Molecular Biology of the Cell - Volume 2 - Alberts B., Bray D., Lewis J., Raff M., Roberts K., Watson J. 1993

Intercellular Signaling
Three strategies of chemical signaling: the use of hormones, local chemical mediators, and neurotransmitters

Chemical signaling mechanisms vary According to the distances over which they act: 1) in endocrine signaling, specialized endocrine Cells secrete Hormones that are carried by the bloodstream and act on target cells located sometimes in very distant PARTS OF THE body; 2) in paracrine signaling, cells secrete local chemical mediators that are taken up, destroyed, or immobilized so rapidly that they only affect cells in their immediate vicinity, perhaps within a radius of about a millimeter; 3) in synaptic transmission, used exclusively in The Nervous system, cells secrete Neurotransmitters at specialized Intercellular junctions called chemical synapses. Neurotransmitters diffuse across the synaptic cleft, typically over a distance of about 50 nm, and act on only a single postsynaptic target Cell (Fig. 12-2). In each case, the target responds to a specific extracellular signal using specialized Proteins called receptors, which bind the signaling molecule and initiate a response. Many signaling molecules and receptors are involved in endocrine, paracrine, and synaptic signaling alike. The main differences lie in the speed and selectivity of the signal's action on specific targets.

12-3

12-4

12.1.1. Endocrine and Nerve Cells are specialized for Different types of chemical signaling [1]

Endocrine and nerve cells jointly coordinate the diverse Functions of the billions of cells that make up the body of higher animals. Endocrine cells are typically grouped into specialized glands and secrete their hormones into the extracellular (interstitial) fluid that surrounds all cells within Tissues. From there, the molecules diffuse into capillaries and are distributed throughout the body by the Blood. In each tissue, they pass from the capillaries into the interstitial fluid and can bind to target cells. Because the spread of an endocrine signal relies on diffusion and blood flow, it occurs relatively slowly: it usually takes minutes for a hormone to reach its target. Moreover, the Specificity of signals in the Endocrine System depends entirely on the Chemical Nature of the signaling substance and the receptors on the target cell surface: each type of endocrine cell secretes its own hormone into the blood, and any cell possessing a complementary receptor for that hormone will respond with a reaction characteristic of that specific cell type (Fig. 12-3, A).

Class="center">

Fig. 12-2. Three forms of signaling via secreted molecules. Not all neurotransmitters act at synapses as shown in the figure; some function as local chemical mediators (in a paracrine manner), affecting an entire group of neighboring target cells simultaneously.

The activity of nerve cells is characterized by much greater speed and precision. They can transmit information over long distances along a nerve fiber via electrical impulses at speeds exceeding 100 m/s. Only at the nerve terminals, where the neurotransmitter is released, are these impulses converted into chemical signals. The chemical signal of a nerve cell can act in either a paracrine or synaptic manner. In the former case, the neurotransmitter, much like a local chemical mediator, diffuses outward and affects all neighboring target cells that possess the appropriate receptor. In synaptic transmission, the signal is much more precise, and the action of the neurotransmitter is restricted to a single target cell, even if adjacent cells have receptors for the same neurotransmitter (Fig. 12-3, B). Because the distance the neurotransmitter must diffuse in such cases is less than 100 nm, the process takes less than a millisecond (Fig. 12-2).

Hormones in the blood and interstitial fluid are diluted to a very high degree and therefore must be capable of acting at extremely low concentrations (typically less than 10^-8 M); in contrast, the dilution of neurotransmitters along their short pathway is negligible, and their concentration near the membrane of the postsynaptic cell can be relatively high. For example, the concentration of acetylcholine in the synaptic cleft of the Neuromuscular Junction is about 5-10^-4 M. Accordingly, neurotransmitter receptors at the synapse possess a relatively low affinity for their Ligand and do not noticeably respond to low concentrations of neurotransmitter arriving by diffusion from neighboring synapses. The neurotransmitter is rapidly cleared from the synaptic cleft by specialized hydrolytic Enzymes or membrane transport proteins that pump it back into the nerve terminal. This ensures spatial and temporal precision in signal action: a brief, "pulse-like" release of neurotransmitter triggers a rapid and short-lived response, preserving the temporal CHARACTERISTICS OF THE signal as it is passed from Cell to Cell.

12.1.2. The Hypothalamus serves as the primary regulator of the endocrine system [1, 2]

In a specific region of the Brain—the hypothalamus—the endocrine and nervous systems are physically and functionally linked. The hypothalamus is located directly above the Pituitary Gland, to which it is connected by the pituitary stalk. The hypothalamus performs its connecting role through cells that combine the features of both Neurons and endocrine cells; accordingly, they are called neuroendocrine (neurosecretory) cells. Most of these hypothalamic cells respond to stimulation by neurons from other brain regions by releasing a specific peptide hormone into the Blood Vessels of the pituitary stalk, which then specifically stimulates or inhibits the secretion of another hormone by the pituitary gland. (Other hypothalamic neuroendocrine cells send axons into the pituitary and release their secretions directly into the general bloodstream via these axons.) Many of the Pituitary Hormones released under hypothalamic control stimulate other Endocrine glands, triggering the secretion of a third hormone into the blood. Thus, the hypothalamus acts as the primary regulator of the endocrine system in vertebrates. As an example, Fig. 12-4 illustrates how it regulates the secretory function of The Thyroid Gland.

Fig. 12-3. The difference between hormonal (A) and synaptic (B) signal transmission. Endocrine cells release numerous hormones into the blood, and target cells sensitive to a given hormone—i.e., possessing receptors for its binding—"capture" the corresponding hormone from the extracellular fluid. In synaptic transmission, however, specificity is determined by the close contact between the nerve fiber terminal and the specific target cell to which the fiber transmits the signal: the mediator released by the nerve terminal reaches only that cell. To communicate specifically with various target cells, different endocrine cells must utilize different hormones, whereas many nerve cells can use the exact same neurotransmitter while still maintaining signaling specificity.

Fig. 12-4. Thyroid hormone secretion is indirectly regulated by the nervous system. Upon stimulation by neurons from higher brain centers, specific neurosecretory Cells of the hypothalamus release thyrotropin-releasing hormone into the blood Vessels of the pituitary stalk, which acts on specific pituitary cells, prompting them to release thyroid-stimulating hormone (TSH). TSH is transported via the bloodstream to the thyroid gland, stimulating its cells to synthesize and secrete thyroid hormone. This hormone stimulates diverse metabolic processes in most cells of the body. Meanwhile, an elevated concentration of thyroid hormone in the blood inhibits the secretion of thyrotropin-releasing hormone and TSH (not shown in the diagram). This negative feedback mechanism prevents excessive increases in blood thyroid hormone levels. Similar mechanisms regulate the secretion of many Other Hormones.

Table 12-1. Some Examples of extracellular signaling molecules

¹ Norepinephrine and enkephalin more commonly act via paracrine rather than synaptic mechanisms; acetylcholine can act in both ways. Excitatory neurotransmitters stimulate target cell activity, whereas inhibitory ones suppress it.

² Many nonsteroidal hormones are also synthesized by certain neurons in the brain.

Table 12-1 provides information on several local chemical mediators, neurotransmitters, and hormones, indicating their sites of synthesis, Structure, and primary action. As can be seen, The structure of signaling molecules is as diverse as their functions. These molecules include short Peptides, larger proteins and Glycoproteins, Amino Acids and related compounds, Steroids (substances derived from Cholesterol with very similar structures), and fatty acid derivatives. Each signaling molecule is listed in Table 12-1 under only one category, although many of them can function in multiple ways. For instance, certain Peptide Hormones in the vertebrate brain act as neurotransmitters (acting as paracrine factors).

12.1.3. Different cells respond differently to the same signal

Most cells in adult animals are specialized to perform a single primary function, and all of them possess a characteristic set of receptors that enable them to respond to chemical signals triggering or modulating that function. Many signaling molecules act at very low concentrations (typically not exceeding 10^-8 M), and their binding receptors generally exhibit a high affinity for them (affinity constant K_a≥ 10⁸ L/mol).

The same signaling molecules often exert different effects on different target cells. For example, acetylcholine stimulates the contraction of Skeletal Muscle fibers, but decreases the rate and force of contraction in Heart muscle cells. In this case, acetylcholine receptors in skeletal muscle differ from those on myocardial cells. However, the reason is not always a difference in receptors. Often, identical signaling molecules bind to identical receptors, yet lead to completely different responses in various target cells (Fig. 12-5). This implies that target cell responses can be programmed in two ways: either by the repertoire of cell-surface receptors themselves, or by the intracellular systems with which these receptors are coupled.

12.1.4. The cellular response to a chemical signal may be rapid and transient in some cases, and slow and prolonged in others [2, 3]

Chemical signals that coordinate cellular functions with environmental changes typically elicit rapid and short-lived responses. For instance, an increase in blood glucose levels stimulates the secretion of the protein hormone Insulin by endocrine cells in the Pancreas. Within minutes, the elevated insulin concentration prompts Liver and muscle cells to dramatically increase glucose uptake, causing blood glucose levels to drop. This response consists of three parts, none of which requires the synthesis of new protein:

1) in the pancreas, the elevated glucose level triggers cells to release stored insulin via exocytosis;

2) in fat and muscle cells, intracellular vesicles contain a reserve of glucose-transporter proteins, and the rise in insulin stimulates the incorporation of these vesicles and their proteins into The Plasma Membrane, thereby accelerating glucose uptake; blood glucose levels then fall, which in turn reduces insulin secretion;

3) because falling insulin levels lead to the rapid removal of these additional glucose transporters from The Cell surface via endocytosis and their return to the intracellular pool, The rate of glucose uptake by fat and muscle cells returns to baseline. In this way, a relatively constant blood glucose concentration is maintained.

Fig. 12-5. The same signaling molecules can elicit different responses in different target cells. In some cases, this is because the signaling molecule binds to distinct receptor proteins (A and B). In other cases, such molecules bind to identical receptors but activate different response pathways within different cells (C and D).

Neurotransmitters trigger even faster reactions: in response to the release of acetylcholine from motor nerve terminals, skeletal muscle fibers contract and relax again within just a few milliseconds.

Chemical signals also play a vital role in animal development, frequently determining the timing and type of Cell Differentiation. Some of these effects manifest slowly and are long-lasting. For example, during Puberty, ovarian cells begin secreting large amounts of the female sex steroid hormone estradiol. This hormone induces changes in numerous cells throughout the body, ultimately leading to The Development of secondary female sex characteristics, such as breast enlargement. If estradiol secretion ceases, these effects gradually fade, yet certain responses triggered by steroid Sex Hormones at very Cytology/cytology/16.html">Early stages of mammalian development are irreversible. Similarly, a tenfold increase in blood thyroid hormone concentrations in tadpoles stimulates a series of radical and irreversible changes culminating in their metamorphosis into frogs (Fig. 12-6).

12.1.5. Only lipid-soluble signaling molecules can independently cross The cell membrane

All known neurotransmitters, as well as the majority of hormones and local chemical mediators, are Water-soluble. There are exceptions, however, which constitute a distinct class of signaling molecules. Important examples include steroid and THYROID HORMONES, which have relatively low water solubility and are transported in the blood as soluble complexes with specific carrier proteins. This difference in solubility underlies fundamental variations in how these two classes of molecules act on target cells. Water-soluble molecules are far too hydrophilic to pass directly through The Lipid Bilayer of the plasma membrane; therefore, they bind to specific protein receptors on the cell surface. Conversely, steroid and thyroid hormones are lipid-soluble and, upon dissociating from their carrier proteins, can readily diffuse across the plasma membrane of the target cell. These hormones bind to intracellular protein receptors (Fig. 12-7).

Another important distinction between these two classes of signaling molecules is their differing lifespans in the bloodstream or tissue fluid. Once secreted into the blood, water-soluble molecules are typically cleared and/or degraded within minutes, whereas local chemical mediators and neurotransmitters are inactivated even faster—within seconds or even milliseconds—after release into the extracellular space. In contrast, Steroid Hormones circulate in the blood for hours, and thyroid hormones may persist for several days. Consequently, water-soluble signaling molecules generally trigger short-term responses, whereas water-insoluble ones elicit more sustained effects. Here too, however, there are exceptions to the rule: Prostaglandins, for instance, are hydrophobic local mediators, yet they bind to cell-surface receptors and provoke rapid, short-lived responses.

Fig. 12-6. Metamorphosis of a tadpole into a frog. The radical changes shown are triggered by thyroid hormone. If the thyroid primordium is removed from a developing embryo, the animal continues to grow as a tadpole without undergoing metamorphosis. Administration of thyroid hormone causes this giant tadpole to transform into a frog.

Fig. 12-7. Extracellular signaling molecules bind to either surface or intracellular receptors depending on their solubility. Hydrophilic molecules cannot directly cross the plasma membrane and therefore bind to receptors on the target cell surface. Many hydrophobic molecules can diffuse through the plasma membrane and bind to intracellular receptors. Being insoluble in aqueous environments, hydrophobic signaling molecules are transported in the blood as complexes with specialized carrier proteins, from which they dissociate before entering the target cell.

12-3

12.1.6. Local chemical mediators are rapidly degraded, taken up, or immobilized after secretion [4]

Paracrine signaling molecules act exclusively on the immediate microenvironment of the cells that secrete them. Such local chemical mediators are taken up by cells, degraded by extracellular enzymes, or immobilized in the Extracellular matrix so rapidly that they generally do not reach the bloodstream in any significant quantity.

Some local mediators are produced by specialized cells. For example, histamine (a derivative of The amino acid Histidine, see Table 13-1) is released primarily by mast cells. Found in Connective Tissue throughout the body, these cells store histamine in large secretory vesicles and rapidly release it via exocytosis upon tissue injury, local infection, or certain immune reactions (Section 18.2.5). Histamine causes local vasodilation and increases vascular permeability, facilitating access of phagocytic leukocytes and Serum proteins (such as Antibodies and Complement components—see Chapter 18) to the site of injury. Mast cells also secrete two tetrapeptides that attract eosinophil leukocytes to the site of secretion; eosinophils, in turn, contain various enzymes involved in inactivating histamine and other mediators released by mast cells, thereby helping to terminate the reaction.

Some local chemical mediators are not destroyed upon secretion, but are rapidly immobilized. This group includes Fibronectin, Proteoglycans, and several other extracellular matrix macromolecules. These cell-secreted macromolecules can be viewed as a specialized category of local mediators, as they exert effects only on neighboring cells (Section 14.2). Unlike other local mediators, they assemble into an insoluble network within the extracellular space, losing their mobility and thus preventing diffusion away from their site of origin. Consequently, although their effect is local, it can be long-lasting. The extracellular matrix also occasionally binds soluble signaling molecules, immobilizing them so that they act only within a restricted region. For instance, fibroblast growth factor (FGF)—a small protein that stimulates the division of A wide variety of cells in culture—binds tightly in vitro to extracellular matrix proteoglycans and is likely immobilized in tissues in a similar manner.

12.1.7. Mammalian cells of all tissues continuously secrete prostaglandins [5]

While many chemical mediators are produced by specialized cells, others have more diverse sources. An important example is prostaglandins—a family of 20-carbon fatty acid derivatives produced in all mammalian tissues. These local mediators are continuously synthesized in cell membranes from precursors cleaved from membrane Phospholipids by phospholipases (Fig. 12-8), and are just as continuously degraded by enzymes in the extracellular fluid. There are at least 16 different prostaglandins, subdivided into 9 classes (PGA, PGB, PGC, ... PGI), which bind to specific cell-surface receptors to elicit a wide range of biological effects.

Unlike most other signaling molecules, prostaglandins are not stored within cells, but are continually released into the extracellular space as they are synthesized. However, when cells are activated by tissue injury or certain chemical stimuli, the rate of prostaglandin synthesis increases; the resulting rise in local prostaglandin concentration affects not only the secreting cell itself (autocrine stimulation) but also neighboring cells. Autocrine stimulation triggered by another chemical signal can amplify the latter's effect and/or duration, as well as extend its reach to a larger local population of identical cells.

A multitude of diverse biological effects are attributed to prostaglandins. They induce smooth Muscle contraction, promote platelet aggregation, and participate in inflammatory responses. Certain prostaglandins produced in the Uterus during labor appear important for stimulating uterine smooth muscle contractions. These prostaglandins are now widely used as abortifacient pharmacological agents. Conversely, the action of anti-inflammatory drugs such as aspirin is based on suppressing prostaglandin Biosynthesis at sites of inflammation.

Fig. 12-8. Prostaglandins are continuously synthesized in membranes from long-chain Fatty acids containing 20 carbon atoms and at least three double bonds. The diagram illustrates the synthesis of PGE2. The subscript indicates two carbon-carbon double bonds outside the PGE2 ring. Prostaglandins, along with chemically related signaling molecules—thromboxanes, Leukotrienes, and lipoxins—are derived mainly from arachidonic acid and are collectively known as Eicosanoids. This metabolic pathway serves as a major target for pharmacological drugs, as eicosanoids play a crucial role in the inflammatory response. Corticosteroid hormones, such as cortisone, are widely used in the Treatment of non-infectious Inflammatory Diseases, such as certain forms of Arthritis. One of their potential Mechanisms of action is the Induction of the synthesis and/or secretion by leukocytes of local chemical mediators called lipocortins (or calpactins). These are proteins that somehow suppress phospholipase activity at the initial step of the eicosanoid synthesis pathway shown here. Nonsteroidal anti-inflammatory drugs, such as aspirin, block the oxidative steps of prostaglandin synthesis. Both corticosteroids and aspirin are used to treat arthritis.

Conclusion

Extracellular signaling molecules can be divided into three main classes based on their "action range": 1) local chemical mediators, which are rapidly taken up or destroyed and thus affect only neighboring cells; 2) hormones, which are carried via the bloodstream to their target cells, often distributed throughout the entire body; 3) neurotransmitters, which act exclusively on the postsynaptic cell. Each cell type in the Organism possesses a characteristic set of receptor proteins, enabling it to respond in a programmed and specific manner to the corresponding set of signaling molecules.

Signaling molecules can also be classified according to their water solubility. Small hydrophobic molecules, such as steroid or thyroid hormones, freely cross the plasma membrane of the target cell and activate receptor proteins within its Cytoplasm. In contrast, hydrophilic molecules, notably neurotransmitters and the majority of hormones and local chemical mediators, activate protein receptors located On the surface of the target cell.