18. HORMONE ACTIVITY

18. HORMONE ACTIVITY

The Role of Hormone Receptors

• Although a given hormone travels throughout the body in the blood, it affects only specific target cells. 
• Hormones, like neuro-transmitters, influence their target cells by chemically binding to specific protein receptors. 
• Only the target cells for a given hormone have receptors that bind and recognize that hormone. 

For example, 

• thyroid-stimulating hormone (TSH) binds to receptors on cells of the thyroid gland, 
• but it does not bind to cells of the ovaries because ovarian cells do not have TSH receptors.

• Receptors, like other cellular proteins, are constantly being synthesized and broken down. 
• Generally, a target cell has 2000 to 100,000 receptors for a particular hormone. 

• If a hormone is present in excess, the number of target-cell receptors may decrease—an effect called down-regulation. 

For example, 

• when certain cells of the testes are exposed to a high concentration of luteinizing hormone (LH), the number of LH receptors decreases. 
• Down-regulation makes a target cell less sensitive to a hormone. 

• In contrast, when a hormone is deficient, the number of receptors may increase. This phenomenon, known as upregulation,
• makes a target cell more sensitive to a hormone.

CLINICAL CONNECTION 

Blocking Hormone Receptors

• Synthetic hormones that block the receptors for some naturally occurring hormones are available as drugs.

 For example, 


RU486 (mifepristone), which is used to induce abortion, 

• binds to the receptors for progesterone (a female sex hormone) 
• and prevents progesterone from exerting its normal effect, in this case preparing the lining of the uterus for implantation. 

When RU486 is given to a pregnant woman, 

• the uterine conditions needed for nurturing an embryo are not maintained, 
• embryonic development stops, 
• and the embryo is sloughed off along the the uterine lining.

 This example illustrates an important endocrine principle:

•  If a hormone is prevented from interacting with its receptors the hormone cannot perform its normal functions. 

Circulating and Local Hormones

• Most endocrine hormones are circulating hormones
• —they pass from the secretory cells that make them into interstitial fluid and then into the blood. 

• Other hormones, termed local hormones, act locally on neighboring cells or on the same cell that secreted them without first entering the bloodstream. 

• Local hormones that act on neighboring cells are called paracrines (para- beside or near), 
• and those that act on the same cell that secreted them are called autocrines (auto- self ). 

One example of a local hormone is 

• interleukin 2 (IL-2), 
• which is released by helper T cells (a type of white blood cell) during immune responses . 
• IL-2 helps activate other nearby immune cells, a paracrine effect. 
• But it also acts as an autocrine by stimulating the same cell that released it to proliferate. 
• This action generates more helper T cells that can secrete even more IL-2 and thus strengthen the immune response.

 Another example of a local hormone is 

• the gas nitric oxide (NO), 
• which is released by endothelial cells lining blood vessels. 
• NO causes relaxation of nearby smooth muscle fibers in blood vessels, which in turn causes vasodilation (increase in  blood vessel diameter). 
• The effects of such vasodilation range from a lowering of blood pressure to erection of the penis in males. 
• The drug Viagra® (sildenafil) enhances the effects stimulated by nitric oxide in the penis.

• Local hormones usually are inactivated quickly; 
• circulating hormones may linger in the blood and exert their effects for a few minutes or occasionally for a few hours. 

• In time, circulating hormones are inactivated by the liver and excreted by the kidneys. 
• In cases of kidney or liver failure, excessive levels of hormones may build up in the blood.

Chemical Classes of Hormones

• Chemically, hormones can be divided into two broad classes:

1. those that are soluble in lipids, 
2. and those that are soluble in water.

• This chemical classification is also useful functionally because the two classes exert their effects differently.

A. Lipid-soluble Hormones

The lipid-soluble hormones include 

• steroid hormones, 
• thyroid hormones, and 
• nitric oxide.

1. Steroid hormones 

• are derived from cholesterol. 
• Each steroid hormone is unique due to the presence of different chemical groups attached at various sites on the four rings at the core of its structure. 
• These small differences allow for a large diversity of functions.

2. Two thyroid hormones (T3 and T4) 

• are synthesized by attaching iodine to the amino acid tyrosine. 
• The benzene ring of tyrosine plus the attached iodines make T3 and T4 very lipid soluble.

3. The gas nitric oxide (NO)

•  is both a hormone and a neurotransmitter. 
• Its synthesis is catalyzed by the enzyme nitric oxide synthase.

B. Water-soluble Hormones

• The water-soluble hormones include 
• amine hormones, 
• peptide and protein hormones, and 
• eicosanoid hormones.

1. Amine hormones 

• are synthesized by decarboxylating (removing a molecule of CO2) and otherwise modifying certain amino acids. 
• They are called amines because they retain an amino group (9NH3 ). 
• The catecholamines—epinephrine, norepinephrine, and dopamine—are synthesized by modifying the amino acid tyrosine. 
• Histamine is synthesized from the amino acid histidine by mast cells and platelets. 
• Serotonin and melatonin are derived from tryptophan.

2. Peptide hormones and protein hormones 

• are amino acid polymers. 
• The smaller peptide hormones consist of chains of 3 to 49 amino acids; 
• the larger protein hormones include 50 to 200 amino acids. 

Examples of peptide hormones are

• antidiuretic hormone and oxytocin; 

protein hormones include

• human growth hormone and insulin. 

• Several of the protein -hormones, such as thyroid-stimulating hormone, have attached carbohydrate groups 
• and thus are glycoprotein hormones.

3. The eicosanoid hormones ( eicos- twenty forms; -oid resembling) 

• are derived from arachidonic acid, a 20-carbon fatty acid. 
• The two major types of eicosanoids are 

1. prostaglandins and
2.  leukotrienes. 

• The eicosanoids are important local hormones,
•  and they may act as circulating hormones-

Hormone Transport in the Blood

• Most water-soluble hormone molecules circulate in the watery blood plasma in a “free” form (not attached to other molecules),
• but most lipid-soluble hormone molecules are bound to transport proteins. 
• The transport proteins, which are synthesized by cells in the liver, have three functions:

1. They make lipid-soluble hormones temporarily watersoluble,

• thus increasing their solubility in blood.

2. They retard passage of small hormone molecules through the filtering mechanism in the kidneys, 

• thus slowing the rate of hormone loss in the urine.

3. They provide a ready reserve of hormone, 

• already present in the bloodstream.

• In general, 0.1–10% of the molecules of a lipid-soluble hormone are not bound to a transport protein. 
• This free fraction diffuses out of capillaries, 
• binds to receptors,
•  and triggers responses. 

• As free hormone molecules leave the blood and bind to their receptors, transport proteins release new ones to replenish the free fraction.

 CLINICAL CONNECTION 

Administering Hormones

• Both steroid hormones and thyroid hormones are effective when taken by mouth. 
• They are not split apart during digestion 
• and easily cross the intestinal lining because they are lipid-soluble. 

• By contrast, peptide and protein hormones, such as insulin, are not effective oral medications because digestive enzymes destroy them by breaking their peptide bonds. 
• This is why people who need insulin must take it by injection.

MECHANISMS OF HORMONE ACTION

• The response to a hormone depends on both the hormone and the target cell. 
• Various target cells respond differently to the same hormone. 

Insulin, for example,

•  stimulates synthesis of glycogen in liver cells 
• and synthesis of triglycerides in adipose cells.

• The response to a hormone is not always the synthesis of new molecules, as is the case for insulin. 

Other hormonal effects include 

• changing the permeability of the plasma membrane, 
• stimulating transport of a substance into or out of the target cells, 
• altering the rate of specific metabolic reactions, 
• or causing contraction of smooth muscle or cardiac muscle. 

• In part, these varied effects of hormones are possible because a single hormone can set in motion several different cellular responses.

• However, a hormone must first “announce its arrival” to a target cell by binding to its receptors. 
• The receptors for lipid-soluble hormones are located inside target cells. 
• The receptors for water-soluble hormones are part of the plasma membrane of target cells.

Action of Lipid-soluble Hormones

•  lipid-soluble hormones, including steroid hormones and thyroid hormones, bind to receptors within target cells. 

Their mechanism of action is as follows 

1. A free lipid-soluble hormone molecule 

• diffuses from the blood, 
• through interstitial fluid, 
• and through the lipid bilayer of the plasma membrane into a cell.

2. If the cell is a target cell, 

• the hormone binds to and activates receptors located within the cytosol or nucleus. 
• The activated receptor–hormone complex then alters gene expression: 
• It turns specific genes of the nuclear DNA on or off.

3. As the DNA is transcribed, 

• new messenger RNA (mRNA) forms, 
• leaves the nucleus, 
• and enters the cytosol. 
• There, it directs synthesis of a new protein, often an enzyme, on the ribosomes.

4 The new proteins 

• alter the cell’s activity
•  and cause the responses typical of that hormone.

Action of Water-soluble Hormones

• Because amine, peptide, protein, and eicosanoid hormones are not lipid-soluble, they cannot diffuse through the lipid bilayer of the plasma membrane and bind to receptors inside target cells.
• Instead, water-soluble hormones bind to receptors that protrude from the target cell surface. 
• The receptors are integral transmembrane proteins in the plasma membrane. 

• When a watersoluble hormone binds to its receptor at the outer surface of the plasma membrane,  
• it acts as the first messenger. 
• The first messenger (the hormone) then causes production of a second messenger inside the cell, where specific hormone-stimulated responses take place.
•  One common second messenger is cyclic AMP (cAMP). 
• Neurotransmitters, 
• neuropeptides, 
• and several sensory transduction mechanisms (for example, vision; ) also act via second-messenger systems. 

The action of a typical water-soluble hormone occurs as follows :

1. A water-soluble hormone (the first messenger) diffuses from the blood through interstitial fluid

•  and then binds to its receptor at the exterior surface of a target cell’s plasma membrane. 
• The hormone–receptor complex activates a membrane protein called a G protein. 
• The activated G protein in turn activates adenylate cyclase.

2. Adenylate cyclase 

• converts ATP into cyclic AMP (cAMP).
• Because the enzyme’s active site is on the inner surface of the plasma membrane, this reaction occurs in the cytosol of the cell.

3 Cyclic AMP (the second messenger) 

• activates one or more protein kinases, which may be free in the cytosol or bound to the plasma membrane. 
• A protein kinase is an enzyme that phosphorylates (adds a phosphate group to) other cellular proteins (such as enzymes). 
• The donor of the phosphate group is ATP, which is converted to ADP.

4. Activated protein kinases 

• phosphorylate one or more cellular proteins. 
• Phosphorylation activates some of these proteins and inactivates others, rather like turning a switch on or off.

5. Phosphorylated proteins 

• in turn cause reactions that produce physiological responses. 
• Different protein kinases exist within different target cells and within different organelles of the same target cell. 

 Thus, 

• one protein kinase might trigger glycogen synthesis,
•  a second might cause the breakdown of triglyceride, 
• a third may promote protein synthesis, and so forth. 

• As noted in step 4 , phosphorylation by a protein kinase can also inhibit certain proteins.

 For example,

• some of the kinases unleashed when epinephrine binds to liver cells inactivate an enzyme needed for glycogen synthesis.

6 After a brief period, 

• an enzyme called phosphodiesterase inactivates cAMP. 
• Thus, the cell’s response is turned off unless new hormone molecules continue to bind to their receptors in the plasma membrane.
• The binding of a hormone to its receptor activates many G-protein molecules, 
• which in turn activate molecules of adenylate cyclase (as noted in step ●1 ). 

• Unless they are further stimulated by the binding of more hormone molecules to receptors, 
• G proteins slowly inactivate, 
• thus decreasing theactivity of adenylate cyclase 
• and helping to stop the hormone response. 

• G proteins are a common feature of most secondmessenger systems.

• Many hormones exert at least some of their physiological effects through the increased synthesis of cAMP. 

Examples include

• antidiuretic hormone (ADH), 
• thyroid-stimulating hormone (TSH), 
• adrenocorticotropic hormone (ACTH), 
• glucagon, 
• epinephrine,
• and hypothalamic–releasing hormones. 

• In other cases, such as growth hormone–inhibiting hormone (GHIH), the level of cyclic AMP decreases in response to the binding of a hormone to its receptor. 

Besides cAMP, other second messengers include 

• calcium ions (Ca2+ ), 
• cGMP (cyclic guanosine monophosphate, a cyclic nucleotide similar to cAMP), 
• inositol trisphosphate (IP3), and
•  diacylglycerol (DAG). 

• A given hormone may use different second messengers in different target cells.

• Hormones that bind to plasma membrane receptors can induce their effects at very low concentrations because they initiate a cascade or chain reaction,
•  each step of which multiplies or amplifies the initial effect. 

For example, 

• the binding of a single molecule of epinephrine to its receptor on a liver cell may activate a hundred or so G proteins, each of which activates an adenylate cyclase molecule. 
• If each adenylate cyclase produces even 1000 cAMP, then 100,000 of these second messengers will be liberated inside the cell. 
• Each cAMP may activate a protein kinase, 
• which in turn can act on hundreds or thousands of substrate molecules. 

• Some of the kinases phosphorylate
•  and activate a key enzyme needed for glycogen breakdown. 
• The end result of the binding of a single molecule of epinephrine to its receptor is the breakdown of millions of glycogen molecules into glucose monomers.

Hormone Interactions

• The responsiveness of a target cell to a hormone depends on

(1) the hormone’s concentration, 
(2) the abundance of the target cell’s hormone receptors, and
(3) influences exerted by other hormones. 

• A target cell responds more vigorously when the level of a hormone rises or when it has more receptors (up-regulation). 

• In addition, the actions of some hormones on target cells require a simultaneous or recent exposure to a second hormone. 
• In such cases, the second hormone is said to have a permissive effect. 

For example, 

• epinephrine alone only weakly stimulates lipolysis (the breakdown of triglycerides),
• but when small amounts of thyroid hormones (T3 and T4) are present, the same amount of epinephrine stimulates lipolysis much more powerfully. 

• Sometimes the permissive hormone increases the number of receptors for the other hormone, and 
• sometimes it promotes the synthesis of an enzyme required for the expression of the other hormone’s effects.

• When the effect of two hormones acting together is greater or more extensive than the effect of each hormone acting alone, the two hormones are said to have a synergistic effect. 

For example, 

• normal development of oocytes in the ovaries requires both follicle-stimulating hormone from the anterior pituitary and estrogens from the ovaries. 
• Neither hormone alone is sufficient.

• When one hormone opposes the actions of another hormone, the two hormones are said to have antagonistic effects. 

An example of an antagonistic pair of hormones is 

• insulin, which promotes synthesis of glycogen by liver cells, and 
• glucagon, which stimulates breakdown of glycogen in the liver.