|Cell-to-Cell Signaling: Hormones and Receptors
No cell lives in isolation. In all multicellular organisms, survival depends on an elaborate intercellular communication network that coordinates the growth, differentiation, and metabolism of the multitude of cells in diverse tissues and organs. Cells within small groups often communicate by direct cell-cell contact. Specialized junctions in the plasma membranes of adjacent cells permit them to exchange small molecules and to coordinate metabolic responses; other junctions between adjacent cells determine the shape and rigidity of many tissues.
In addition, the establishment of specific cell-cell interactions between different types of cells is a necessary step in the development of many tissues. In some cases a particular protein on one cell binds to a receptor protein on the surface of an adjacent target cell, triggering its differentiation.
How cells communicate by means of extracellular signaling molecules. These substances are synthesized and released by signaling cells and produce a specific response only in target cells that have receptors for the signaling molecules. An enormous variety of chemicals, including small molecules (e.g., amino acid derivatives, acetylcholine), peptides, and proteins, are used in this type of cell-to-cell communication. The extracellular products synthesized by signaling cells can diffuse away or be transported in the blood, thus providing a means for cells to communicate over longer distances than is possible by chains of direct cell-cell contacts.
Overview of Extracellular Signaling
Communication by extracellular signals usually involves six steps: (1) synthesis and (2) release of the signaling molecule by the signaling cell; (3) transport of the signal to the target cell; (4) detection of the signal by a specific receptor protein; (5) a change in cellular metabolism, function, or development triggered by the receptor-signal complex; and (6) removal of the signal, which often terminates the cellular response.
In many eukaryotic microorganisms (e.g., yeast, slime molds, and protozoans), secreted molecules coordinate the aggregation of free-living cells for sexual mating or differentiation under certain environmental conditions. Chemicals released by one organism that can alter the behavior or gene expression of other organisms of the same species are called pheromones. Yeast mating-type factors are a well-understood example of pheromone-mediated cell-to-cell signaling. Some algae and animals also release pheromones, usually dispersing them into the air or water, to attract members of the opposite sex. More important in plants and animals are extracellular signaling molecules that function within an organism to control metabolic processes within cells, the growth of tissues, the synthesis and secretion of proteins, and the composition of intracellular and extracellular fluids.
Signaling Molecules Operate over Various Distances in Animals
In animals, signaling by extracellular, secreted molecules can be classified into three types endocrine, paracrine, or autocrine based on the distance over which the signal acts. In addition, certain membrane-bound proteins on one cell can directly signal an adjacent cell (Figure 1).
In endocrine signaling, signaling molecules, called hormones, act on target cells distant from their site of synthesis by cells of endocrine organs. In animals, an endocrine hormone usually is carried by the blood from its site of release to its target.
In paracrine signaling, the signaling molecules released by a cell only affect target cells in close proximity to it. The conduction of an electric impulse from one nerve cell to another or from a nerve cell to a muscle cell (inducing or inhibiting muscle contraction) occurs via paracrine signaling. The role of this type of signaling, is mediated by neurotransmitters, in transmitting nerve impulses. Many signaling molecules regulating development in multicellular organisms also act at short range.
In autocrine signaling, cells respond to substances that they themselves release. Many growth factors act in this fashion, and cultured cells often secrete growth factors that stimulate their own growth and proliferation. This type of signaling is particularly common in tumor cells, many of which overproduce and release growth factors that stimulate inappropriate, unregulated proliferation of themselves as well as adjacent nontumor cells; this process may lead to formation of tumor mass.
Some compounds can act in two or even three types of cell-to-cell signaling. Certain small amino acid derivatives, such as epinephrine, function both as neurotransmitters (paracrine signaling) and as systemic hormones (endocrine signaling). Some protein hormones, such as epidermal growth factor (EGF), are synthesized as the exoplasmic part of a plasma- membrane protein; membrane-bound EGF can bind to and signal an adjacent cell by direct contact. Cleavage by a protease releases secreted EGF, which acts as an endocrine signal on distant cells.
Receptor Proteins Exhibit Ligand-Binding and Effector Specificity
The cellular response to a particular extracellular signaling molecule depends on its binding to a specific receptor protein located on the surface of a target cell or in its nucleus or cytosol. The signaling molecule (a hormone, pheromone, or neurotransmitter) acts as a ligand, which binds to, or "fits," a site on the receptor. Binding of a ligand to its receptor causes a conformational change in the receptor that initiates a sequence of reactions leading to a specific cellular response.
The response of a cell or tissue to specific hormones is dictated by the particular hormone receptors it possesses and by the intracellular reactions initiated by the binding of any one hormone to its receptor. Different cell types may have different sets of receptors for the same ligand, each of which induces a different response. Or the same receptor may occur on various cell types, and binding of the same ligand may trigger a different response in each type of cell. Clearly, different cells respond in a variety of ways to the same ligand. For instance, acetylcholine receptors are found on the surface of striated muscle cells, heart muscle cells, and pancreatic acinar cells. Release of acetylcholine from a neuron adjacent to a striated muscle cell triggers contraction, whereas release adjacent to a heart muscle slows the rate of contraction. Release adjacent to a pancreatic acinar cell triggers exocytosis of secretory granules that contain digestive enzymes. On the other hand, different receptor-ligand complexes can induce the same cellular response in some cell types. In liver cells, for example, the binding of either glucagon to its receptors or of epinephrine to its receptors can induce degradation of glycogen and release of glucose into the blood.
These examples show that a receptor protein is characterized by binding specificity for a particular ligand, and the resulting hormone-ligand complex exhibits effector specificity (i.e., mediates a specific cellular response). For instance, activation of either epinephrine or glucagon receptors on liver cells by binding of their respective ligands induces synthesis of cyclic AMP (cAMP), one of several intracellular signaling molecules, termed second messengers, which regulate various metabolic functions; as a result, the effects of both receptors on liver-cell metabolism are the same. Thus, the binding specificity of epinephrine and glucagon receptors differ, but their effector specificity is identical.
In most receptor-ligand systems, the ligand appears to have no function except to bind to the receptor. The ligand is not metabolized to useful products, is not an intermediate in any cellular activity, and has no enzymatic properties. The only function of the ligand appears to be to change the properties of the receptor, which then signals to the cell that a specific product is present in the environment. Target cells often modify or degrade the ligand and, in so doing, can modify or terminate their response or the response of neighboring cells to the signal.
Hormones Can Be Classified Based on Their Solubility and Receptor Location
Most hormones fall into three broad categories: (1) small lipophilic molecules that diffuse across the plasma membrane and interact with intracellular receptors; and (2) hydrophilic or (3) lipophilic molecules that bind to cell-surface receptors (Figure 2). Recently, nitric oxide, a gas, has been shown to be a key regulator controlling many cellular responses.
Lipophilic Hormones with Intracellular Receptors
Many lipid-soluble hormones diffuse across the plasma membrane and interact with receptors in the cytosol or nucleus. The resulting hormone-receptor complexes bind to transcription-control regions in DNA thereby affecting expression of specific genes. Hormones of this type include the steroids (e.g., cortisol, progesterone, estradiol, and testosterone), thyroxine, and retinoic acid All steroids are synthesized from cholesterol and have similar chemical skeletons. After crossing the plasma membrane, steroid hormones interact with intracellular receptors, forming complexes that can increase or decrease transcription of specific genes. These receptor-steroid complexes also may affect the stability of specific mRNAs. Steroids are effective for hours or days and often influence the growth and differentiation of specific tissues. For example, estrogen and progesterone, the female sex hormones, stimulate the production of egg-white hormones in chickens and cell proliferation in the hen oviduct. In mammals, estrogens stimulate growth of the uterine wall in preparation for embryo implantation. In insects and crustaceans, -ecdysone (which is chemically related to steroids) triggers the differentiation and maturation of larvae; like estrogens, it induces the expression of specific gene products.
Thyroxine (tetraiodothyronine) and triiodothyronine the principal iodinated compounds in the body are formed in the thyroid by intracellular proteolysis of the iodinated protein thyroglobulin and immediately released into the blood.
These two thyroid hormones stimulate increased expression of many cytosolic enzymes (e.g., liver hexokinase) that catalyze the catabolism of glucose, fats, and proteins and of mitochondrial enzymes that catalyze oxidative phosphorylation.
Retinoids are polyisoprenoid lipids derived from retinol (vitamin A). They perform multiple regulatory functions in diverse cellular processes. Retinoids regulate cellular proliferation, differentiation, and death, and they have numerous clinical applications. Their diverse effects reflect, at least in part, the multiplicity of retinoid derivatives, the existence of two different classes of receptors that form heterodimers, and differences in their cis-acting regulatory sites on DNA. During development retinoids act as local mediators of cell-cell interaction. For instance, during the formation of motor neurons in the chick, one class of motor neurons generates a retinoid signal which regulates the number and type of neighboring motoneurons.
Water-Soluble Hormones with Cell-Surface Receptors
Because water-soluble signaling molecules cannot diffuse across the plasma membrane, they all bind to cell-surface receptors. This large class of compounds is composed of two groups: (1) peptide hormones, such as insulin, growth factors, and glucagon, which range in size from a few amino acids to protein-size compounds, and (2) small charged molecules, such as epinephrine and histamine (Figure 3), that are derived from amino acids and function as hormones and neurotransmitters.
Many water-soluble hormones induce a modification in the activity of one or more enzymes already present in the target cell. In this case, the effects of the surface-bound hormone usually are nearly immediate, but persist for a short period only. These signals also can give rise to changes in gene expression that may persist for hours or days. In yet other cases water-soluble signals may lead to irreversible changes, such as cellular differentiation.
Lipophilic Hormones with Cell-Surface Receptors
The primary lipid-soluble hormones that bind to cell-surface receptors are the prostaglandins. There are at least 16 different prostaglandins in nine different chemical classes, designated PGA PGI. Prostaglandins are part of an even larger family of 20 carboncontaining hormones called eicosanoid hormones. In addition to prostaglandins, they include prostacyclins, thromboxanes, and leukotrienes. Eicosonoid hormones are synthesized from a common precursor, arachidonic acid. Arachidonic acid is generated from phospholipids and diacylglycerol.
In both vertebrates and invertebrates, prostaglandins are synthesized and secreted continuously by many types of cells and rapidly broken down by enzymes in body fluids.
Many prostaglandins act as local mediators during paracrine and autocrine signaling and are destroyed near the site of their synthesis. They modulate the responses of other hormones and can have profound effects on many cellular processes. Certain prostaglandins cause blood platelets to aggregate and adhere to the walls of blood vessels. Because platelets play a key role in clotting blood and plugging leaks in blood vessels, these prostaglandins can affect the course of vascular disease and wound healing; aspirin inhibits their synthesis by acetylating (and thereby irreversibly inhibiting) prostaglandin H2 synthase. Other prostaglandins initiate the contraction of smooth muscle cells; they accumulate in the uterus at the time of childbirth and appear to be important in inducing uterine contraction.
Recent studies have shown that a family of plant steroids, called brassinosteroids, regulates many aspects of development. These lipophilic compounds, like prostaglandins, act through cell-surface receptors.
Cell-Surface Receptors Belong to Four Major Classes
The different types of cell-surface receptors that interact with water-soluble ligands are schematically represented in Figure 4. Binding of ligand to some of these receptors induces second-messenger formation, whereas ligand binding to others does not. For convenience, we can sort these receptors into four classes:
G protein coupled receptors (Figure 4a): Ligand binding activates a G protein, which in turn activates or inhibits an enzyme that generates a specific second messenger or modulates an ion channel, causing a change in membrane potential. The receptors for epinephrine, serotonin, and glucagon are examples.
Ion-channel receptors (Figure 4b): Ligand binding changes the conformation of the receptor so that specific ions flow through it; the resultant ion movements alter the electric potential across the cell membrane. The acetylcholine receptor at the nerve-muscle junction is an example.
Tyrosine kinase linked receptors (Figure 4c): These receptors lack intrinsic catalytic activity, but ligand binding stimulates formation of a dimeric receptor, which then interacts with and activates one or more cytosolic protein-tyrosine kinases. The receptors for many cytokines, the interferons, and human growth factor are of this type. These tyrosine kinase linked receptors sometimes are referred to as the cytokine-receptor superfamily.
Receptors with intrinsic enzymatic activity (Figure 4d): Several types of receptors have intrinsic catalytic activity, which is activated by binding of ligand. For instance, some activated receptors catalyze conversion of GTP to cGMP; others act as protein phosphatases, removing phosphate groups from phosphotyrosine residues in substrate proteins, thereby modifying their activity. The receptors for insulin and many growth factors are ligand-triggered protein kinases; in most cases, the ligand binds as a dimer, leading to dimerization of the receptor and activation of its kinase activity. These receptors often referred to as receptor serine/threonine kinases or receptor tyrosine kinases autophosphorylate residues in their own cytosolic domain and also can phosphorylate various substrate proteins.