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.
- 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.
Blocking Hormone Receptors
- Synthetic hormones that block the receptors for some naturally occurring hormones are available as drugs.
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.
- 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 ).
- 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.
- 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.
- Chemically, hormones can be divided into two broad classes:
- those that are soluble in lipids,
- and those that are soluble in water.
- This chemical classification is also useful functionally because the two classes exert their effects differently.
The lipid-soluble hormones include
1. Steroid hormones
- steroid hormones,
- thyroid hormones, and
- nitric oxide.
- 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.
- 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.
- is both a hormone and a neurotransmitter.
- Its synthesis is catalyzed by the enzyme nitric oxide synthase.
- The water-soluble hormones include
- amine hormones,
- peptide and protein hormones, and
- eicosanoid 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.
- 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.
- antidiuretic hormone and oxytocin;
- human growth hormone and insulin.
- Several of the protein -hormones, such as thyroid-stimulating hormone, have attached carbohydrate groups
- and thus are glycoprotein hormones.
- are derived from arachidonic acid, a 20-carbon fatty acid.
- The two major types of eicosanoids are
- prostaglandins and
- leukotrienes.
- The eicosanoids are important local hormones,
- and they may act as circulating hormones-
- 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:
- thus increasing their solubility in blood.
- thus slowing the rate of hormone loss in the urine.
- 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.
Administering Hormones
MECHANISMS OF HORMONE ACTION
Action of Lipid-soluble 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.
- The response to a hormone depends on both the hormone and the target cell.
- Various target cells respond differently to the same hormone.
- 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.
- 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.
- lipid-soluble hormones, including steroid hormones and thyroid hormones, bind to receptors within target cells.
1. A free lipid-soluble hormone molecule
3. As the DNA is transcribed,
4 The new proteins
Action of Water-soluble Hormones
- diffuses from the blood,
- through interstitial fluid,
- and through the lipid bilayer of the plasma membrane into a 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.
- 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.
- alter the cell’s activity
- and cause the responses typical of that hormone.
- 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
2. Adenylate cyclase
3 Cyclic AMP (the second messenger)
4. Activated protein kinases
5. Phosphorylated proteins
6 After a brief period,
Hormone Interactions
(2) the abundance of the target cell’s hormone receptors, and
(3) influences exerted by other hormones.
- 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.
- 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.
- 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.
- phosphorylate one or more cellular proteins.
- Phosphorylation activates some of these proteins and inactivates others, rather like turning a switch on or off.
- 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.
- 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.
- some of the kinases unleashed when epinephrine binds to liver cells inactivate an enzyme needed for glycogen synthesis.
- 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.
- 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.
- 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.
- 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.
- The responsiveness of a target cell to a hormone depends on
(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.
- 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.
- 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.
- insulin, which promotes synthesis of glycogen by liver cells, and
- glucagon, which stimulates breakdown of glycogen in the liver.