Transcript 28.2 Hormones and the Endocrine System

Outline
28.1
28.2
28.3
Messenger Molecules
Hormones and the Endocrine System
How Hormones Work: Epinephrine and Fight-orFlight
28.4 Amino Acid Derivatives and Polypeptides as
Hormones
28.5 Steroid Hormones
28.6 Neurotransmitters
28.7 How Neurotransmitters Work: Acetylcholine, Its
Agonists and Antagonists
28.8 Histamine and Antihistimines
28.9 Serotonin, Norepinephrine, and Dopamine
28.10 Neuropeptides and Pain Relief
28.11 Drug Discovery and Drug Design
Goals
1. What are hormones, and how do they function?
Be able to describe in general the origins, pathways, and actions of hormones.
2. What is the chemical nature of hormones?
Be able to list, with examples, the different chemical types of hormones.
3. How does the hormone epinephrine deliver its message, and what is its
major mode of action?
Be able to outline the sequence of events in epinephrine’s action as a hormone.
4. What are neurotransmitters, and how do they function?
Be able to describe the origins, pathways, and actions of neurotransmitters.
5. How does acetylcholine deliver its message, and how do drugs alter its
function?
Be able to outline the sequence of events in acetylcholine’s action as a
neurotransmitter and give examples of its agonists and antagonists.
6. Which neurotransmitters and what kinds of drugs play roles in allergies,
mental depression, drug addiction, and pain?
Be able to identify neurotransmitters and drugs active in these conditions.
7. What are neurotransmitters, and how do they function?
Be able to explain the general roles of ethnobotany, chemical synthesis,
combinatorial chemistry, and computer-aided design in the development of new
drugs.
28.1 Messenger Molecules
• Coordination and control of vital functions
are accomplished by chemical messengers.
• Hormones that arrive via the bloodstream or
neurotransmitters released by nerve cells
ultimately connect with a target.
• The message is delivered by interaction
between the chemical messenger and a
receptor.
• The receptor acts like a switch, causing
some biochemical response to occur.
28.1 Messenger Molecules
• Non-covalent
attractions draw
messengers and
receptors together
long enough for the
message to be
delivered, but
without any
permanent chemical
change to the
messenger or the
receptor.
28.1 Messenger Molecules
• Hormones are the chemical messengers of the
endocrine system, and are produced by glands
and tissues often at distances far from their
ultimate site of action.
• Hormones travel through the bloodstream to their
targets and the responses they produce can
require anywhere from seconds to hours to
begin, but action or actions they elicit, however,
may last a long time and can be wide-ranging.
• A single hormone will often affect many different
tissues and organs—any cell with the appropriate
receptors is a target.
28.1 Messenger Molecules
• Insulin is a hormone secreted by the pancreas
in response to elevated blood glucose levels.
• At target cells throughout the body, insulin
accelerates uptake and utilization of glucose.
• In muscles, it accelerates formation of
glycogen, a glucose polymer that is
metabolized when muscles need quick
energy.
• In fatty tissue, it stimulates storage of
triacylglycerols.
28.1 Messenger Molecules
• The chemical messengers of the nervous
system are neurotransmitters.
• The electrical signals of the nervous system
travel along nerve fibers, taking only a fraction
of a second to reach their highly specific
destinations.
• Most nerve cells do not make direct contact with
the cells they stimulate. A neurotransmitter must
carry the message across the tiny gap
separating the nerve cell from its target.
28.1 Messenger Molecules
• Because neurotransmitters are released in
very short bursts and are quickly broken
down or reabsorbed by the nerve cell, their
effects are short-lived.
• The nervous system is organized so that
nearly all of its vital switching, integrative,
and information-processing functions
depend on neurotransmitters.
• Neurotransmitters are typically synthesized
and released very close to their site of
action.
28.1 Messenger Molecules
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Homeostasis
Homeostasis is as important to the study of living things as atomic structure
is to the study of chemistry.
Conditions such as body temperature, the availability of chemical compounds
that supply energy, and the disposal of waste products must remain within
specific limits for an organism to function properly.
Sensors track the internal environment and send signals to restore proper
balance if the environment changes. If oxygen is in short supply, a signal is
sent that makes us breathe harder. When we are cold, a signal is sent to
constrict surface blood vessels and prevent further loss of heat.
At the chemical level, the concentrations of ions and many different organic
compounds are maintained so they stay near normal levels.
The predictability of the concentrations of such substances is the basis for
clinical chemistry—the chemical analysis of body tissues and fluids.
In the clinical lab, various tests measure concentrations of significant ions
and compounds in blood, urine, feces, spinal fluid, or other samples from a
patient’s body. Comparing the lab results with “norms” (average
concentration ranges in a population of healthy individuals) shows which
body systems are struggling, or possibly failing, to maintain homeostasis.
28.2 Hormones and the Endocrine System
• The endocrine system includes all cells
that secrete hormones into the
bloodstream.
• Some are found in organs that also have
non-endocrine functions; others occur in
glands devoted solely to hormonal control.
• Hormones do NOT carry out chemical
reactions. Hormones are simply
messengers that alter the biochemistry of
a cell.
28.2 Hormones and the Endocrine System
• The major endocrine glands are the thyroid
gland, the adrenal glands, the ovaries and
testes, and the pituitary gland.
• The hypothalamus, a section of the brain just
above the pituitary gland, is in charge of the
endocrine system. It 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.
28.2 Hormones and the Endocrine System
– 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
still other hormones by their own target tissues.
28.2 Hormones and the Endocrine System
• Hormones are of three major types: (1) amino acid
derivatives; (2) polypeptides, which range from just a few
amino acids to several hundred amino acids; and (3)
steroids, which are lipids with the distinctive molecular
structure based on four connected rings common to all
sterols.
28.2 Hormones and the Endocrine System
28.2 Hormones and the Endocrine System
• Upon arrival at its target cell, a hormone must
deliver its signal to create a chemical response
inside the cell.
• The steroid hormones are nonpolar, so they can
enter the cell directly by diffusion.
• Once within the cell’s cytoplasm, a steroid
hormone encounters a receptor molecule that
carries it to its target, DNA in the nucleus of the
cell.
• The result is some change in production of a
protein governed by a particular gene.
28.2 Hormones and the Endocrine System
28.2 Hormones and the Endocrine System
• Polypeptide and amine hormones cannot cross
the hydrophobic cell membranes.
• They deliver their messages by bonding
noncovalently with receptors on cell surfaces.
The result is release of a second messenger.
• In general, three membrane-bound proteins
participate in release of the second messenger:
• Interaction of the hormone with its receptor
causes a change in the receptor.
• This stimulates the G protein to activate an
enzyme that participates in release of the
second messenger.
28.3 How Hormones Work:
Epinephrine and Fight or Flight
• The main function of epinephrine in a
“startle” reaction is a dramatic increase in
the availability of. The time elapsed from
initial stimulus to glucose release into the
bloodstream is only a few seconds.
28.3 How Hormones Work:
Epinephrine and Fight or Flight
• Epinephrine acts via cyclic adenosine
monophosphate (cyclic AMP, or cAMP), an
important second messenger. The sequence of
events in this action, illustrates one type of
biochemical response to a change in an
individual’s external or internal environment.
28.3 How Hormones Work:
Epinephrine and Fight or Flight
• Epinephrine binds to a receptor on the surface of a cell.
• The hormone–receptor complex activates a nearby G protein
embedded in the interior surface of the cell membrane.
• GDP (guanosine diphosphate) associated with the G protein is
converted to GTP (guanosine triphosphate) by addition of a
phosphate group.
• The G protein–GTP complex activates adenylate cyclase, an
enzyme that also is embedded in the interior surface of the cell
membrane.
• Adenylate cyclase catalyzes production within the cell of the second
messenger—cyclic AMP—from ATP.
• Cyclic AMP initiates reactions that activate glycogen phosphorylase,
the enzyme responsible for release of glucose from storage.
• When the emergency has passed, cyclic AMP is converted to ATP.
28.3 How Hormones Work:
Epinephrine and Fight or Flight
28.3 How Hormones Work:
Epinephrine and Fight or Flight
• Epinephrine also increases blood pressure, heart rate,
and respiratory rate. It also decreases blood flow to the
digestive system and counteracts spasms in the
respiratory system.
• The resulting effects make epinephrine the most crucial
drug for treatment of anaphylactic shock.
• Anaphylactic shock is the result of a severe allergic
reaction; it is an extremely serious medical emergency.
• The major symptoms include a severe drop in blood
pressure due to blood vessel dilation and difficulty
breathing due to bronchial constriction. Epinephrine
directly counters these symptoms.
28.4 Amino Acid Derivatives and
Polypeptides as Hormones
• Several amino acid derivatives classified as
hormones because of their roles in the
endocrine system are also synthesized in
neurons and function as neurotransmitters in the
brain.
28.4 Amino Acid Derivatives and
Polypeptides as Hormones
• Thyroxine is one of two iodine-containing
hormones produced by the thyroid gland.
• Thyroxine is a nonpolar compound that
can cross cell membranes and enter cells,
where it activates the synthesis of various
enzymes.
• When dietary iodine is insufficient, the
thyroid gland compensates by enlarging. A
greatly enlarged thyroid gland (a goiter) is
a symptom of iodine deficiency.
28.4 Amino Acid Derivatives and
Polypeptides as Hormones
• In developed countries where iodine is added to
table salt, goiter is uncommon.
• In some regions of the world, iodine deficiency is
a common and serious problem that results in
goiter and severe mental retardation in infants
(cretinism).
28.4 Amino Acid Derivatives and
Polypeptides as Hormones
Polypeptides
• Polypeptides are the largest class of hormones.
• They range widely in molecular size and
complexity.
28.5 Steroid Hormones
• Sterol hormones, referred to as steroids, are
divided according to function into three types:
mineralocorticoids and glucocorticoids and the
sex hormones.
• The two most important androgens, are
testosterone and androsterone.
28.5 Steroid Hormones
• Estrone and estradiol, the estrogens, are
synthesized from testosterone.
• The progestins, principally progesterone, are
released by the ovaries during the second half of
the menstrual cycle.
28.5 Steroid Hormones
• Anabolic steroids are drugs that resemble
androgenic (male) hormones, such as
testosterone.
• Many serious side effects can arise from
abuse of anabolic steroids.
• Today, most organized sports have
banned the use of these and other
“performance enhancing” drugs.
• Despite bans, the use of “roids” is
widespread in sports.
28.5 Steroid Hormones
• Some athletes attempt to
get around drug
screenings by using
designer steroids—
identification depends on
knowing the compound’s
structure.
• Analysis of a synthetic
steroid to determine its
structure is easily done,
and tests can be quickly
developed.
28.5 Steroid Hormones
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Plant Hormones
Plants do not have endocrine systems or fluids that continuously circulate.
Phhytohormones affect the cells in which they are synthesized.
They may also reach nearby cells by diffusion or travel upward with water from the
roots or downward with sugars made by photosynthesis in the leaves.
A very simple alkene, ethylene gas, functions as a hormone in plants. At one time,
citrus growers ripened oranges in rooms heated with kerosene stoves. When the
stoves were replaced with other means of heating, the oranges no longer ripened. It
turned out that ripening is hastened by the ethylene released by burning kerosene.
Plants turn toward the sun, a phenomenon known as phototropism.
Charles Darwin observed that covering the growing tips of the plants prevented
phototropism. The explanation lies in the formation in the tip of an auxin, a hormone
that travels downward and stimulates elongation of the stem. Auxin concentrates on
the shady side of the stem, causing it to grow faster so that the stem bends toward
the sun.
Auxin is produced in seed embryos, young leaves, and growing tips of plants.
Interestingly, plants synthesize auxin from tryptophan, the starting compound in the
synthesis of several mammalian chemical messengers.
An excessive concentration of auxin kills plants by overaccelerating their growth. The
most familiar synthetic auxin, 2,4-D, is an herbicide that is widely used to kill broadleaved weeds in this manner.
28.6 Neurotransmitters
• Neurotransmitters are the chemical
messengers of the nervous system.
• They are released by neurons and
transmit signals to neighboring target cells.
• The target cells can be
– other nerve cells,
– muscle cells, or
– endocrine cells.
28.6 Neurotransmitters
• Nerve cells that rely on neurotransmitters
typically have a bulb-like body connected
to a long, thin stem called an axon.
• Short, tentacle-like appendages,
dendrites, protrude from the bulbous end
of the neuron, and filaments protrude from
the axon at the opposite end.
• The filaments lie close to the target cell,
separated only by a narrow gap—the
synapse.
28.6 Neurotransmitters
28.6 Neurotransmitters
• A nerve impulse is transmitted along a nerve
cell by variations in electrical potential.
• Chemical transmission of the impulse between
a nerve cell and its target occurs when
neurotransmitter molecules are released from
a presynaptic neuron, cross the synapse, and
bind to receptors on the target cell.
• 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.
28.6 Neurotransmitters
• Neurotransmitter molecules are synthesized in
the presynaptic neurons and stored in vesicles,
from which they are released as needed.
• After a neurotransmitter has done its job, it must
be rapidly removed from the synaptic cleft so
that the postsynaptic neuron is ready to receive
another impulse.
• Either 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.
28.6 Neurotransmitters
• Most neurotransmitters are amines synthesized
from amino acids.
28.7 How Neurotransmitters Work:
Acetylcholine, Its Agonists and Antagonists
• Acetylcholine is a neurotransmitter
responsible for the control of skeletal
muscles.
• It is also widely distributed in the brain.
• Nerves that rely on acetylcholine as their
neurotransmitter are classified as
cholinergic nerves.
• Acetylcholine is synthesized in presynaptic
neurons and stored in their vesicles.
28.7 How Neurotransmitters Work:
Acetylcholine, Its Agonists and Antagonists
28.7 How Neurotransmitters Work:
Acetylcholine, Its Agonists and Antagonists
• A nerve impulse arrives at the presynaptic neuron.
• The vesicles move to the cell membrane, fuse with it, and
release their acetylcholine molecules.
• Acetylcholine crosses the synapse and binds to receptors
on the postsynaptic neuron, causing a change in
membrane permeability to ions.
• The resulting change initiates the nerve impulse in that
neuron.
• With the message delivered, acetylcholinesterase present
in the synaptic cleft catalyzes the decomposition of
acetylcholine.
• Choline is absorbed back into the presynaptic neuron
where new acetylcholine is synthesized.
28.7 How Neurotransmitters Work:
Acetylcholine, Its Agonists and Antagonists
Drugs and Acetylcholine
• Many drugs act at acetylcholine synapses.
• The action is at the molecular level, and it can
be either therapeutic or poisonous.
• Pharmacologists classify some drugs as
agonists, while others are antagonists.
• Many agonists and antagonists compete with
normal signaling molecules for interaction with
the receptor.
28.7 How Neurotransmitters Work:
Acetylcholine, Its Agonists and Antagonists
Botulinus toxin blocks acetylcholine release and causes
botulism.
• The toxin binds irreversibly to the presynaptic neuron,
preventing acetylcholine release and causing death due to
muscle paralysis.
Black widow spider venom releases excess acetylcholine.
• The synapse is flooded with acetylcholine, resulting in muscle
cramps and spasms.
Organophosphorus insecticides (antagonists), inhibit
acetylcholinesterase.
• All of the organophosphorus insecticides prevent
acetylcholinesterase from breaking down acetylcholine within
the synapse.
28.7 How Neurotransmitters Work:
Acetylcholine, Its Agonists and Antagonists
Nicotine binds to acetylcholine receptors.
• Nicotine at low doses is a stimulant (an agonist) because it activates
acetylcholine receptors. The sense of alertness and well-being
produced by inhaling tobacco smoke is a result of this effect. At high
doses, nicotine is an antagonist.
Atropine (an antagonist), competes with acetylcholine at
receptors.
• Atropine can be used for acceleration of abnormally slow heart rate,
paralysis of eye muscles during surgery, and relaxation of intestinal
muscles in gastrointestinal disorders. Most importantly, it is a
specific antidote for acetylcholinesterase poisons.
Tubocurarine (an antagonist), competes with acetylcholine at
receptors.
• The alkaloid is used to paralyze patients in conjunction with
anesthesia drugs prior to surgery.
28.8 Histamine and Antihistamines
• Histamine is the neurotransmitter
responsible for the symptoms of allergic
reaction.
• Histamine is produced by decarboxylation
of histidine.
• Antihistamines are histamine receptor
antagonists.
• Histamine also activates secretion of acid
in the stomach.
28.9 Serotonin, Norepinephrine and Dopamine
The Monoamines and Therapeutic Drugs
• Serotonin, norepinephrine, and dopamine are
monoamines.
• All are active in the brain and all have been
identified in various ways with mood, the
experiences of fear and pleasure, mental
illness, and drug addiction.
• There is a well-established relationship
between major depression and a deficiency
of serotonin, norepinephrine, and dopamine.
28.9 Serotonin, Norepinephrine and Dopamine
• Amitriptyline is representative of the tricyclic antidepressants,
which prevent the re-uptake of serotonin and norepinephrine
from within the synapse.
• Phenelzine is a monoamine oxidase (MAO) inhibitor, one of a
group of medications that inhibit the enzyme that breaks down
monoamine neurotransmitters.
• Fluoxetine represents the newest class of antidepressants,
the selective serotonin re-uptake inhibitors (SSRI). They
inhibit only the re-uptake of serotonin. Most antidepressants
cause unpleasant side effects; fluoxetine does not.
28.9 Serotonin, Norepinephrine and Dopamine
Dopamine and Drug Addiction
• Dopamine plays a role in the brain in processes that
control movement, emotional responses, and the
experiences of pleasure and pain.
• Cocaine blocks re-uptake of dopamine from the
synapse, and amphetamines accelerate release of
dopamine. Studies have linked increased brain levels of
dopamine to alcohol and nicotine addiction as well. The
stimulation of dopamine receptors by drugs results in
tolerance, which contributes to addiction.
• Marijuana also creates an increase in dopamine levels.
The use of marijuana medically for chronic pain relief
has become a controversial topic in recent years, as
questions about its benefits and drawbacks are debated.
28.10 Neuropeptides and Pain Relief
• Studies of opium derivatives revealed that
these pain-killing substances act via specific
brain receptors.
• The pentapeptides Met-enkephalin and Leuenkephalin exert morphine-like suppression of
pain. Structural similarity between Metenkephalin and morphine make it likely that
both interact with the same receptors.
• Natural pain-killing polypeptides that act via the
opiate receptors are classified as endorphins.
28.11 Drug Discovery and Drug Design
• Today ethnobotanists work in remote regions
of the world to learn what indigenous people
have discovered about the healing powers of
plants.
• The technique of modifying a known structure
to improve its biochemical activity was
developed after cocaine was first used as a
local anesthetic in 1884. Experiments with
other benzoic acid esters in the early 1900s
yielded benzocaine and procaine
(novocaine), both still in use.
28.11 Drug Discovery and Drug Design
• Combinatorial chemistry, arrived on the scene in
1991. By combining reactants, dividing up the
products, adding other reactants, and continuing
this process, millions of related compounds can
be synthesized.
• If the tertiary structure of an enzyme has been
found and the active site identified, a computer
can consult a database of quantitative
information about drug–receptor interactions.
• Once potential inhibitors are identified, it is
increasingly possible to design a molecule with
just the right chemical and physical properties.
Chapter Summary
1. What are hormones, and how do they
function?
• Hormones are the chemical messengers of the
endocrine system.
• Under control of the hypothalamus they are
released from various locations, many in
response to intermediate, regulatory
hormones.
• Hormones travel in the bloodstream to target
cells, where they connect with receptors that
initiate chemical changes within cells.
Chapter Summary, Continued
2. What is the chemical nature of hormones?
• Hormones are polypeptides, steroids, or amino acid
derivatives.
• Many are polypeptides, which range widely in size and
include small molecules such as vasopressin and
oxytocin, larger ones like insulin, and all of the regulatory
hormones.
• Steroids have a distinctive four-ring structure and are
classified as lipids because they are hydrophobic. All of
the sex hormones are steroids.
• Hormones that are amino acid derivatives are
synthesized from amino acids.
• Epinephrine and norepinephrine act as hormones
throughout the body and also act as neurotransmitters in
the brain.
Chapter Summary, Continued
3. How does the hormone epinephrine deliver
its message, and what is its mode of
action?
• Epinephrine, the fight-or-flight hormone, acts
via a cell-surface receptor and a G protein that
connects with an enzyme, both of which are
embedded in the cell membrane.
• The enzyme adenylate cyclase transfers the
message to a second messenger, a cyclic
adenosine mono-phosphate (cyclic AMP),
which acts within the target cell.
Chapter Summary, Continued
4. What are neurotransmitters, and how do they
function?
• Neurotransmitters are synthesized in presynaptic
neurons and stored there in vesicles from which
they are released when needed.
• They travel across a synaptic cleft to receptors on
adjacent target cells.
• Some act directly via their receptors; others utilize
cyclic AMP or other second messengers.
• After their message is delivered, neurotransmitters
must be broken down rapidly or taken back into
the presynaptic neuron so that the receptor is free
to receive further messages.
Chapter Summary, Continued
5. How does acetylcholine deliver its message, and how
do drugs alter its function?
• Acetylcholine is released from the vesicles of a
presynaptic neuron and connects with receptors that
initiate continuation of a nerve impulse in the postsynaptic
neuron.
• It is then broken down in the synaptic cleft by
acetylcholinesterase to form choline that is returned to
the presynaptic neuron where it is converted back to
acetylcholine.
• Agonists, such as nicotine at low doses activate
acetylcholine receptors and are stimulants.
• Antagonists, such as tubocurarine or atropine, which
block activation of the receptors, are toxic in high doses,
but at low doses are useful as muscle relaxants.
Chapter Summary, Continued
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Which neurotransmitters and what kinds of drugs play roles
in allergies, mental depression, drug addiction, and pain?
Histamine, an amino acid derivative, causes allergic symptoms.
Antihistamines are antagonists with a general structure that
resembles histamines, but with bulky groups at one end.
Monoamines (serotonin, norepinephrine, and dopamine) are brain
neurotransmitters. A deficiency of any of these molecules is
associated with mental depression.
Drugs that increase their activity include tricyclic antidepressants
(for example, amitriptyline), monoamine oxidase (MAO) inhibitors
(for example, phenelzine), and selective serotonin re-uptake
inhibitors (SSRI) (for example, fluoxetine).
An increase of dopamine activity in the brain is associated with
the effects of most addictive substances. A group of
neuropeptides acts at opiate receptors to counteract pain; all may
be addictive.
Chapter Summary, Continued
7. What are some of the methods used in drug
discovery and design?
• Ethnobotanists work to identify the medicinal
products of plants known to native peoples.
• Chemical synthesis is used to improve on the
medicinal properties of known compounds by
creating similar structures.
• Combinatorial chemistry produces many
related molecules for drug screening.
• Computer design is used to select the precise
molecular structure to fit a given receptor.