Wednesday 25 December 2013

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.