cells at distant body sites. A classic example is provided by the steroid hormone estrogen, which is produced by the ovary and stimulates development and maintenance of the female reproductive system and secondary sex characteristics. In animals, more than 50 different hormones are produced by endocrine glands, including the pituitary, thyroid, parathyroid, pancreas, adrenal glands, and gonads.

In contrast to hormones, some signaling molecules act locally to affect the behavior of nearby cells. In paracrine signaling, a molecule released by one cell acts on neighboring target cells. An example is provided by the action of neurotransmitters in carrying signals between nerve cells at a synapse. Finally, some cells respond to signaling molecules that they themselves produce. One important example of such autocrine signaling is the response of cells of the vertebrate immune system to foreign antigens. Certain types of T lymphocytes respond to antigenic stimulation by synthesizing a growth factor that drives their own proliferation, thereby increasing the number of responsive T lymphocytes and amplifying the immune response. It is also noteworthy that abnormal autocrine signaling frequently contributes to the uncontrolled growth of cancer cells (see Chapter 15). In this situation, a cancer cell produces a growth factor to which it also responds, thereby continuously driving its own unregulated proliferation.

Steroid Hormones and the Steroid Receptor Superfamily

As already noted, all signaling molecules act by binding to receptors expressed by their target cells. In many cases, these receptors are expressed on the target cell surface, but some receptors are intracellular proteins located in the cytosol or the nucleus. These intracellular receptors respond to small hydrophobic signaling molecules that are able to diffuse across the plasma membrane. The steroid hormones are the classic examples of this group of signaling molecules, which also includes thyroid hormone, vitamin D₃, and retinoic acid (Figure 13.2).

Figure 13.2

Structure of steroid hormones, thyroid hormone, vitamin D ₃, and retinoic acid. The steroids include the sex hormones (testosterone, estrogen, and progesterone), glucocorticoids, and mineralocorticoids.

The steroid hormones (including testosterone, estrogen, progesterone, the corticosteroids, and ecdysone) are all synthesized from cholesterol. Testosterone, estrogen, and progesterone are the sex steroids, which are produced by the gonads. The corticosteroids are produced by the adrenal gland. They include the glucocorticoids, which act on a variety of cells to stimulate production of glucose, and the mineralocorticoids, which act on the kidney to regulate salt and water balance. Ecdysone is an insect hormone that plays a key role in development by triggering the metamorphosis of larvae to adults.

Although thyroid hormone, vitamin D₃, and retinoic acid are both structurally and functionally distinct from the steroids, they share a common mechanism of action in their target cells. Thyroid hormone is synthesized from tyrosine in the thyroid gland; it plays important roles in development and regulation of metabolism. Vitamin D₃ regulates Ca 2+ metabolism and bone growth. Retinoic acid and related compounds (retinoids) synthesized from vitamin A play important roles in vertebrate development.

Because of their hydrophobic character, the steroid hormones, thyroid hormone, vitamin D₃, and retinoic acid are able to enter cells by diffusing across the plasma membrane (Figure 13.3). Once inside the cell, they bind to intracellular receptors that are expressed by the hormonally responsive target cells. These receptors, which are members of a family of proteins known as the steroid receptor superfamily, are transcription factors that contain related domains for ligand binding, DNA binding, and transcriptional activation. Ligand binding regulates their function as activators or repressors of their target genes, so the steroid hormones and related molecules directly regulate gene expression.

Figure 13.3

Action of steroid hormones. The steroid hormones diffuse across the plasma membrane and bind to nuclear receptors, which directly stimulate transcription of their target genes. The steroid hormone receptors bind DNA as dimers.

Ligand binding has distinct effects on different receptors. Some members of the steroid receptor superfamily, such as the estrogen and glucocorticoid receptors, are unable to bind to DNA in the absence of hormone. The binding of hormone induces a conformational change in the receptor, allowing it to bind to regulatory DNA sequences and activate transcription of target genes. In other cases, the receptor binds DNA in either the presence or absence of hormone, but hormone binding alters the activity of the receptor as a transcriptional regulatory molecule. For example, thyroid hormone receptor acts as a repressor in the absence of hormone, but hormone binding converts it to an activator that stimulates transcription of thyroid hormone-inducible genes (Figure 13.4).

Figure 13.4

Gene regulation by the thyroid hormone receptor. Thyroid hormone receptor binds DNA in either the presence or absence of hormone. However, hormone binding changes the function of the receptor from a repressor to an activator of target gene transcription. (more. )

Nitric Oxide and Carbon Monoxide

The simple gas nitric oxide (NO) is a major paracrine signaling molecule in the nervous, immune, and circulatory systems. Like the steroid hormones, NO is able to diffuse directly across the plasma membrane of its target cells. The molecular basis of NO action, however, is distinct from that of steroid action; rather than binding to a receptor that regulates transcription, NO alters the activity of intracellular target enzymes.

Nitric oxide is synthesized from the amino acid arginine by the enzyme nitric oxide synthase (Figure 13.5). Once synthesized, NO diffuses out of the cell and can act locally to affect nearby cells. Its action is restricted to such local effects because NO is extremely unstable, with a half-life of only a few seconds. One well-characterized example of NO action is signaling the dilation of blood vessels. The first step in this process is the release of neurotransmitters, such as acetylcholine, from the terminus of nerve cells in the blood vessel wall. These neurotransmitters act on endothelial cells to stimulate NO synthesis. NO then diffuses to neighboring smooth muscle cells where it reacts with iron bound to the active site of the enzyme guanylyl cyclase. This increases enzymatic activity, resulting in synthesis of the second messenger cyclic GMP (discussed later in this chapter), which induces muscle cell relaxation and blood vessel dilation. For example, NO is responsible for signaling the dilation of blood vessels that leads to penile erection. It is also interesting to note that the medical use of nitroglycerin in treatment of heart disease is based on its conversion to NO, which dilates coronary blood vessels and increases blood flow to the heart.

Figure 13.5

Synthesis of nitric oxide. The enzyme nitric oxide synthase (NOS) catalyzes the formation of nitric oxide from arginine.

Another simple gas, carbon monoxide (CO), also functions as a signaling molecule in the nervous system. CO is closely related to NO and appears to act similarly as a neurotransmitter and mediator of blood vessel dilation. The synthesis of CO in brain cells, like that of NO, is stimulated by neurotransmitters. In addition, CO can stimulate guanylate cyclase, which may also represent the major physiological target of CO signaling.

Neurotransmitters

The neurotransmitters carry signals between neurons or from neurons to other types of target cells (such as muscle cells). They are a diverse group of small hydrophilic molecules including acetylcholine, dopamine, epinephrine (adrenaline), serotonin, histamine, glutamate, glycine, and γ-aminobutyric acid (GABA) (Figure 13.6). The release of neurotransmitters is signaled by the arrival of an action potential at the terminus of a neuron (see Figure 12.22). The neurotransmitters then diffuse across the synaptic cleft and bind to receptors on the target cell surface. Note that some neurotransmitters can also act as hormones. For example, epinephrine functions both as a neurotransmitter and as a hormone produced by the adrenal gland to signal glycogen breakdown in muscle cells.

Figure 13.6

Structure of representative neurotransmitters. The neurotransmitters are hydrophilic molecules that bind to cell surface receptors.

Because the neurotransmitters are hydrophilic molecules, they are unable to cross the plasma membrane of their target cells. Therefore, in contrast to steroid hormones and NO or CO, the neurotransmitters act by binding to cell surface receptors. Many neurotransmitter receptors are ligand-gated ion channels, such as the acetylcholine receptor discussed in the preceding chapter (see Figure 12.23). Neurotransmitter binding to these receptors induces a conformational change that opens ion channels, directly resulting in changes in ion flux in the target cell. Other neurotransmitter receptors are coupled to G proteins—a major group of signaling molecules (discussed later in this chapter) that link cell surface receptors to a variety of intracellular responses. In the case of neurotransmitter receptors, the associated G proteins frequently act to indirectly regulate ion channel activity.

Peptide Hormones and Growth Factors

The widest variety of signaling molecules in animals are peptides, ranging in size from only a few to more than a hundred amino acids. This group of signaling molecules includes peptide hormones, neuropeptides, and a diverse array of polypeptide growth factors (Table 13.1). Well-known examples of peptide hormones include insulin, glucagon, and the hormones produced by the pituitary gland (growth hormone, follicle-stimulating hormone, prolactin, and others).

Table 13.1

Representative Peptide Hormones, Neuropeptides, and Growth Factors.

Neuropeptides are secreted by some neurons instead of the small-molecule neurotransmitters discussed in the previous section. Some of these peptides, such as the enkephalins and endorphins, function not only as neurotransmitters at synapses but also as neurohormones that act on distant cells. The enkephalins and endorphins have been widely studied because of their activity as natural analgesics that decrease pain responses in the central nervous system. Discovered during studies of drug addiction, they are naturally occurring compounds that bind to the same receptors on the surface of brain cells as morphine does.

The polypeptide growth factors include a wide variety of signaling molecules that control animal cell growth and differentiation. The first of these factors (nerve growth factor, or NGF) was discovered by Rita Levi-Montalcini in the 1950s. NGF is a member of a family of polypeptides (called neurotrophins) that regulate the development and survival of neurons. During the course of experiments on NGF, Stanley Cohen serendipitously discovered an unrelated factor (called epidermal growth factor, or EGF) that stimulates cell proliferation. EGF, a 53-amino-acid polypeptide (Figure 13.7), has served as the prototype of a large array of growth factors that play critical roles in controlling animal cell proliferation, both during embryonic development and in adult organisms.

Figure 13.7

Structure of epidermal growth factor (EGF). EGF is a single polypeptide chain of 53 amino acids. Disulfide bonds between cysteine residues are indicated. (After G. Carpenter and S. Cohen, 1979. Ann. Rev. Biochem. 48: 193.)

A good example of growth factor action is provided by the activity of platelet-derived growth factor (PDGF) in wound healing. PDGF is stored in blood platelets and released during blood clotting at the site of a wound. It then stimulates the proliferation of fibroblasts in the vicinity of the clot, thereby contributing to regrowth of the damaged tissue. Members of another large group of polypeptide growth factors (called cytokines) regulate the development and differentiation of blood cells and control the activities of lymphocytes during the immune response. Other polypeptide growth factors (membrane-anchored growth factors) remain associated with the plasma membrane rather than being secreted into extracellular fluids, therefore functioning specifically as signaling molecules during direct cell-cell interactions.

Peptide hormones, neuropeptides, and growth factors are unable to cross the plasma membrane of their target cells, so they act by binding to cell surface receptors, as discussed later in this chapter. As might be expected from the critical roles of polypeptide growth factors in controlling cell proliferation, abnormalities in growth factor signaling are the basis for a variety of diseases, including many kinds of cancer. For example, abnormal expression of a close relative of the EGF receptor is an important factor in the development of many human breast and ovarian cancers.

Eicosanoids

Several types of lipids serve as signaling molecules that, in contrast to the steroid hormones, act by binding to cell surface receptors. The most important of these molecules are members of a class of lipids called the eicosanoids, which includes prostaglandins, prostacyclin, thromboxanes, and leukotrienes (Figure 13.8). The eicosanoids are rapidly broken down and therefore act locally in autocrine or paracrine signaling pathways. They stimulate a variety of responses in their target cells, including blood platelet aggregation, inflammation, and smooth-muscle contraction.

Figure 13.8

Synthesis and structure of eicosanoids. The eicosanoids include the prostaglandins, prostacyclin, thromboxanes, and leukotrienes. They are synthesized from arachidonic acid, which is formed by the hydrolysis of phospholipids catalyzed by phospholipase (more. )

All eicosanoids are synthesized from arachidonic acid, which is formed from phospholipids. The first step in the pathway leading to synthesis of either prostaglandins or thromboxanes is the conversion of arachidonic acid to prostaglandin H₂. Interestingly, the enzyme that catalyzes this reaction (cyclooxygenase) is the target of aspirin and other nonsteroidal anti-inflammatory drugs. By inhibiting synthesis of the prostaglandins, aspirin reduces inflammation and pain. By inhibiting synthesis of thromboxane, aspirin also reduces platelet aggregation and blood clotting. Because of this activity, small daily doses of aspirin are frequently prescribed for prevention of strokes. In addition, aspirin and nonsteroidal anti-inflammatory drugs have been found to reduce the frequency of colon cancer in both animal models and humans, apparently by inhibiting the synthesis of prostaglandins that act to stimulate cell proliferation and promote cancer development.

Plant Hormones

Plant growth and development are regulated by a group of small molecules called plant hormones. The levels of these molecules within the plant are typically modified by environmental factors, such as light or infection, so they coordinate the responses of tissues in different parts of the plant to environmental signals.

The plant hormones are generally divided into five major classes: auxins, gibberellins, cytokinins, abscisic acid, and ethylene (Figure 13.9), although several additional plant hormones have recently been discovered. The first plant hormone to be identified was auxin, with the early experiments leading to its discovery having been performed by Charles Darwin in the 1880s. One of the effects of auxins is to induce plant cell elongation by weakening the cell wall (see Figure 12.49). In addition, auxins regulate many other aspects of plant development, including cell division and differentiation. The other plant hormones likewise have multiple effects in their target tissues, including stem elongation (gibberellins), fruit ripening (ethylene), cell division (cytokinins), and the onset of dormancy (abscisic acid).

Figure 13.9

Our understanding of the molecular mechanisms of plant hormone action is less advanced than comparable studies of animal cells, and the receptors for plant hormones are just beginning to be identified and characterized. One area of noteworthy progress has been in understanding the mechanism by which plant cells respond to ethylene. Using the small weed Arabidopsis as a model, several of the genes required for ethylene responsiveness have been identified. These include genes encoding the ethylene receptor, which is similar to a family of receptors commonly found in bacteria and yeast. Additional genes that have been identified in the ethylene signaling pathway include a protein related to the Raf protein kinase, which plays a key role in animal cell signaling pathways (discussed later in this chapter), and transcription factors, which regulate the expression of ethylene-responsive genes.