2. 4 main systems of metabolism regulation:
• Central nervous system (by transmitting signals via nerve
impulses and neurotransmitters);
• Endocrine system (with the help of hormones that are
synthesized in the glands and transported to target cells);
• Paracrine and autocrine systems (with the participation of
signaling molecules secreted from cells into the intercellular
space - eicosanoids, histamines, gastrointestinal hormones,
cytokines);
• The immune system (by using specific proteins – antibodies,
T-receptors, proteins of the major histocompatibility
complex.)
• All levels of regulation are integrated and act as a single unit.
2
3. 3
Regulative systems form 3 hierarchical levels
The first level is CNS. Nerve cells receive signals
from the external and internal environment,
convert them into the nerve impulse and transmit
them through synapses using chemical signals -
mediators. Mediators cause changes in metabolism
in effector cells.
The second level is the endocrine system. It
includes the hypothalamus, pituitary and peripheral
endocrine glands (or individual cells) that synthesize
hormones and release them into the blood when
the corresponding stimulus is applied.
The third level is intracellular. The metabolic
products, histohormons and substrate influence on
metabolic cellular processes and provoke:
• changes in enzyme activity by activation or
inhibition;
• changes in the number of enzymes by the
mechanism of induction or repression of protein
synthesis or changes in the rate of their destruction.
mediators
4. Classical hormones have some characteristics
• Distance of action – synthesis in the endocrine glands,
and regulation of distant tissues
• Selectivity of action
• Strict specificity of action
• Short time of action
• They act in very low concentrations under CNS control
• Regulation of their action is carried out in most cases
by negative feedback
• They act indirectly through protein receptors and
enzymatic systems
4
5. Classification of hormones:
• According the place of biosynthesis (anterior
pituitary, adrenal glands…)
• Chemical structure
• Solubility (hydrophobic, hydrophilic)
• Functions:
–Catabolic, anabolic
–Hypoglycemic, hyperglycemic
–Lipolitic, lipogenetic
5
6. Classification of hormones according to chemical
nature
1. Protein-peptide hormones are divided into:
A - hormones oligopeptides and peptides (vasopressin, oxytocin -
9, glucagon - 29, calcitonin – 32 amino acid residues);
B - hormones simple proteins (insulin, GH)
C - hormones - complex proteins, more often glycoproteins (FSH,
LH, etc.).
2. Derivatives of amino acids: catecholamines
(epinephrine and norepinephrine), thyroxin,
triiodthyronin, hormones of epiphysis.
3. Steroid (derivatives of cholesterol): hormones of the
cortex of adrenal glands, sex hormones, calcitriol.
4. Derivatives of polyunsaturated fatty (arachidonic)
acids: prostaglandins, prostacyclins, leucotriens,
tromboxans.
6
7. Hormonal secretion is regulated by:
• Nervous impulse
• Concentration of the certain compound in blood passing
through the endocrine gland
Transport of hormones in blood:
Protein and peptide nature – in free state.
Steroid hormones and thyroid hormones – bound with
alpha-globulins or albumins.
Catechol amines – in free state or bound with albumins,
sulphates or glucuronic acid.
Reach the target organs;
Cells have the specific receptors to certain hormone.
8. Localization of hormonal receptors
For hydrophilic hormones, the membrane is not permeable and information is
transmitted to the cell through membrane receptors specific to each hormone.
• There are 3 types of hydrophilic hormone receptors:
1. receptors are allosteric enzymes, their contact site for hormone is located on the
outer membrane, and the active center is on the inner side of the membrane.
Many of them are tyrosine protein kinases (i.e. they activate phosphorylation of
tyrosine residues in a number of cytoplasmic proteins). Insulin receptors,
cytokines and some other hormones belong to this type.
2. receptors of the second type are oligomeric membrane proteins, from which an
ion "channel" is formed. The binding of the hormone leads to the opening of a
channel for a number of ions (Na+, K+ or Cl-). These receptors are used with
neurotransmitters (acetylcholine, γ-aminobutyric acid).
3. receptors of the third type transmit signals using secondary messengers: c-AMP,
c-GMP, Ca++, inositol-3-phosphate, diglycerol, nitrogen monoxide. The hormone
is attached to a specific receptor on the outside of the membrane and activates
the formation or releasing of second messengers inside the cell. This is the type
of working of catecholamines, glucagon, and other hormones of a protein nature
act. These mechanisms are realized through:
– Adenylate cyclase system
– Guanylate cyclase system
– Inositol phosphate system
8
9. Hormonal effects on cell
Early effects Later effects
Types of
receptors
Cell-surface receptors Internal (nucleic)
receptors
Mechanism of
action
Adenylate cyclase, guanylate
cyclase, inositol phosphate,
insulin-receptor
Perform the gene
expression, activate DNA
gene, synthesis m-RNA,
activate ribosomes and
process of translation.
Result Generation of second messengers
which alter the activity of other
molecules - usually enzymes -
within the cell
Alter transcriptional
activity of responsive
genes
Examples of
hormones
Protein and peptides, catechol
amines like epinephrine, and
eicosanoids such as
prostaglandins
Steroids and thyroid
hormones
9
11. Early hormonal effects
Binding of hormone to
receptor initiates series
of events which lead to
generation of second
messengers within the
cell (the hormone is the
first messenger).
The second messengers
provoke a sequence of
molecular interactions
that alter the physiologic
state of the cell. This
process is also described
as signal transduction.
11
12. Second Messengers
Second Messenger
Examples of Hormones Which Utilize This
System
Cyclic AMP
Epinephrine and norepinephrine, glucagon,
luteinizing hormone, follicle stimulating
hormone, thyroid-stimulating hormone,
calcitonin, parathyroid hormone, antidiuretic
hormone
Protein kinase activity
Insulin, growth hormone, prolactin, oxytocin,
erythropoietin, several growth factors
Calcium and/or
phosphoinositides
Epinephrine and norepinephrine, angiotensin
II, antidiuretic hormone, gonadotropin-
releasing hormone, thyroid-releasing hormone.
Cyclic GMP Atrial sodium-uretic hormone, nitric oxide
12
13. Inactivation of hormones
After biochemical effect hormones are released and
metabolized.
Hormones are inactivated mainly in liver.
Inactive metabolites are excreted mainly with urine.
Half-time life
-from several min to 20 min – for the majority of hormones
-till 1 h – for steroid hormones
-till 1 week – for thyroid hormones
13
14. 1. Change the permeability of cell membrane, accelerate the
penetration of substrates, enzymes, coenzymes into the cell
and out of cell.
2. Acting on the allosteric centers and affect the activity of
enzymes (Hormones penetrating membranes).
3. Affect the activity of enzymes through the messengers
(cAMP). (Hormones that can not penetrate the membrane).
4. Act on the genetic apparatus of the cell (nucleus, DNA) and
promote the synthesis of enzymes (Steroid and thyroid
hormones).
THE FINAL EFFECTS OF HORMONES
ACTION
14
16. • Hormone (Adrenaline) binds to β2-adrenergic receptor inserted in the
plasma membrane of liver cells. The receptor is changing its conformation
and activates the intracellular G-protein.
• Inactive G-protein consists of three subunits (α, β and γ). Inactive α-unit is
associated with the molecule GDF. After activation, GDP is replaced by GTP
and α-unit-GTP separates from G-protein.
• The α-unit-GTP reacts with the enzyme “Adenylyl cyclase” and activates it.
• Adenylyl cyclase catalyzes the conversion of ATP into c-AMP (this is a
secondary mediator of this chain of signal transmission in the cell).
• c-AMP binds to c-AMP-dependent protein kinase a (PKA). Inactive PKA
consists of four chains: 2 – catalytic and 2 – receptors. Activated one
molecule of PKA binds to 4 molecules of c-AMP.
• Activated PKA is divided into four parts, two of which have no catalytic
activity (receptors). Each of the catalytic subunits capable to phosphorylate
(activate) the enzyme – kinase phosphorylase.
• Finally, the process of glycogenolysis is started and glucose-1-phosphate
enters the blood.
Adenylate cyclase mechanism
16
17. • Activation of the receptor by the signal molecule stimulates the functioning
of Gi-protein according to the same rules as for Gs-protein. But interaction
of αi-GTP subunit with adenylate cyclase, the activity of the enzyme
decreases.
• When α-GTP interacts with adenylate cyclase and begins to show
enzymatic (GTP-phosphatase) activity and hydrolyzes GTP. Formed GDP
molecule stays in the active center of the α-subunit, changes its
conformation, and reduces its affinity for AC.
• The complex of AC and α-GDP dissociates, and α-GDP is included in the G-
protein. Separation of α-GDP from adenylate cyclase inactivates the
enzyme and c-AMP synthesis stops.
• Phosphodiesterase - the "anchored" enzyme of the cytoplasmic
membrane hydrolyzes formed c-AMP molecule to AMP. Decreasing the
concentration of c-AMP in the cell causes the cleavage of c-AMP and
increases the affinity of the R - and C-subunits, form inactive PKA.
17
Adenylate cyclase mechanism
19. • Hormone (Adrenaline, vasopressin, angiotensin II)
binds to their receptors inserted in the plasma
membrane of liver cells. The receptor is changing its
conformation and activates the intracellular G-protein.
• Inactive G-protein consists of three subunits (α, β and
γ). Inactive α-unit is associated with the molecule GDF.
After activation, GDP is replaced by GTP and α-unit-
GTP separates from G-protein.
• Activated α-unit-GTP stimulates phospholipase C (PLC),
which hydrolyses phospholipid – phosphatidylinositol
phosphate (PIP) to two second messengers – inositol-
3-phosphate (IP3) and diacylglycerol (DAG).
Inositol-phosphate mechanism or phospholipase-
calcium system
19
20. • IP3 opens calcium channels in the endoplasmic reticulum and
provokes the increasing of the concentration of Ca2+ ions.
• The accumulation of Ca2+ in the cytoplasm causes activation of
certain calcium-binding proteins (e.g., calmodulin). 4 Ca-
calmodulin complex activates some enzyme reaction in
cytoplasm.
• DAG together with Ca2+ ions activate protein kinase C.
• Protein kinase C phosphorylates a number of enzymes and
involves in the processes of cell proliferation.
• Hydrolysis PIP2 ongoing for some time, until the decreasing of
concentration of GTP. After this the α-unit-GTP is inactivated and
loses its influence on phospholipase C, and comes back to the β -
and γ-subunits. Everything returns to its original position.
20
Inositol-phosphate mechanism or
phospholipase-calcium system
22. • There are four varieties of guanylate cyclase: three of which are associated
with the membrane, the fourth – cytosolic.
• Membrane-bound forms are called guanylate cyclase receptors and at the
same time they provide catalytic activity. The cytosolic enzyme is a dimer
and contains the gem in its composition.
• One of the hormones to membrane guanylate cyclase is atriopeptin (atrial
natriuretic peptide), the cytosolic enzyme is activated by nitric oxide (NO).
•
• Activated guanylate cyclase (all types) hydrolyses GTP to c-GMP (the
secondary messenger), which activates protein kinase G, which
phosphorylates certain proteins which change the activity of cells.
• Used in cardiology drugs nitrates (nitroglycerin, isosorbide dinitrate) form
the nitric oxide into the cell, which activates cytosolic guanylate cyclase in
the presence of Ca2+ ions and calmodulin (protein). Formed c-GMP
stimulates Ca2+-ase of sarcoplasmic reticulum, which leads to the pumping
of calcium from sarcoplasm and relaxes the smooth muscle cells.
Guanylate cyclase mechanism
22
23. Each β-unit includes 10-12
residues of tyrosine.
ATP is the source of phosphate
only for first thyrosines of each
β-unit. This activation provokes
the autophosphorilation of
all thyrosines. 23
Insulin receptor (insulin-dependent tyrosine kinase)
24. • The insulin receptor consists of two a - and two β-subunits.
• a-subunits are located on the outer surface of the cell membrane and have the
binding center for insulin, β-subunits penetrate the membrane bilayer.
• The each cytosolic part of the β-subunits has 10-12 tyrosine residues, which can be
phosphorylated and dephosphorylated.
• The reaction with insulin activates a-subunits, and then β-Subunits, which has
tyrosine kinase activity and catalyze transautophosphorylation (the first β-subunit
phosphorylates the second β-subunit, and Vice versa) for several tyrosine residues
(Tyrosine-PK).
• Tyrosine-PK phosphorylates certain cellular proteins that are involved in the
activation of phosphorylation reactions:
• phosphoprotein phosphatase, which dephosphorylates specific phosphoproteins;
• phosphodiesterase, which converts c-AMP to AMP and c-GMP to GMP;
• GLUT 4 - glucose transporter in insulin-dependent tissues, so increases the flow of
glucose to muscle cells and adipose tissue;
• tyrosine protein phosphatase, which dephosphorylates the β-subunits of the insulin
receptor;
• regulatory core proteins, transcription factors that increase or decrease gene
expression of certain enzymes.
24
Insulin receptor (insulin-dependent tyrosine kinase)
25. MAPK (mitogen-activated protein kinase)
• group of Serine/Threonine Kinases
• Activated in response to a various extracellular stimuli
• Mediate signal transduction from the cell surface to the nucleus
• Control cell growth, division, morphology, survival.
• Regulate cancer, inflammation, cardiovascular diseases.
25
(MAPK kinase
kinase inactive)
(MAPK kinase
kinase active)
extracellular signal-
regulated kinase
26. Neuroendocrine regulation
• Neuroendocrinology is the study of the interaction between the
nervous system and the endocrine system, including the
biological features of the cells involved, and how they
communicate.
• The nervous and endocrine systems often act together in a
process called neuroendocrine integration, to regulate the
physiological processes of the human body.
• Neuroendocrinology arose from the recognition that the brain,
especially the hypothalamus, controls secretion of pituitary gland
hormones, and has subsequently expanded to investigate
numerous interconnections of the endocrine and nervous
systems.
26
30. Secretion of Posterior pituitary
• Hormones synthesized in the
hypothalamus are transported down the
axons to the endings in the posterior
pituitary
• Hormones are stored in vesicles in the
posterior pituitary until release into the
circulation
Main hormones are
• Oxytocin
– Target = smooth ms. Uterus and Breast
– Function = labor and delivery, milk
ejection
• ADH (Vasopressin)
– Target = kidneys
– Function = water reabsorption 30
38. Regulation of phosphorus-calcium metabolism
Calcium
The adult body contains 1.2 kg of calcium.
The bones contain 99% of the total amount of calcium:
– 85%- calcium phosphate,
– 10%- calcium carbonate
– 5%- calcium citrate and calcium lactate.
The blood contains 2.25-2.75 mmol/l of calcium:
50%- ionized calcium,
40%- calcium bound to protein,
10%- calcium salts.
Daily requirement: 1.3-1.4 g of calcium.
During pregnancy and lactation - 2 g/day.
Food sources: milk, cheese, fish, nuts, beans, vegetables.
38
39. Calcium absorption
• occurs in the small intestine with the participation of calcitriol.
• It depends on the ratio of phosphorus and calcium in food.
• The optimal ratio for absorption is 1:1-1.5 is found in milk.
• To absorption of calcium help:
– vitamin D,
– zinc,
– bile acids,
– citrate.
• Fatty acids inhibit the absorption of calcium.
39
40. Biological role of calcium
• in bone and dental tissue calcium is found in the form of
hydroxyapatite CA10(PO4)6(OH)2,
• secondary messenger in the transmission of regulatory signals,
• affects heart activity,
• factor of the blood clotting system,
• participates in the processes of neuromuscular excitability,
• activator of enzymes (lipases, protein kinases),
• affects the permeability of cell membranes.
40
41. Phosphorus
• The adult body contains 1 kg of phosphorus.
• 90% of phosphorus is found in bone tissue:
– as calcium phosphate (2/3)
– soluble compounds (1/3).
• 8-9% - inside cells,
• 1% in extracellular fluid.
• Blood contains 0.6 - 1.2 mmol/l of phosphorus (3-4 times more in
children) in the form of: ions, phospholipids, nucleic acids, esters.
• The daily requirement is -2 g of phosphorus.
• Food sources: sea fish, milk, eggs, nuts, cereals.
• Biological role of phosphorus: it Is a part of bone tissue,
phospholipids, phosphoproteins, coenzymes, nucleic acids, esters,
buffer plasma systems and tissue fluid.
41
42. Regulation of phosphorus-calcium metabolism
• Parathormone
• Calcitonin
• Vitamin D:
– 1,25 dihydroxycalciferol
– 24,25 dihydroxycalciferol
• Other hormones also affect calcium metabolism, the
processes of growth and renewal of bone tissue:
glucocorticoids, growth hormone, sex and thyroid
hormones.
• Target organs: bone, intestines, kidneys.
42
43. Vitamin D
The vitamin D enters into the body:
– with food (with animal products: animal fats, cod liver, fish caviar,
egg yolk; in less extent, women's and cow's milk, butter) – 10%.
– the formation from 7-dehydrocholesterol in the skin under the
influence of ultraviolet (UV) rays – 90%.
First stage of activation: received from the gastrointestinal tract or
formed in the skin, vitamin D is transported to the liver, where, under
the influence of the enzyme 25-hydroxylase, it is converted into 25-
hydroxycholecalciferol or calcidiol, which is the main form of circulating
vitamin D in the blood.
43
44. Active forms of vitamin D
• Decreasing Ca level and inorganic phosphate in the blood or increasing PTH secretion,
the activity of renal α1-hydroxylase and the synthesis of 1,25-dihydroxycalciferol
sharply increase:
– In the intestine: stimulates the absorption of Ca and equivalent amounts of
inorganic phosphates.
– In the kidneys: activates reabsorption of Ca and inorganic phosphates.
– Causes demineralization of cartilage and bone apatites.
– Immunomodulating effect, activates phagocytosis and production of interferons,
synthesis of interleukins 1 and 2.
– Enhances the synthesis of collagen
• At normal and elevated levels of Ca and phosphorus in plasma another kidney enzyme,
24 – hydroxylase, is activated, and 24,25-dihydroxycalciferol is synthesized: it promotes
the deposition of Ca and phosphorus in bone tissue and suppresses the secretion of
PTH.
– In the intestine: blocks the absorption of Ca and inorganic phosphates.
– In the kidneys: reduces the reabsorption of Ca and inorganic phosphates.
– Causes mineralization of cartilage and bone apatites.
– Regulates the activity of Krebs cycle enzymes, increases the synthesis of citric acid,
and citrates are part of bone tissue 44
45. Regulation of phosphorus-calcium metabolism
• Neuroendocrine regulation of calcium-phosphorus
metabolism is carried out through the secretion of PTH.
• Decreasing concentration of ionized CA associated with
vitamin D deficiency is a signal to increase the production
of PTH. Under the influence of PTH, the Ca of bone
apatites passes into a soluble form and restores the level
of ionized Ca.
• Calcitonin (CT) is antagonist of PTH: under its influence,
the content of ionized CA in the blood serum decreases,
and the processes of bone mineralization increase.
45
