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Hormones and Second Messengers
The metabolic processes within a given cell are frequently regulated by signals from outside the cell. A usual means of intercellular communication takes place through the workings of the endocrine system, in which the ductless glands produce hormones as intercellular messengers.
Hormones are transported from the sites of their synthesis to the sites of action by the bloodstream (Figure 24.5). In terms of their chemical structure, some typical hormones are steroids, such as estrogens, androgens, and mineralocorticoids; polypeptides, such as insulin and endorphins; and amino acid derivatives, such as epinephrine and norepinephrine (Table 24.3).
Hormones have several important functions in the body. They help main-tain homeostasis, the balance of biological activities in the body. The effect of insulin in keeping the blood glucose level within narrow limits is an example of this function. The operation of epinephrine and norepinephrine in the “fight-or-flight” response is an example of the way in which hormones medi-ate responses to external stimuli. Finally, hormones play roles in growth and development, as seen in the roles of growth hormone and the sex hormones.
The methods and insights of biochemistry and physiology alike have helped illuminate the workings of the endocrine system.
The release of hormones exerts control on the cells of target organs; other control mechanisms, however, determine the workings of the endocrine gland that releases the hormone in question. Simple feedback mechanisms, in which the action of the hormone leads to feedback inhibition of the release of hor-mone, can be postulated (Figure 24.6). The workings of the endocrine system are, in fact, much less simple, with the added complexity allowing for a greater degree of control. To illustrate with a rather restricted example, insulin is released in response to a rapid rise in the level of blood glucose. In the absence of control mechanisms, an excess of insulin can produce hypoglycemia, the condition of low blood glucose. In addition to negative feedback control on the release of insulin, the action of the hormone glucagon tends to increase the level of glucose in the bloodstream. The two hormones together regulate blood glucose.
A more sophisticated control system involves the action of the hypothalamus, the pituitary, and specific endocrine glands (Figure 24.7). The central nervous system sends a signal to the hypothalamus.
The hypothalamus secretes a hormone-releasing factor, which in turn stimulates release of a trophic hor-mone by the anterior pituitary (Table 24.3). (The action of the hypothalamus on the posterior pituitary is mediated by nerve impulses.) Trophic hormones act on specific endocrine glands, which release the hormones to be transported to target organs. Note that feedback control is exerted at every stage of the process. Even more fine-tuning is possible with zymogen activation mechanisms, which exist for many well-known hormones.
The chemical natures of hormones play a predictably important role in their roles in cell signaling. Steroid hormones, for example, can enter the cell directly through the plasma membrane or can bind to plasma membrane receptors. Nonsteroid hormones enter the cell exclusively as a result of binding to plasma membrane receptors (Figure 24.8).
The releasing factors and trophic hormones listed in Table 24.3 tend to be polypeptides, but the chemical natures of the hormones released by specific endocrine glands show greater variation. Thyroxine, for example, produced by the thyroid, is an iodinated derivative of the amino acid tyrosine. Abnormally low levels of thyroxine lead to hypothyroidism, characterized by lethargy and obesity, whereas increased levels produce the opposite effect (hyperthyroidism). Low levels of iodine in the diet often lead to hypothyroid-ism and an enlarged thyroid gland (goiter). This condition has largely been eliminated by the addition of sodium iodide to commercial table salt (“iodized” salt). (It is virtually impossible to find table salt that is not iodized.)
Steroid hormones are produced by the adrenal cortex and the gonads (testes in males, ovaries in females). The adrenocortical hormones include glucocorticoids, which affect carbohydrate metabolism, modulate inflammatoryreactions, and are involved in reactions to stress. The mineralocorticoids control the level of excretion of water and salt by the kidneys. If the adrenal cortex does not function adequately, one result is Addison’s disease, characterized by hypogly-cemia, weakness, and increased susceptibility to stress. This disease is eventually fatal unless it is treated by administration of mineralocorticoids and glucocor-ticoids to make up for what is missing. The opposite condition, hyperfunction ofthe adrenal cortex, is frequently caused by a tumor of the adrenal cortex or of the pituitary. The characteristic clinical manifestation is Cushing’s syndrome, marked by hyperglycemia, water retention, and the easily recognized “moon face.”
The adrenal cortex produces some steroid sex hormones, the androgens and estrogens, but the main site of production is the gonads. Estrogens are requiredfor female sexual maturation and function, but not for embryonic sexual devel-opment of female mammals. Animals that are male genetically appear to be females if they are deprived of androgens during embryonic development. As a final example, we shall discuss growth hormone (GH), which is a polypeptide. When overproduction of GH occurs, it is usually because of a pituitary tumor. If this condition occurs while the skeleton is still growing, the result is gigantism. If the skeleton has stopped growing before the onset of GH overproduction, the result is acromegaly, characterized by enlarged hands, feet, and facial features. Underproduction of GH leads to dwarfism, but this condition can be treated by the injection of human GH before the skeleton reaches maturity. Animal GH is ineffective in treating dwarfism in humans. Supplies of human GH were very lim-ited when it could be obtained only from cadavers, but it can now be synthesized by recombinant DNA techniques. Human growth hormone (HGH) has recently become avail-able to individuals who believe it will help alleviate the effects of aging. It was known that the level of HGH decreases after middle age is reached. Many have assumed that the availability of growth hormone, if one could afford it, would be a virtual fountain of youth. Even though few results are conclusive at this time, HGH is being prescribed, and the medical community has adopted rules for its use. For example, doctors will consider prescribing it only for patients over age
The same hormone is also used illegally by endurance athletes, and there is currently no reliable test to stop this illegal use.
When a hormone binds to its specific receptor on a target cell, it sets off a chain of events in which the actual response within the cell is elicited. Several kinds of receptors are known. The receptors for steroid hormones tend to occur within the cell rather than as part of the membrane (steroids can pass through the plasma membrane); steroid–receptor complexes affect the transcription of specific genes. More frequently, the receptor proteins are a part of the plasma membrane. Binding of hormone to the receptor triggers a change in concentration of a second messenger. The second messenger brings about the changes within the cell as a result of a series of reactions.
Cyclic AMP (adenosine-3',5'-monophosphate, cAMP) is one example of a second messenger. The mode of action starts with binding of a hormone to a specific receptor called a β1- or β2-adrenergic receptor, which triggers the production of cAMP from ATP, catalyzed by adenylate cyclase.
This reaction is mediated by a stimulatory G protein, a trimer consisting of three subunits—α, β, and γ. Binding of the hormone to the receptor activates the G protein; the α-subunit binds GTP while releasing GDP, giving rise to the name of the protein. The active protein has GTPase activity and slowly hydrolyzes GTP, returning the G protein to the inactive state. GDP remains bound to the α-subunit and must be exchanged for GTP when the protein is activated the next time (Figure 24.9). The G protein and adenylate cyclase are bound to the plasma membrane, while cAMP is released into the interior of the cell to act as a second messenger. As we have already seen in several pathways, cAMP stimulates protein kinase A, which phosphorylates a host of enzymes and transcription factors. Some examples are known in which the binding of hormone to receptor (anα2-receptor) inhibits rather than stimulates adenylate cyclase. A G protein with a different kind of α-subunit mediates the process. The modified G protein is referred to as aninhibitory G protein to distinguish it from the kind that stimulates response tohormone binding (Figure 24.10).
In eukaryotic cells, the usual mode of action of cAMP is to stimulate a cAMP-dependent protein kinase, a tetramer consisting of two regulatory subunits and two catalytic subunits. When cAMP binds to the dimer of regulatory subunits, the two active catalytic subunits are released. The active kinase catalyzes the phosphorylation of a target enzyme or transcription factor (Figure 24.11). In the scheme shown in Figure 24.11, phosphorylation activates the enzyme. Cases are also known in which phosphorylation inactivates a target enzyme. The usual site of phosphorylation is the hydroxyl group of a serine or a threonine. ATP is the source of the phosphate group that is trans-ferred to the enzyme. The target enzyme then elicits the cellular response.
G proteins are very important signaling molecules in eukaryotes. They can be activated by combinations of hormones. For example, both epinephrine and glucagon act via a stimulatory G protein in liver cells. The effect can be cumulative, so that if both glucagons and epinephrine have been released, the cellular effect is greater. Besides the effect on cAMP, G proteins are involved in activating many other cellular processes, including stimulating phospholipase C and opening or closing membrane ion channels. They are also involved in vision and smell. There are currently more than 100 known G protein–coupled receptors and more than 20 known G proteins.
A G protein is permanently activated by cholera toxin, leading to excessive stimulation of adenylate cyclase and chronic elevation of cAMP levels. The main danger in cholera, caused by the bacterium Vibrio cholerae, is severe dehy-dration as a result of diarrhea. The unregulated activity of adenylate cyclase in epithelial cells leads to the diarrhea because cAMP in epithelial cells stimulates active transport of Na+. Excessive cAMP in the epithelial cells of the small intes-tine produces a large flow of Na+ and water from the mucosal surface of the epithelial cells into the lumen of the intestine. If the lost fluid and salts can be replaced in cholera victims, the immune system can eliminate the actual infec-tion within a few days.
Calcium ion (Ca2+) is involved in another ubiquitous second-messenger scheme. Much of the calcium-mediated response depends on release of Ca2+ from intracellular reservoirs, similar to the release of Ca2+ from the sarcoplasmic reticulum in the action of the neuromuscular junction. A component of the inner layer of the phospholipid bilayer, phosphatidylinositol 4,5-bisphosphate (PIP2), is also required in this scheme (Figure 24.12).
When the external trigger binds to its receptor on the cell membrane, it activates phospholipase C, which hydrolyzes PIP2 to inositol 1,4,5-triphosphate (IP3) and a diacylglycerol (DAG), in a process mediated by a differentmember of the family of G proteins. The IP3 is the actual second messenger. It diffuses through the cytosol to the endoplasmic reticulum (ER), where it stimulates the release of Ca2+. A complex is formed between the calcium-binding protein calmodulin and Ca2+. This calcium–calmodulin complex activates a cyto-solic protein kinase, which phosphorylates target enzymes in the same fashion as in the cAMP second-messenger scheme. DAG also plays a role in this scheme; it is nonpolar and diffuses through the plasma membrane. When DAG encoun-ters the membrane-bound protein kinase C, it too acts as a second messenger by activating this enzyme (actually a family of enzymes).
Protein kinase C also phosphorylates target enzymes, including channel proteins that control the flow of Ca2+ into and out of the cell. By controlling the flow of Ca2+, this second-messenger system can produce sustained responses even when the supply of Ca2+ in the intracellular reservoirs becomes exhausted.
Another important type of second-messenger system involves a receptor type called a receptor tyrosine kinase. These receptors span the membrane of the cell and have a hormone receptor on the outside and a tyrosine kinase portion on the inside. There are several subclasses of these receptor kinases, as shown in Figure 24.13. The best known of these is class II, which includes the insulin receptor.
These kinases are allosteric enzymes. When the hormone binds to the bind-ing region on the outside of the cell, it induces a conformational change in the tyrosine kinase domain that activates the kinase activity.
The activated tyrosine kinases phosphorylate tyrosines on a variety of target proteins, causing altera-tions in membrane transport of ions and amino acids and the transcription of certain genes. Phospholipase C (seen in Figure 24.12) is one of the targets of tyrosine kinases. Another is an insulin-sensitive protein kinase, which phos-phorylates and activates protein phosphatase 1.
Sophisticated fine-tuning of metabolic processes in multicellular organisms is possible through the actions of hormones and second messengers.
In humans, a complex hormonal system has evolved that requires releas-ing factors (under the control of the hypothalamus), trophic hormones (under the control of the pituitary), and specific hormones for target organs (under the control of endocrine glands).
Feedback control occurs at every level of the system.
One important system involves hormones that stimulate a membrane-bound G protein, which then stimulates adenylate cyclase to produce cAMP. In these cases, cAMP is the second messenger.
In another important system, a hormone stimulates a different G protein that then stimulates phospholipase C. Phospholipase C converts phospha-tidylinositol 4,5-bisphosphate (PIP2) to diacylglycerol (DAG) and inositol 1,4,5-triphosphate (IP3), both of which stimulate the opening of calcium channels and the release of Ca2+. In this scenario, the Ca2+ is the second messenger.
Receptor tyrosine kinases are a third important type of membrane protein involved in second-messenger systems.
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