Ch. 20: Chemical Messengers: Hormones, Neurotransmitters, & Drugs

1. Ch. 20: Chemical Messengers:Hormones, Neurotransmitters, & Drugs

2. Body Chemistry • regulated by two major systems: • endocrine system • depends on hormones (chemical messengers that circulate in the blood stream) • nervous system • primarily relies on electrical impulses in the nerve cells. • also has chemical messengers (neurotransmitters) that carry signals from one nerve cell to another and from nerve cells to their targets. We will see that many drugs act by mimicking, modifying, or opposing these chemical messengers.

3. Messenger Molecules • Coordination and control of our vital functions is accomplished by messengers and are delivered through the interaction of the messenger and a receptor at the target. • receptor: a molecule or portion of a molecule with which a hormone, neurotransmitter, or other biochemically active molecule connects to in order to initiate a response in a target cell • Interaction between a messenger and a receptor results in chemical changes within the target cell.

4. What draws messengers and receptors together? Noncovalent attractions (such as hydrogen bonding) These attractions hold the messenger and receptor together long enough for the message to be delivered (but without any permanent chemical change to either messenger or receptor).

5. hormone: a chemical messenger secreted by cells of the endocrine system and transported through the blood stream to target cells with appropriate receptors where it elicits a response • endocrine system: a system of specialized cells, tissues, and ductless glands that excretes hormones and shares responsibility with the nervous system for maintaining constant internal body conditions and responding to changes in the environment • neurotransmitter: a chemical messenger that travels between a neuron and a neighboring neuron or other target cell to transmit a nerve impulse

6. Since hormones travel through blood stream, the responses they produce require minutes to hour to begin. • The chemical messages of the nervous system travel along nerve fibers, taking only a fraction of a second to reach their destination. • Most nerve cells do not make direct contact with their target, neurotransmitters carry the messages across a small gap between the nerve cell and the target. • Neurotransmitters are released in very short bursts and are quickly broken down or reabsorbed by the nerve cells.

7. Hormones and the Endocrine System • Endocrine system includes all cells that secrete hormones into the blood stream. • Hypothalamus: A section of brain just above the pituitary gland that is in charge of the endocrine system. • The major endocrine glands are the: - pituitary gland - thyroid gland - adrenal gland -ovaries and testes.

8. Hypothalamus • The hypothalamus communicates with other tissues in three ways: • Direct neural control: A nervous system message from the hypothalamus initiates release of hormones by the adrenal gland. • Direct release of hormones: Hormones move from the hypothalamus to the posterior pituitary gland, where they are stored until needed. • Indirect control through release of regulatory hormones: Regulatory hormones from the hypothalamus stimulate or inhibit the release of hormones by the anterior pituitary gland. Many of these pituitary hormones in turn stimulate release of other hormones from their target tissues.

9. Examples • direct neural control nerve messenger hypothalamus --------> adrenal gland ---------> epinephrine (epinephrine targets many cells and increases heart rate, blood pressure, and glucose availability) • direct release of hormones hypothalamus ---------> antidiuretic hormone (antidiuretic hormone is stored in the posterior pituitary gland; it targets the kidneys causing retention of water and elevation of blood pressure) • indirect control through regulatory hormones releasing factor hypothalamus ---------> pituitary gland -------> thyrotropin (a regulatory hormone) ----> thyroid gland ------> thyroid hormones (thyroid hormones target cells throughout the body and affect oxygen availability, blood pressure, and other endocrine tissues

10. Hormones are of 3 Major Chemical Types (1) amino acid derivatives small molecules containing amino groups (2) polypeptides ranging from just a few amino acids to several hundred amino acids (3) steroids lipids with a molecular structure based on four connected rings

11. Hormone Signal Delivery • Upon arrival at its target cell, a hormone must deliver its signal to create a chemical response inside the cell. The signal enters the cell in one of the two ways determined by the chemical nature of the hormone. • Hydrophobic steroids (such as steriods) can directly go through the cell membrane which is made up of hydrophobic molecules. • Within the cell, the steroid hormone encounters a receptor that carries it to its target, DNA in the nucleus of the cell. • Water soluble polypeptide and amine hormones can not cross the hydrophobic cell membranes. They bind to the receptors on cell surfaces resulting into release of a second messenger within the cell.

12. Second Messengers • second messenger: a chemical messenger released inside a cell when a hydrophilic hormone or neurotransmitter connects with a receptor on the cell surface • In general, 3 membrane-bound proteins participate in the release of the second messenger: • the receptor • a G protein that transfers the message to an enzyme • the enzyme

13. Figure 20.1

14. How Hormones Work: Epinephrine and Fight-or-Flight • Epinephrine (adrenaline) is released when we need an instant response to danger. • Epinephrine • makes glucose available • reacts with other receptors that increase blood pressure, heart rate, and respiratory rate • decreases blood flow to the digestive system • counteracts spasms in the respiratory system

15. Epinephrine acts via an important second messenger cyclic adenosine monophosphate (cyclic AMP, or cAMP) Epinephrine is carried in the bloodstream and finds a receptor on cell surface.

16. The ephinephrine binds to the receptor on the cell surface. On formation of the hormone-receptor complex, the guanosine diphosphate (GDP) of the G protein is converted to guanosine triphosphate (GTP) by addition of a phosphate group.

17. The active G protein-GTP complex activates adenylate cyclase (another enzyme in the cell membrane), causing production of cyclic AMP (the second messenger inside the cell where it will initiate the action called for by the hormone. Once the emergency has passed, cyclic AMP is converted back to ATP.

18. Epinephrine Cont. • Epinephrine is a crucial drug for treating anaphylactic shock. • Anaphylactic shock is a result of severe allergic reaction (such as from bee stings or drug). • The major symptoms include severe drop in blood pressure due to blood vessel dilation and difficulty breathing due to bronchial constriction. • Epinephrine counters these symptoms directly. • Some people with know allergies to bee stings carry EpiPens.

19. Amino Acid Derivatives & Polypeptides as Hormones • Amino Acid derivatives • Several amino acid derivatives are classified as hormones becauseof their roles in the endocrine system. Many of them also function as neurotransmitters in the brain. • For example: Epinephrine: A hormone produced in the adrenal gland is also a neurotransmitter. • Thyroxine: One of the two iodine containing hormones produced in the thyroid gland. Unlike other hormones derived from amino acids, thyroxine is a nonpolar compound that can cross the hydrophobic cell membranes and enters the cell where it activates the synthesis of various enzymes. • Iodine deficiency results in a greatly enlarged thyroid gland (goiter). In developed countries iodine is added to table salt, so goiter is uncommon. However, there are regions in the world where iodine deficiency is common and not only goiter occurs but severe mental retardation in infants (cretinism) also occurs.

20. Polypeptides • Polypeptides are the largest class of hormones. • They range widely in molecular size and complexity. • Thyrotropin-releasing hormone (TRH), a regulatory hormone released by hypothalamus, has 208 amino acid residues in two chains. • Insulin contains 51 amino acids and is released by the pancreas in response to high concentrations of glucose in the blood. It stimulates cells to take up glucose and put it to use or into storage.

21. Steroid Hormones • Steroids are important “biological regulators” • steroid: a lipid whose structure is based on a specific tetracyclic (four-ring) carbon structure. • The rings are given letter designations A-D • Steroid carbons are numbered as shown below

22. Classification of Steroids by Function • Because steroids are soluble in hydrophobic solvents and not in water they are classified as lipids. They are divided into three groups according to their function: • Mineralocorticoids: Regulate the delicate cellular fluid balance between Na+ and K+ ions. • ex. aldosterone • Glucocorticoids: Help to regulate glucose metabolism and inflammation. • ex. hydrocortisone (cortisol) and cortisone • Sex hormones: Responsible for the development of secondary sex characteristics during puberty • ex. testosterone, androsterone, estrone, progesterone

23. Cholesterol • most widely occurring steroid • biosynthetic precursor of all other steroids • human body makes sufficient cholesterol for its needs • Dietary cholesterol usually causes the body to make less of its own • High levels of blood cholesterol have been implicated in development of arterioschlerosis (hardening of the arteries) and in heart attacks

24. Cholesterol Cont. • Cholesterol is found in the body often as an aggregate with other lipids and proteins • These aggregates are called chylomicrons, high-density lipoproteins (HDLs) and low-density lipoproteins (LDLs) and are generally in micelle form • These aggregates serve to transport water-insoluble cholesterol and other lipids in the body

25. Cholesterol Cont. • HDLs (“good cholesterol”) carry lipids from the tissues to the liver for degradation and excretion • LDLs (“bad cholesterol”) carry biosynthesized cholesterol from the liver to tissues • Chylomicrons carry dietary lipids from the intestines to the tissues

26. Sex Hormones • There are 3 major classes of sex hormones • Androgens (male sex hormones) • Estrogens (female sex hormones) • Progestins (pregnancy hormones)

27. Sex Hormones • Because of their importance, androgens and estrogens were the first steroidal hormones studied in great detail. • It was a difficult area. • For example, 1 ton of bull testicles was processed to yield just 5 mg of testosterone • 4 tons of pig ovaries provided only 12 mg of estrone.

28. Androgens (Male Sex Hormones) • Testosterone is the primary male sex hormone • secreted by the testes and promotes the development of secondary male characteristics and promotes tissue and muscle growth • Androsterone is a metabolized form of testosterone that is excreted

29. Estrogens (Female Sex Hormones) • Estradiol is the major female sex hormone • secreted by the ovaries (and to small extent the adrenal cortex) and promotes the development of secondary female characteristics • Estrone is a metabolized form of estradiol that is excreted • Estrogens: • are synthesized from testosterone • participate in the regulation of the menstrual cycle • stimulate the mammary glands during pregnancy

30. Progestins (Pregnancy Hormones) • Progesterone is the most important pregnancy hormone • After ovulation, the ruptured ovarian follicle begins to secrete progesterone to prepare the lining of the uterus for implantation of the fertilized ovum • Progesterone is also secreted by the placenta and is necessary for pregnancy to continue

31. Oral Contraceptives • Uses steroids to “trick” the body into thinking it is already pregnant so ovulation is inhibited. • Progesterone suppresses ovulation; this is the basis for its use in oral contraceptives • Progesterone is degraded in the intestinal tract, however, and therefore more robust synthetic progestins such as norethindrone are used • Synthetic estrogens such as ethynylestradiol are also used in oral contraceptives

32. The Pill • In 1962, 1.2 million women used birth control pills that contained 150 mg of estrogen and 10 mg of progestin. • Since then, further molecular modifications have led to a decreased dosage and minimized side effects. • Today over 16 million women use oral contraceptives with only 20-35 mg of estrogen and about 1 mg of progestin.

33. Anabolic Steroids • Anabolic steroids were initially developed to help patients suffering from wasting illnesses to regain muscle tissue. • Testosterone promotes muscle growth as well as the development of male secondary sexual characteristics. • Drug companies wanted to produce a testosterone-like drug that would stimulate muscle growth in debilitated patients, but modified in such a way that the drug would not have serious side effects. The result was anabolic steroids.

34. Anabolic Steroids Cont. • Want to increase muscle mass (an anabolic effect). • Do not want an increased prostate mass, accentuated female characteristics in males, or male characteristics in females. • While the risks have been reduced, they are still present. • Long term, large dose use can result in shrinking testes, difficulty in urination, impotence, fluid retention, baldness, high blood pressure, heart attack, increased aggressiveness, unpredictable periods of violent mood changes and other behavior disorders (“roid rage”).

35. Androstrendione (“Andro”) • developed in the 1970s in East Germany to enhance the Olympic performance of its athletes. • sold in the U.S. as a nutritional supplement, not a steroid • can be purchased “over the counter” (i.e. without a prescription) • “andro” is a very close chemical relative of testosterone. Once ingested, “andro” is converted directly to testosterone, which is an anabolic steroid

36. Adrenocortical Hormones • The adrenal glands (located on the top of the kidneys) produce many steroid hormones • Adrenocortical hormones are very important in the regulation of carbohydrate, protein and lipid metabolism • They are also important in water and electrolyte balance and the inflammatory response • Cortisol is the primary adrenocortical hormone

37. D Vitamins • Vitamin D2 is important for bone growth • Ergosterol is converted to Vitamin D2 by a photochemical-ring opening reaction

38. Neurotransmitters • Neurotransmitters: the chemical messengers of the nervous system. • Most neurotransmitters are amines. • They are released by nerve cells (neurons) and transmit signals to neighboring target cells. • Synapses: a small, narrow gap where the tip of a neuron and its target cell lie adjacent to each other.

39. Transmission of a nerve signal by neurotransmitter

40. Neurotransmitter Comments • Once the neurotransmitter-receptor binding has occurred, the message has been delivered. • The postsynaptic neuron then transmits the nerve impulse down its own axon until a neurotransmitter delivers the message to the next neuron or other target cell. • After a neurotransmitter has done its job, it must be rapidly removed so that the postsynaptic neuron is ready to receive another impulse • Either a chemical change catalyzed by an enzyme available in the synaptic cleft inactivates the neurotransmitter, or • The neurotransmitter is returned to the presynaptic neuron and placed in storage until it is needed again

41. How Neurotransmitters Work: Acetylcholine, Its Agonists, & Antagonists • Acetylcholine (Ach) is a neurotransmitter • produced in presynaptic neuron and stored in their vesicles • is responsible for the control of skeletal muscle • may play role in the sleep-wake cycle, learning and memory, and mood. • Nerves that rely on Ach as their neurotransmitter are classified as cholinergic nerves

42. Ach Release & Uptake ACh made in presynaptic neuron and stored in its vesicle Vesicle moves to cell membrane and fuses with it, and releases its ACh. ACh crosses synapse and binds to receptor.

43. A nerve impulse arrives at the presynaptic neuron. • The vesicle move to the cell membrane, fuse with it, and release their ACh molecules. • ACh crosses the synapse and binds to receptor on the postsynaptic neuron. • The resulting change initiates the nerve impulse in that neuron. • With the message delivered, Acetyl cholinesterase present in the synaptic cleft catalyzes the decomposition of acetylcholine. • Choline is absorbed back into the presynaptic neuron where new ACh is synthesized.

44. Drugs & Acetylcholine • Many drugs act at acetylcholine synapses, the places where the tip of a neuron that releases acetylcholine and its target lie adjacent to each other. • drug: any molecule that alters normal functions when it enters the body from an external source. • Drugs are classified as Agonists: substance that acts to produce or prolong the normal biochemical responses of a receptor. Antagonists: – substance that blocks or inhibits the normal response of a receptor.

45. Agonist Examples • Black widow spider venom • releases excess acetylcholine • synapse is flooded with acetylcholine resulting in muscle cramps and spasms • Nicotine • at low doses is an agonist because it activates acetylcholine receptors • a stimulant • at high doses an antagonist

46. Antagonist Examples • Botulinus toxin • blocks acetylcholine release by binding irreversibly to the presynaptic neuron where acetylcholine would be released • causes botulism which may result in death due to muscle paralysis • Organophosphorus insecticides • prevent the cholinesterase enzyme from breaking down acetylcholine within the synapse • as a result, nerves are overstimulated (muscle contractions, weakness, lack of coordination, convulsions) • Nicotine • at high doses (orally or through the skin) • irreversibly blocks the acetylcholine receptors and can cause their degeneration • Atropine • competes with acetylcholine at receptors • poison at high doses • at controlled doses its therapeutic uses include accelerating abnormally slow heart rate, paralysis of eye muscles during surgery, and relaxation of intestinal muscles in gastrointestinal disorders • specific antidote for cholinesterase poisons such as the organophosphorus insecticides (by blocking activation of the receptors, it counteracts the excess of acetylcholine created by cholinesterase inhibitors

47. Histamine & Antihistamines • Histamine: a neurotransmitter responsible for the symptoms of the allergic reaction. • Antihistamines: a family of drugs that counteract the effect of histamine because they are histamine receptor antagonists. (They competitively block the attachment of histamine to its receptor.) • members of this family have a disubstituted ethylamine side chain

48. Serotonin, Norepinephrine, & Dopamine • the ‘big three’ of neurotransmitters. • Collectively, they are called monoamines. • All are active in the brain and all been identified to play role in mood, the experience of fear and pleasure, mental illness, and drug addiction. • Connection between major depression and a deficiency of serotonin, norepinephrine, and dopamine is well established.

49. Antidepressants • amitriptyline, phenelzine, and fluoxetine increases the concentration of neurotransmitters at synapses • amitriptyline: tricyclic antidepressant which were the first generation of these drugs; prevents the re-uptake of serotonin and norepinephrine from within the synapse • phenelzine: a monamine oxidase (MAO) inhibitor, one of a group of medications that inhibit the enzyme that breaks down monoamine neurotransmitters; allows the concentrations of monoamines at synapses to increase • fluoxetine (Prozac): represents the newest class of antidepressants, the selective serotonin re-uptake inhibitors (SSRI); more selective than the tricyclics because they inhibit only the re-uptake of serotonin; does not cause the unpleasant side effects common to other antidepressants

50. Dopamine & Drug Addiction • Dopamine plays a role in the brain in processes that control movement, emotional responses, and the experiences of pleasure and pain. • An oversupply of dopamine is associated with schizophrenia, while an undersupply results in the loss of fine motor control in Parkinson’s disease. • An amply supply of brain dopamine produces the pleasantly satisfied feeling – a natural high. • A number of street drugs such as marijuana, heroin, and cocaine increases the dopamine level in the brain – causing a high.