HORMONE ACTION MECHANISM
CLASS
№ 29
HORMONE
ACTION MECHANISM
1. General
characteristics of hormones: properties, types of biological action.
Classification of hormones on the chemical structure, site of formation,
mechanism of action. Target tissues and the cell receptors of hormones.
2.
Mechanisms of action of hormones binding with the membrane receptors. Second
messengers: cyclic purine nucleotides, calcium ions, products of hydrolysis of
phosphatidylinositol. Diversity of protein kinases and their role in
transmission of hormonal signal.
3. Mechanism
of action of hormones binding with the intracellular receptors.
4. Thyroid
hormones: structure, target tissues, biological effects. Hyper- and
hypoproduction of the hormones.
5.
Parathyroid hormone, calcitonin: target tissues, biological effects. Hyper- and
hypofunction of parathyroid hormone.
6.
Pancreatic hormones: insulin, glucagon. Target tissues, biological effects.
Hyper- and hypoproduction of the hormones.
7.
Adrenaline and noradrenaline: structure, target tissues, biological effects.
Hyperproduction of adrenaline.
1. General characteristics of hormones:
properties, types of biological action. Classification of hormones on the
chemical structure, site of formation, mechanism of action. Target tissues and
the cell receptors of hormones.
Hormones are
REGULATORY molecules
Hormones
-
are
produced by endocrine glands,
-
secreted
into the bloodstream, and
-
transported
via the blood to target tissues where they
-
exert
their biological action,
i.e. REGULATE: metabolism, functions, growth and cell division, development
and differentiation of cells in ontogenesis, support homeostasis (constancy of
the inner medium of the organism).
CLASSIFICATION OF HORMONES
I. On
their chemical structure:
1) polypeptide
hormones (hormones of hypophysis, hypothalamus, parathyroid glands,
insulin, glucagon);
2)
derivatives of amino acids (thyroxine,
epinephrine);
3) steroid
hormones (hormones of adrenal cortex, male and female sex hormones).
II. On the place of their synthesis:
hormones of
hypothalamus, pituitary gland, thyroid gland, parathyroid glands, pancreas,
adrenal glands (medulla and cortex), hormones of male and female sex glands,
local or tissue hormones.
III. On
their effects on biochemical processes and functions:
1. hormones regulating
metabolism of proteins, lipids and carbohydrates (insulin, glucagon,
epinephrine, hydrocortisone)
2. hormones regulating
the salt and water balance (aldosterone, vasopressin);
3. hormones regulating metabolism
of calcium and phosphorus (parathyroid hormone, calcitonin, calcitriol);
4. hormones stimulating
growth (growth hormone – GH, sex hormones, thyroid hormones, cortisol,
insulin);
5. hormones controlling
reproductive function (male and female sex hormones);
6. hormones regulating
functions of other endocrine glands (adrenocorticotropic hormone – ACTH,
thyroid stimulating hormone – TSH, follicle-stimulating hormone – FSH,
prolactin – PRL, or lactotropic hormone – LTH, luteinizing hormone – LH).
7. hormones mediating
response to stress (epinephrine, glucocorticoids);
8. hormones effecting the highest nervous activity (HNA), i.e. memory,
attention, mentation, behaviour, mood, e.g. glucocorticoids, parathyroid
hormone, thyroxine, adrenocorticotropic hormone.
PROPERTIES OF HORMONES
1. High biological activity.
-
Concentration
of hormones in the blood is extremely low (10-8 M) but their action is
very noticeable;
-
therefore
the slightest increase or decrease of hormone content in the blood can
immensely change metabolism and functions.
2. Short "life span" (ranging from a few minutes to a half an hour).
-
After
hormones exert their physiological effects, they undergo degradation or
inactivation but their action may last for hours and up to day (24 hours)
or days.
3. Distance of action.
-
Hormones
are synthesized in organs of one type (endocrine glands) and act in distant
organs of the other type (target tissues).
4. High specificity of the action.
-
Hormones
exert their action only after binding with a receptor of a hormone.
-
Receptor
represents a conjugated protein (glycoprotein), consisted of two parts –
the carbohydrate and the protein ones.
-
Hormone
is bound precisely to the carbohydrate part of the receptor.
-
The
structure of the carbohydrate part is unique, specific and, on its three-dimensional
conformation corresponds to the structure of the hormone.
-
Therefore,
the hormone is always bound to its receptor unerringly, precisely,
specifically, notwithstanding the small concentration of the hormone in the
blood.
-
Tissues
which contain receptors to the definite hormone are called target tissues.
-
Receptors
to thyroxine, glucocorticoids, or insulin are present in many tissues.
-
There
are also hormones to which receptors are present only in a few tissues
(e.g. oxitocin).
2. Mechanisms of action of hormones
binding with the membrane receptors. Second messengers: cyclic purine
nucleotides, calcium ions, products of hydrolysis of phosphatidylinositol.
Diversity of protein kinases and their role in transmission of hormonal signal.
MECHANISM OF ACTION OF POLYPEPTIDE HORMONES AND EPINEPHRINE
Receptors to
these hormones are located on the external surface of the cell membrane and the
hormone doesn't enter the cell.
The action
of the hormone is transferred into the cell due to second messengers,
e.g. such as
-
cyclic
AMP (cAMP),
-
cyclic
GMP (cGMP),
-
inositol
triphosphate,
-
diacylglicerol,
and
-
calcium
ions.
Each second
messenger stimulates specific protein kinase which phosphorylates
cell proteins (enzymes) thus altering the activity of the proteins
(enzymes)
Most hormones
act via this compound.
But other
hormones acting via their specific protein kinases are able to alter the cAMP
concentration in the cell due to the increase or decrease of the activity of
enzymes generating or degrading cAMP.
Cyclic AMP, cAMP
1. specific receptor,
2. G-protein, and
3. adenylate cyclase.
The hormone
binds to the receptor to form the hormone-receptor complex.
G-protein is
so called because of its ability to bind to guanylic nucleotides (either
GDP or GTP).
The
G-protein is active when it is bound to GTP, and vice versa, being bound to GDP
it is non-active.
The binding
of the hormone with its receptor causes consequent changes in the
three-dimensional structure of all the components of adenylate cyclase
system.
As a result,
G-protein exchanges its GDP for GTP, thus becoming active, and stimulates
adenylate cyclase which converts ATP to cAMP.
Cyclic
AMP stimulates cAMP dependent
protein kinase (protein kinase A).
Protein
kinase consists of four subunits, two of them are regulatory and two are
catalytic ones.
Four-subunit
protein kinase is not active.
After
binding four molecules of cAMP by regulatory subunits, the whole enzyme
disintegrates releasing active catalytic subunits which phosphorylate proteins
(enzymes) altering their activity or functions.
Activation of protein kinase A activity
The enzyme phosphordiesterase
cleaves cAMP to form AMP thereby decreasing intracellular level of cAMP.
Cyclic GMP …
is
synthesized from GTP as a result of guanylate cyclase activity similar to the
cAMP generation.
-
The
enzyme phosphodiesterase cleaves cGMP.
Calcium ions, Ca 2+……
Concentration
of Ca 2+ in the extracellular fluid is about 10,000 as much as
that in the cytoplasm.
Such a
content of Ca 2+ inside the cell would be lethal for it.
The cell is
pumping out the excess of Ca 2+ from the cytoplasm due to the functioning
Ca2+-ATPase located in the cell membrane.
Some
hormones can increase the cytoplasmic calcium concentration.
They open
calcium channels within the cell membrane, allowing extracellular
calcium to move into the cell or can release Ca2+ from
endoplasmic reticulum and mitochondria.
Inside the
cell, Ca2+ binds with the protein calmodulin to form calcium-calmodulin complex.
This complex
activates Ca2+calmodulin-dependent protein
kinase which catalyzes
phosphorylation of intracellular enzymes (proteins) thereby altering their
activity.
Inositol triphosphate (IP3) and diacylglycerol (DAG)
IP3 and
DAG are formed from
the membrane phospholipid called phosphatidylinositol bisphosphate (PIP2).
Some
hormones activate the membranebound enzyme phospholipase
C which cleaves PIP2 in the cell membrane to produce two second
messengers – IP3 and DAG.
Biological
effects of these second messengers are realized differently.
DAG
activates protein kinase C, which phosphorylates certain proteins, altering
their activity.
IP3 binds
with specific receptor on endoplasmic reticulum causing Ca2+ to be released
from intracellular stores (EPR) to cytoplasm.
Ca2+, either
directly or bounded to calmodulin, may interact with proteins, altering their
activity.
3. Mechanism of action of hormones
binding with the intracellular receptors.
The hormone-receptor
complex is transferred into the nucleus where it binds with DNA
and stimulates synthesis of mRNA which becomes a template for
synthesis of proteins.
Translation
of the mRNA produces proteins which are responsible for certain biological effects.)
• Peptide
hormones change the activity of enzymes,
• Steroid
hormones change the amount of enzymes.
4. Thyroid hormones: structure, target
tissues, biological effects. Hyper- and hypoproduction of the hormones.
Biochemical features of the thyroid gland.
1) The
thyroid gland (follicular cells) takes up iodine from the blood.
2) The
follicular cells contain specific protein – thyroglobulin which contains
many residues of amino acid tyrosine.
-
Iodination
of tyrosine residues within the molecule of thyroglobulin results in the
formation of monoiodotyrosine and diiodotyrosine which are then
condensed to produce T3 and T4.
Thyroid
stimulating hormone (TSH) stimulates ultimately the release of free T3 and
T4 into the blood.
In the
blood, thyroid hormones bind with transporting proteins and reach the target
tissues.
-
The
T4 concentration in the blood is 10 times as much as that of T3;
-
therefore
T4 is considered to be the major form of thyroid hormones in the blood.
-
But
T3 is 10 times as active as T4.
Target
tissues for the thyroid hormones are almost all tissues of the body excepting
for the spleen and testes.
In the
target tissues, thyroid hormones are separated from the transporting proteins
and enter the cell.
In the cell,
90% of T4 loses one atom of iodine and converts to T3.
Thus, the
major intracellular form of thyroid hormones is T3.
The action
of thyroid hormones depends on their concentration in the blood:
-
in
small (normal, physiological) concentrations of thyroid hormones exert anabolic
effect,
-
and
in high (excessive) concentrations they cause catabolic effect.
Action of normal (physiological) concentrations of thyroid hormones
The major
effects of thyroid hormones include:
1. stimulation of both nucleic acid
and protein synthesis, and
2. stimulation of energy metabolism.
1) The
increase of the nucleic acid and protein synthesis stimulates growth,
development, cell division and differentiation of all organs and tissues.
This effect
is especially important for the growing organism.
Thyroid
hormones are absolutely required for the structural, biochemical and
functional maturation of the brain.
-
It
is known that in the CNS, cells keep dividing during 1-1.5 years after
birth.
Therefore
thyroid-hormone deficiency occurred at fetal life or at early ages leads
to the decrease of protein synthesis in the whole organism, and in the brain
tissue in particular.
As a result,
the differentiation of large hemispheres and cerebellum is impaired which is
accompanied by mental and physical retardation.
Hypothyroidism in children is called cretinism.
The earlier
is the age at which the thyroid hormone deficiency appeared the more it impairs
the CNS development.
Thyroid
hormones stimulate energy metabolism, i.e. both the use and synthesis of ATP.
As these
two processes (opposite directed) are activated simultaneously, the equilibrium
is preserved between them.
The outer
sign of the equilibrium is the heat formation for maintenance of the
normal body temperature.
Thus,
thyroid hormones maintain the energy equilibrium in the organism.
Under normal
conditions, due to participation of thyroid hormones, processes of excitation
and inhibition in the brain are coordinated.
The work for
the maintenance of electrochemical gradient of sodium and potassium ion
concentrations on both sides of the cell membrane is the basis for the neuron
functioning.
That is why
the preservation of the energy equilibrium in the cell is of great importance
for the normal functioning of nervous tissue.
Both excess
and deficiency of thyroid hormones cause impairment of energy equilibrium and
electrochemical processes in the CNS, and this is accompanied by certain
symptoms of brain dysfunctions.
Effect of high concentrations of thyroxine (in
hyperthyroidism)
The action of high (excessive) concentrations of thyroid hormones
is observed in hyperthyroidism (Graves’ disease).
In hyperthyroidism, the energy balance (the balance
between production and wasting of ATP) is impaired.
High concentrations of thyroid hormones act on mitochondria where
in the inner mitochondrial membrane the electron transport chain (the
ETC) is situated.
Normally, major portion of energy produced in the ETC is
accumulated in the phosphate bonds of ATP, and the other portion of energy
is dissipated as heat for the maintenance of the normal body temperature.
The process of ATP generation from ADP and Pi as a result of
energy production in the electron transport chain is called oxidative
phosphorylation.
High concentrations of thyroid hormones uncouple the ETC and
oxidative phosphorylation.
As a result, the ETC keeps functioning, substrates are
oxidized, oxygen is consumed, and energy is generated, but because of
uncoupling the ETC and oxidative phosphorylation the
ATP is not formed, and all the energy produced is dissipated
as heat.
That is why the symptoms of hyperthyroidism include
· the enhanced body temperature
(hyperthermia, due to intensive heat generation)
· muscle weakness (because of the decreased ATP
production required for muscle contraction).
As excessive quantities of thyroid hormones exert catabolic
action, the degradation of body fuels (carbohydrate, lipid and protein
stores) is increased which results in severe body weight loss.
The other symptoms of hyperthyroidism:
1.
enlarged
thyroid gland (goitre)
2.
protruding
eyes (exophthalmos)
3.
↑
heart rate (tachycardia)
4.
↑
BP(systolic blood pressure)
5.
psychic abnormalities (nervousness, excitement, emotional lability, sleeplessness (insomnia)
6.
Due
to the increased heat production, patients with hyperthyroidism have sensation
of heat intolerance, as well as excessive perspiration which
occurs because of the need to dissipate heat through increased sweating.
Therefore the skin of patient with
hyperthyroidism is wet, reddened (hyperemic), and hot with palpation.
Hypothyroidism in adults is called myxedema.
Mucus-like substances (glycosaminoglycans) are
accumulated in subcutaneous tissues;
therefore, the common symptoms in hypothyroidism are mucoid-like
(mucous-like) swelling of tissues.
In adult patients with hypothyroidism,
the generation of ATP is decreased,
which leads to general brain disorder and psychic
aberrations, such as a sense of weakness, hypokinesis (slow to action),
fatigue, lethargy (somnolence), apathy, decreased memory, slowed mentation,
psychical inertness, the speech becomes slow and indistinct (unclear), mimics
is unexpressive.
The heat production is diminished which causes the sense of cold
intolerance and decreased sweating.
The skin is dry, pale and cool in palpation, the body
temperature is decreased.
The heart rate is slowed, and the blood pressure may be
decreased.
Obesity, hyperlipemia, hypercholesterolemia, loss of hair and
teeth are also observed.
In children hypothyroidism is called cretinism (see
above).
The special form of hypothyroidism is called endemic goitre.
-
It
appears as a result of insufficient dietary iodine supply.
-
Most
commonly, this disease occurs in the mountain regions, where the iodine content
in water and plant (and, consequently, in the diet) is low.
-
The
iodine deficiency leads to the compensatory enlargement (hypertrophy) of the
thyroidal tissue at the expense of prevalent growth of the connective tissue;
but due to the lack of iodine the enlargement of the thyroid gland is not
accompanied by the increased secretion of thyroid hormones.
5. Parathyroid hormone, calcitonin:
target tissues, biological effects. Hyper- and hypofunction of parathyroid
hormone.
PARATHYROID
GLANDS produce
parathyroid hormone (PTH).
PTH ↑ [Ca2+
] and ↓ [ phosphate ] in the blood.
The target tissues and effects of PTH:
• Bones – inhibits collagen synthesis in osteoblasts; ↑
mobilization of Ca2+ and phosphate from the bone; as a result, Ca2+ and
phosphate concentrations increase in the blood.
• Kidney – ↑ reabsorption of Ca2+ and ↓reabsorption of
phosphate.
• Intestine – ↑ absorption of Ca2+ and phosphate.
Hyperparathyroidism is observed
in tumor
of parathyroid glands(Increased secretion of parathyroid hormone)
Calcium ions
released from the bones enter the blood and result in hypercalcemia
(increased blood calcium concentration).
Chronic
hypercalcemia leads to Symptoms:
1) fractures
at minimal trauma;
2)
calcification of internal organs, hurts and bruises.
3) the
decrease of neuromuscular excitability which in turn results in
- muscle atrophy and weakness,
- psychoses,
slowed mentation, impairments of memory and attention.
4) Chronic
renal filtration of blood rich in calcium leads to saturation of the
tubular fluid with calcium salts; as a consequence, renal calculi (kidney and
urinary tract stones) may occur.
• Due to the
excess of PTH, secretion of gastrin in the stomach is increased.
-
Enhanced
gastrin secretion stimulates production of HCl and pepsin, and may lead
to stomach ulcers.
Hypoparathyroidism is observed:
1) After
operations on the thyroid gland when parathyroid glands were removed by
mistake.
2) In child,
due to infections of respiratory tract.
Deficiency
of PTH leads to the lowered levels of calcium in the blood (hypocalcemia)
which causes the increase of neuromuscular excitability.
• Symptoms:
1) tetany
(continuous muscle contraction – convulsions, cramps, involuntary twitching of
muscles)
2) spasmophilia
(crying child becomes cyanotic because of spasms of respiratory muscles).
CALCITONIN
is
synthesized in the thyroid gland.
Calcitonin ↓
Ca2+ and ↓ phosphate concentration in the blood.
The target
tissues are the same as for PTH, but the action is opposite to PTH, and only in
kidney calcitonin (as well as PTH) ↑ phosphate excretion into the urine.
Thus,
calcitonin:
· decreases release of Ca2+ and
phosphate from the bone into the blood
· decreases Ca2+ and phosphate
reabsorption by renal tubular cells;
· decreases Ca2+ epithelial cells. and
phosphate absorption by intestinal
No kinds of
pathology involving calcitonin have been described.
6. Pancreatic hormones: insulin,
glucagon. Target tissues, biological effects. Hyper- and hypoproduction of the
hormones.
Insulin is
synthesized in β-cells of the pancreas and deposited in secretory
granules bound with zinc.
The pancreas
releases insulin into the blood in response to the increased blood glucose
levels.
The target
tissues (on sensitivity to insulin):
1)
The absolutely dependent on insulin: adipose tissue and muscle.
Glucose may
enter these cells and metabolize in them only in the presence of insulin.
2) Absolutely independent
on (or insensitive to) insulin tissues.
Glucose may
enter cells of these tissues even in the absence of insulin, and glucose is the
only energy substrate for these cells.
The most
important (essential to life) functions of the organism are fulfilled by these
tissues:
- the brain
– central regulation;
- medulla of
kidney – secretion;
-
erythrocytes – oxygen and carbon dioxide exchange in the tissues;
- intestinal
epithelial cells – nutrition (absorption of products of digestion);
- testicles
– breeding.
The brain
consumes 50% of free glucose of the blood, erythrocytes and kidneys – 20%,
total 70%; thus, it is extremely important to the organism that major metabolic
glucose pool and life providing functions of the organism are independent on
insulin.
3)
Relatively dependent on insulin - all the other tissues.
The action of insulin
01. It is the only hormone which ↓ the
blood glucose level.
• Insulin ↑ membrane
permeability for glucose to enter the cell (transport of glucose into the
cell);
• Insulin ↑ glucose
utilization (glycolysis, and on glycogen synthesis);
• Insulin ↓ production
of glucose (gluconeogenesis and cleavage of glycogen).
02. It is a universal anabolic hormone:
insulin ↑ synthesis of DNA, RNA, proteins, triacylglycerols, fatty acids,
glycogen, and decreases their breakdown
Hyperinsulinemia
is observed
in insulinoma(excess of insulin) and in overdose of insulin which may
take place in the course of treatment of diabetes mellitus.
Symptoms:
hypoglycemia, cramps, loss of consciousness.
Severe
hypoglycemia may lead to death.
Hypoinsulinemia
is observed
in type I diabetes mellitus.
In type II
(insulin-independent) diabetes mellitus, the adipose and muscle tissues are
unable to take up glucose in the presence of normal amounts of insulin.
Symptoms of
diabetes mellitus:
1. Hyperglycemia
2. Glucosuria
3. The ↑ catabolism of glycogen,
proteins, fats;
4. ↓glycolysis and ↑ gluconeogenesis;
5. ↑ [ketone bodies] in the blood and
urine.
Glucagon
is formed in
α2-cells of Langerhans islets of the pancreas.
The liver
is the major target tissue for the glucagon action.
The other
target tissues include adipose tissue, kidney and the cardiac (but not
skeletal) muscle.
The maximal
amounts of glucagon are released from the islets during starvation.
This is the
main hormone which maintains the blood glucose levels.
During the
first day of starvation, glucagon increases cleavage of glycogen
(glycogenolysis) in the liver.
However the
glycogen storages appear to be completely depleted after 24 hours of
starvation.
Therefore
since the 2nd day of starvation glucagon stimulates gluconeogenesis, i.e.
synthesis of glucose form amino acids which are produced due to the protein
degradation. Unlike epinephrine, glucagon doesn’t affect muscle glycogen.
Thus, in starvation,
glucose in the blood is entirely of the liver origin.
The other
effects of glucagon in the liver are:
-
the
decrease of the glycogen synthesis,
-
inhibition of glycolysis, the increase of the ketone bodies production.
In adipose
tissue, glucagon increases lipolysis (triacylglycerol degradation)
and decreases lipogenesis (triacylglycerol synthesis).
In all
target tissues glucagon stimulates proteolysis (cleavage of protein) and
inhibits its synthesis.
In the
kidney cortex, the hormone stimulates gluconeogenesis.
The excess
of glucagon in the organism may occur in glucagonoma (glucagon-secreting tumor).
7. Adrenaline and noradrenaline:
structure, target tissues, biological effects. Hyperproduction of adrenaline.
Adrenal
medulla produces noradrenaline
(norepinephrine) and adrenaline (epinephrine) which are synthesized in
response to stress and physical exertion.
Synthesis of adrenaline
Normally adrenalin is absent in the urine.
The major degradation product excreted into the urine is vanillylmandelic acid (VMA) which is used for
diagnostics.
Degradation of adrenaline and noradrenaline
The target tissues and effects of adrenaline:
1) The liver –↑ degradation of glycogen to form
glucose, and ↑ [glucose] in the blood.
2) Muscles –↑ degradation of glycogen to form lactic acid and
↑ [lactic acid] in the blood.
3) Adipose tissue –↑ degradation of triacylglycerol to form
fatty acids and ↑ [fatty acids] in the blood.
4) Cardiovascular system –↑ BP, ↑ heartbeat, respiration
(causes tachycardia), bronchodilation and hypertension.
The hormone Narrows arterioles: in the skin and vas
afferentis of kidney, therefore, in stress, paleness and anuria are observed.
Dilates arteries in the heart, skeletal muscles and inner
organs.
Dilates bronchi and pupil of the eye, relax smooth muscles of
GIT and bladder, but contracts sphincters of GIT and bladder, muscles rising
skin hair.
Via the cardiovascular system, adrenaline affects almost all
functions of practically all organs resulting in efficient mobilization of the
organism for resisting to the stressful situations.
Pheochromocytoma (hyperproduction
of adrenaline and noradrenaline).
The
concentration of epinephrine and norepinephrine in the blood increases in 500
and more times.
The
symptoms:
•
Hypertension, tachycardia
• In the
blood – the ↑ concentration of adrenaline, glucose and fatty acids
• In the
urine – adrenaline and glucose are present (they are normally absent in the
urine), and the ↑ amount of VMA.
Comments
Post a Comment