What are Secondary Intermediaries? List the secondary messengers, give examples of receptors that transmit an intracellular signal with their help. Signal cascades

I. Penetration of steroid (C) into the cell

II. Formation of the CP complex

All P steroid hormones are globular proteins of approximately the same size, binding hormones with very high affinity

III. The transformation of CP into a form capable of binding with nuclear acceptors [CP]

Any cell contains all the genetic information. However, with cell specialization most of DNA is deprived of the opportunity to be a template for mRNA synthesis. It does this by folding histones around the proteins, which leads to obstruction of transcription. In this regard, the genetic material of the cell can be divided into DNA of 3 types:

1.transcriptionally inactive

2.constantly expressed

3. Induced by hormones or other signaling molecules.

IV. Binding of [CP] to the chromatin acceptor

It should be noted that this stage of action C has not been fully studied and has a number of controversial points. It is believed that [CP] interacts with specific regions of DNA so that it allows RNA polymerase to come into contact with specific DNA domains.

Interesting is the experience that showed that the half-life of mRNA increases with hormone stimulation. This leads to many contradictions: it becomes unclear ¾ an increase in the amount of mRNA indicates that [CP] increases the rate of transcription or increases the half-life of mRNA; at the same time, an increase in the half-life of mRNA is explained by the presence of a large number of ribosomes in a hormone-stimulated cell, which stabilize mRNA, or by another action [SR] unknown to us at the moment.

V. Selective initiation of transcription of specific mRNA; coordinated synthesis of tRNA and rRNA

It can be assumed that the main effect of [SR] is the loosening of condensed chromatin, which leads to the opening of access to it for RNA polymerase molecules. An increase in the amount of mRNA leads to an increase in the synthesis of tRNA and rRNA.

Vi.Primary RNA processing

Vii.Transport of mRNA into the cytoplasm

VIII.Protein synthesis

IX.Post-translational protein modification

However, studies show that this is the main, but not the only possible mechanism of action of hormones. For example, androgens and estrogens cause an increase in cAMP in some cells, suggesting that there are also membrane receptors for steroid hormones. This shows that steroid hormones act on some sensitive cells as water-soluble hormones.

Secondary intermediaries

Peptide hormones, amines and neurotransmitters, unlike steroids, are hydrophilic compounds and cannot easily penetrate the plasma membrane of a cell. Therefore, they interact with membrane receptors located on the cell surface. The hormone-receptor interaction initiates a highly coordinated biological response, in which many cellular components can participate, some of which are located at a considerable distance from the plasma membrane.

cAMP is the first compound, which Sutherland, who discovered it, called the “second mediator”, because he considered the “first mediator” itself to be the hormone that causes the intracellular synthesis of the “second mediator”, which mediates the biological effect of the first.

Today, at least 3 types of secondary mediators can be named: 1) cyclic nucleotides (cAMP and cGMP); 2) Ca ions; and 3) phosphatidylinositol metabolites.

With the help of such systems, a small number of hormone molecules, binding to receptors, causes the production of much more molecules of the second mediator, and the latter, in turn, affect the activity of an even larger number of protein molecules. Thus, there is a progressive amplification of the signal that initially arises when the hormone binds to the receptor.

TSAMF

Simplified, the action of the hormone through cAMP can be represented as follows:

1.hormone + stereospecific receptor

2.activation of adenylate cyclase

3.cAMP formation

4.Ensuring a coordinated cAMP response

Hormone Environment

Receptor Membrane

5'-cAMP 3 ', 5'-cAMP ATP

Inactive protein kinase

Phosphodiesterase

Active protein kinase

Dephosphoprotein Phosphoprotein

Phosphoprotein Phosphatase

Biological effect

Fig 1

1. It should be noted that receptors are also dynamic structures. This means that their number can either decrease or increase. For example, people with increased body weight decrease the number of insulin receptors. Experiments have shown that when their mass is normalized, an increase in the number of receptors to a normal level is observed. In other words, with an increase or decrease in insulin concentration, there are reciprocal changes in the concentration of receptors. It is believed that this phenomenon can protect the cell from too intense stimulation when inadequately high level hormone.

2. Activation of adenylate cyclase (A) is also a regulated process. Previously, it was believed that the hormone (G), binding to the receptor (P), changes its conformation, which leads to the activation of A. However, it turned out that A is an allosteric enzyme that is activated by the action of GTP. GTP is transported by a special protein (transducer) G. In this regard, a model was adopted that describes not only the activation of A, but also the termination of this process

a) G + R + G GDF ® G R G + GDF

b) G R G + GTP ® G + R + G GTP

c) G · GTP + A ® cAMP + G · HDF

Thus, GTP hydrolysis serves as a signal “turning off” the system. To resume the cycle, HDF must detach from G, which occurs when the hormone binds to P.

Several factors have an inhibitory effect on A and cause a decrease in the concentration of cAMP. Examples of cyclase-stimulating agonists include glucagon, ADH, LH, FSH, TSH, and ACTH. Cyclase inhibitory factors include opioids, somatostatin, angiotensin II, and acetylcholine. Epinephrine can both stimulate (via b-receptors) and inhibit (via a-receptors) this enzyme. The question arises how the bidirectional regulation of A is carried out. It turned out that the inhibitory system includes a three-dimensional protein that is extremely similar to the above G-protein. The Gi effect can be described as follows:

a) G + R + Gi * GDF ® G * R * Gi + GDF

b) Г · Р · Gi + GTP ® Г + R + Gi · GTP

c) Gi · GTP + A ® ¯cAMP + Gi · GDF

After phosphorylation of enzyme proteins in the course of the above described reactions (see Fig. 1), their conformation changes. Consequently, the conformation of their active center also changes, which leads to their activation or inhibition. It turns out that due to the secondary messenger cAMP, the action of enzymes specific to it is activated or inhibited in the cell, which causes a certain biological effect inherent for this cell. In this regard, despite the large number of enzymes that act through the secondary messenger cAMP, a certain, specific response occurs in the cell.

Messengers - low molecular weight substances that carry hormone signals inside the cell. They have a high speed of movement, cleavage or removal (Ca 2+, cAMP, cGMP, DAG, ITP).

Disruptions in the exchange of instant messengers lead to serious consequences. For example, phorbol esters, which are analogs of DAG, but unlike which they are not cleaved in the body, contribute to the development of malignant tumors.

cAMP discovered by Sutherland in the 50s of the last century. For this discovery, he received the Nobel Prize. cAMP is involved in the mobilization of energy reserves (the breakdown of carbohydrates in the liver or triglycerides in fat cells), in water retention by the kidneys, in the normalization of calcium metabolism, in increasing the strength and heart rate, in the formation of steroid hormones, in relaxing smooth muscles, and so on.

cGMP activates PK G, PDE, Ca 2+ -ATPase, closes Ca 2+ -channels and reduces the level of Ca 2+ in the cytoplasm.

Enzymes

Enzymes of cascade systems catalyze:

• the formation of secondary mediators of the hormonal signal;
• activation and inhibition of other enzymes;
• transformation of substrates into products;

Adenylate cyclase (AC)

A glycoprotein weighing from 120 to 150 kDa, has 8 isoforms, the key enzyme of the adenylate cyclase system, with Mg 2+ catalyzes the formation of a secondary messenger cAMP from ATP.

AC contains 2 -SH groups, one for interaction with the G-protein, the other for catalysis. AC contains several allosteric centers: for Mg 2+, Mn 2+, Ca 2+, adenosine and forskolin.

Found in all cells, located on the inner side of the cell membrane. AC activity is controlled by: 1) extracellular regulators - hormones, eicosanoids, biogenic amines through G-proteins; 2) an intracellular regulator of Ca 2+ (4 Ca 2+ -dependent isoforms of AC are activated by Ca 2+).

Protein kinase A (PK A)

PK A is present in all cells, catalyzes the phosphorylation reaction of OH-groups of serine and threonine of regulatory proteins and enzymes, participates in the adenylate cyclase system, stimulates cAMP. PC A consists of 4 subunits: 2 regulatory R (weight 38000 Da) and 2 catalytic FROM (weight 49000 Da). Regulatory subunits have 2 cAMP binding sites. The tetramer has no catalytic activity. The addition of 4 cAMP to 2 R subunits leads to a change in their conformation and dissociation of the tetramer. This releases 2 active catalytic C subunits, which catalyze the phosphorylation reaction of regulatory proteins and enzymes, which changes their activity.

Protein kinase C (PK C)

PC C is involved in the inositol triphosphate system, stimulated by Ca 2+, DAG and phosphatidylserine. Has a regulatory and catalytic domain. PC C catalyzes the phosphorylation reaction of protein-enzymes.

Protein kinase G (PK G)there is only in the lungs, cerebellum, smooth muscles and platelets, is involved in the guanylate cyclase system. PK G contains 2 subunits, stimulated by cGMP, catalyzes the phosphorylation of enzyme proteins.

Phospholipase C (PL C)

It hydrolyzes the phosphoester bond in phosphatidylinositols with the formation of DAG and IF 3, has 10 isoforms. PL C is regulated through G-proteins and is activated by Ca 2+.

Phosphodiesterase (PDE)

PDE converts cAMP and cGMP into AMP and GMP, inactivating the adenylate cyclase and guanylate cyclase systems. PDE is activated by Ca 2+, 4Ca 2+ -calmodulin, cGMP.

NO synthase Is a complex enzyme that is a dimer, to each of the subunits of which several cofactors are attached. NO synthase has isoforms.

Most cells of the human and animal body are capable of synthesizing and secreting NO, however, three cell populations are the most studied: the endothelium of blood vessels, neurons, and macrophages. By the type of synthesizing tissue, NO synthase has 3 main isoforms: neuronal, macrophage and endothelial (designated as NO synthase I, II, and III, respectively).

Neuronal and endothelial isoforms of NO-synthase are constantly present in cells in small amounts, and synthesize NO in physiological concentrations. They are activated by the complex calmodulin-4Ca 2+.

Normally, NO synthase II is absent in macrophages. When macrophages are exposed to microbial lipopolysaccharides or cytokines, they synthesize a huge amount of NO synthase II (100-1000 times more than NO synthase I and III), which produces NO in toxic concentrations. Glucocorticoids (hydrocortisone, cortisol), known for their anti-inflammatory activity, inhibit the expression of NO synthase in cells.

Action NO

NO is a low-molecular gas, easily penetrates through cell membranes and components of the intercellular substance, has a high reactivity, its half-life is on average no more than 5 s, the distance of possible diffusion is small, on average 30 microns.

At physiological concentrations, NO has a powerful vasodilator effect.:

· The endothelium constantly produces small amounts of NO.

· Under various influences - mechanical (for example, with increased current or blood pulsation), chemical (lipopolysaccharides of bacteria, cytokines of lymphocytes and platelets, etc.) - the synthesis of NO in endothelial cells increases significantly.

· NO from the endothelium diffuses to neighboring smooth muscle cells of the vessel wall, activates guanylate cyclase in them, which synthesizes cGMP through 5s.

· CGMP leads to a decrease in the level of calcium ions in the cytosol of cells and a weakening of the connection between myosin and actin, which allows the cells to relax after 10 s.

The drug nitroglycerin works on this principle. When nitroglycerin breaks down, NO is formed, which leads to vasodilation of the heart and relieves the feeling of pain as a result.

NO regulates the lumen of cerebral vessels. The activation of neurons in any area of \u200b\u200bthe brain leads to the excitation of neurons containing NO synthase and / or astrocytes, in which NO synthesis can also be induced, and the gas released from the cells leads to local vasodilation in the excitation area.

NO participates in the development septic shock, when a large number of microorganisms circulating in the blood sharply activate the synthesis of NO in the endothelium, which leads to a long and strong expansion of small blood vessels and, as a consequence, a significant decrease in blood pressuredifficult to treat therapeutically.

In physiological concentrations, NO improves the rheological properties of blood:

NO produced in the endothelium prevents the adhesion of leukocytes and platelets to the endothelium and also reduces the aggregation of the latter.

NO can act as an anti-growth factor that prevents the proliferation of smooth muscle cells of the vascular wall, an important link in the pathogenesis of atherosclerosis.

In high concentrations, NO has a cytostatic and cytolytic effect on cells (bacterial, cancer, etc.) as follows:

· When NO interacts with the radical superoxide anion, peroxynitrite (ONOO-) is formed, which is a strong toxic oxidant;

NO strongly binds to the heminic group of iron-containing enzymes and inhibits them (inhibition of mitochondrial oxidative phosphorylation enzymes blocks aTP synthesis, inhibition of DNA replication enzymes contributes to the accumulation of damage in DNA).

· NO and peroxynitrite can directly damage DNA, this leads to the activation of defense mechanisms, in particular the stimulation of the enzyme poly (ADP-ribose) synthetase, which further reduces the level of ATP and can lead to cell death (through apoptosis).

Similar information.

The systems of secondary mediators of hormone action are:

1. Adenylate cyclase and cyclic AMP,

2. Guanylate cyclase and cyclic HMP,

3. Phospholipase C:

Diacylglycerol (DAG),

Inositol-tri-fsfate (IF3),

4. Ionized Ca - calmodulin

Heterothromic protein G-protein.

This protein forms loops in the membrane and has 7 segments. They are compared to serpentine ribbons. Has a protruding (outer) and inner parts. A hormone is attached to the outer part, and on the inner surface there are 3 subunits - alpha, beta and gamma. In an inactive state, this protein contains guanosine diphosphate. But when activated, guanosine diphosphate changes to guanosine triphosphate. A change in the activity of the G-protein leads either to a change in the ionic permeability of the membrane, or the enzyme system (adenylate cyclase, guanylate cyclase, phospholipase C) is activated in the cell. This causes the formation of specific proteins, protein kinase is activated (necessary for phospholylation processes).

G-proteins can be activating (Gs) and inhibitory, or in other words, inhibitory (Gi).

The destruction of cyclic AMP occurs under the action of the enzyme phosphodiesterase. Cyclic GMF has the opposite effect. When phospholipase C is activated, substances are formed that contribute to the accumulation of ionized calcium inside the cell. Calcium activates protein cinases, promotes muscle contraction. Diacylglycerol promotes the conversion of membrane phospholipids into arachidonic acid, which is the source of the formation of prostaglandins and leukotrienes.

The hormone-receptor complex penetrates the nucleus and acts on DNA, which changes the processes of transcription and mRNA is formed, which leaves the nucleus and goes to the ribosomes.

Therefore, hormones can have:

1. Kinetic or triggering action,

2. Metabolic action,

3. Morphogenetic action (tissue differentiation, growth, metamorphosis),

4. Corrective action (correcting, adapting).

Mechanisms of action of hormones in cells:

Changes in the permeability of cell membranes,

Activation or inhibition of enzyme systems,

Impact on genetic information.

Regulation is based on the close interaction of the endocrine and nervous systems. Excitation processes in the nervous system can activate or inhibit activity endocrine glands... (Consider, for example, the process of ovulation in a rabbit. Ovulation in a rabbit occurs only after the act of mating, which stimulates the release of gonadotropic hormone from the pituitary gland. The latter causes the process of ovulation).

After suffering mental trauma, thyrotoxicosis may occur. Nervous system controls the release of pituitary hormones (neurohormones), and the pituitary gland affects the activity of other glands.

Feedback mechanisms are in place. The accumulation of the hormone in the body leads to inhibition of the production of this hormone by the corresponding gland, and the deficiency will be a mechanism for stimulating the formation of the hormone.

There is a self-regulation mechanism. (For example, blood glucose determines the production of insulin and / or glucagon; if sugar levels rise, insulin is produced, and if sugar levels go down, glucagon is produced. Na deficiency stimulates aldosterone production).

5. The hypothalamic-pituitary system. Its functional organization. The neurosecretory cells of the hypothalamus. Characteristics of tropic hormones and releasing hormones (liberins, statins). Epiphysis (pineal gland).

6. Adenohypophysis, its connection with the hypothalamus. The nature of the action of the hormones of the anterior pituitary gland. Hypo- and hypersecretion of hormones of the adenohypophysis. Age changes the formation of hormones of the anterior lobe.

The cells of the adenohypophysis (see their structure and composition in the course of histology) produce the following hormones: somatotropin (growth hormone), prolactin, thyrotropin (thyroid stimulating hormone), follicle-stimulating hormone, luteinizing hormone, corticotropin (ACTH), melanotropin, beta-endorphin peptide exophthalmic factor and ovarian growth hormone. Let's consider in more detail the effects of some of them.

Corticotropin ... (adrenocorticotropic hormone - ACTH) is secreted by the adenohypophysis in continuously pulsating flashes with a clear daily rhythm. The secretion of corticotropin is regulated by direct and feedback loops. A direct connection is represented by a hypothalamic peptide - corticoliberin, which enhances the synthesis and secretion of corticotropin. Feedback are triggered by the content of cortisol in the blood (a hormone of the adrenal cortex) and are closed both at the level of the hypothalamus and the adenohypophysis, and an increase in the concentration of cortisol inhibits the secretion of corticoliberin and corticotropin.

Corticotropin has two types of action - adrenal and extra-adrenal. The adrenal action is the main one and consists in stimulating the secretion of glucocorticoids, to a much lesser extent - mineralocorticoids and androgens. The hormone enhances the synthesis of hormones in the adrenal cortex - steroidogenesis and protein synthesis, leading to hypertrophy and hyperplasia of the adrenal cortex. The extra-adrenal action is lipolysis of adipose tissue, increased insulin secretion, hypoglycemia, increased deposition of melanin with hyperpigmentation.

An excess of corticotropin is accompanied by the development of hypercortisolism with a predominant increase in the secretion of cortisol and is called "Itsenko-Cushing's disease." The main manifestations are typical for an excess of glucocorticoids: obesity and other metabolic changes, a decrease in the effectiveness of immunity mechanisms, the development of arterial hypertension and the possibility of diabetes. Corticotropin deficiency causes insufficiency of glucocorticoid function of the adrenal glands with pronounced metabolic changes, as well as a decrease in the body's resistance to adverse environmental conditions.

Somatotropin. . Growth hormone possesses wide range metabolic effects providing morphogenetic action. The hormone affects protein metabolism, enhancing anabolic processes. It stimulates the entry of amino acids into cells, protein synthesis by accelerating translation and activating RNA synthesis, increases cell division and tissue growth, and inhibits proteolytic enzymes. Stimulates the inclusion of sulfate in cartilage, thymidine in DNA, proline in collagen, uridine in RNA. The hormone induces a positive nitrogen balance. Stimulates the growth of epiphyseal cartilage and its replacement bone tissueby activating alkaline phosphatase.

The effect on carbohydrate metabolism is twofold. On the one hand, growth hormone increases insulin production both due to a direct effect on beta cells and due to hormone-induced hyperglycemia due to the breakdown of glycogen in the liver and muscles. Growth hormone activates liver insulinase, an enzyme that breaks down insulin. On the other hand, somatotropin has a contrainsular effect, inhibiting the utilization of glucose in tissues. The specified combination of effects in the presence of a predisposition in conditions of excessive secretion can cause diabetes, called pituitary by origin.

The effect on fat metabolism is to stimulate lipolysis of adipose tissue and the lipolytic effect of catecholamines, increase the level of free fatty acids in the blood; due to their excessive intake in the liver and oxidation, the formation of ketone bodies increases. These effects of growth hormone are also referred to as diabetogenic.

If an excess of the hormone occurs in early age, gigantism is formed with proportional development of the limbs and trunk. An excess of the hormone in adolescence and adulthood causes an increase in the growth of the epiphyseal areas of the bones of the skeleton, zones with incomplete ossification, which is called acromegaly. ... Internal organs also increase in size - splanchomegaly.

With congenital hormone deficiency, dwarfism is formed, which is called "pituitary dwarfism". After the publication of J. Swift's novel about Gulliver, such people are colloquially called midgets. In other cases, the acquired hormone deficiency causes a mild growth retardation.

Prolactin ... The secretion of prolactin is regulated by hypothalamic peptides - an inhibitor of prolactinostatin and a stimulant prolactoliberin. The production of hypothalamic neuropeptides is under dopaminergic control. The amount of prolactin secretion is influenced by the level of estrogens, glucocorticoids in the blood

and thyroid hormones.

Prolactin specifically stimulates breast development and lactation, but not its secretion, which is stimulated by oxytocin.

In addition to the mammary glands, prolactin has an effect on the sex glands, helping to maintain the secretory activity of the corpus luteum and the formation of progesterone. Prolactin is a regulator of water-salt metabolism, reducing the excretion of water and electrolytes, potentiates the effects of vasopressin and aldosterone, stimulates growth internal organs, erythropoiesis, contributes to the manifestation of the instinct of motherhood. In addition to enhancing protein synthesis, it increases the formation of fat from carbohydrates, contributing to postpartum obesity.

Melanotropin . ... Formed in the cells of the intermediate lobe of the pituitary gland. Melanotropin production is regulated by hypothalamic melanoliberin. The main effect of the hormone is to act on the melanocytes of the skin, where it causes a depression of pigment in the processes, an increase in free pigment in the epidermis surrounding melanocytes, and an increase in melanin synthesis. Increases skin and hair pigmentation.

The neurohypophysis, its connection with the hypothalamus. Effects of hormones of the posterior lobe of the pituitary gland (oxygocin, ADH). The role of ADH in the regulation of fluid volume in the body. Diabetes insipidus.

Vasopressin . ... It is formed in the cells of the supraoptic and paraventricular nuclei of the hypothalamus and accumulates in the neurohypophysis. The main stimuli that regulate the synthesis of vasopressin in the hypothalamus and its secretion into the blood by the pituitary gland can generally be called osmotic. They are represented by: a) increased osmotic pressure of blood plasma and stimulation of vascular osmoreceptors and neurons-osmoreceptors of the hypothalamus; b) an increase in the sodium content in the blood and stimulation of hypothalamic neurons, which act as sodium receptors; c) a decrease in the central volume of circulating blood and blood pressure, perceived by the volumoreceptors of the heart and mechanoreceptors of the vessels;

d) emotional pain stress and physical activity; e) activation of the renin-angiotensin system and stimulating neurosecretory neurons by the influence of angiotensin.

The effects of vasopressin are realized due to the binding of the hormone in tissues with two types of receptors. Binding to Y1-type receptors, mainly localized in the wall of blood vessels, through the secondary messengers inositol triphosphate and calcium, causes vascular spasm, which contributes to the name of the hormone - "vasopressin". Binding to Y2-type receptors in the distal nephron through the secondary mediator c-AMP provides an increase in the permeability of the collecting ducts of the nephron for water, its reabsorption and urine concentration, which corresponds to the second name of vasopressin - "antidiuretic hormone, ADH".

In addition to the effect on the kidney and blood vessels, vasopressin is one of the important brain neuropeptides involved in the formation of thirst and drinking behavior, memory mechanisms, and regulation of the secretion of adenohypophyseal hormones.

Lack or even complete absence of vasopressin secretion is manifested in the form of a sharp increase in diuresis with the release of a large amount of hypotonic urine. This syndrome has received the name " diabetes insipidus ", it can be congenital or acquired. Syndrome of excess vasopressin (Parkhon's syndrome) is manifested

in excessive fluid retention in the body.

Oxytocin . The synthesis of oxytocin in the paraventricular nuclei of the hypothalamus and its release into the blood from the neurohypophysis is stimulated by a reflex route upon irritation of the stretch receptors of the cervix and mammary gland receptors. Estrogens increase the secretion of oxytocin.

Oxytocin causes the following effects: a) stimulates the contraction of the smooth muscles of the uterus, facilitating childbirth; b) causes a contraction of smooth muscle cells of the excretory ducts of the lactating mammary gland, ensuring the release of milk c) has a diuretic and natriuretic effect under certain conditions; d) participates in the organization of drinking and eating behavior; e) is an additional factor in the regulation of the secretion of adenohypophyseal hormones.

The hormone molecule is usually called the primary mediator of the regulatory effect, or ligand. The molecules of most hormones bind to their specific receptors in the plasma membranes of target cells, forming a ligand-receptor complex. For peptide, protein hormones and catecholamines, its formation is the main initial link in the mechanism of action and leads to the activation of membrane enzymes and the formation of various secondary mediators of the hormonal regulatory effect, which realize their action in the cytoplasm, organelles and the cell nucleus. Among the enzymes activated by the ligand-receptor complex, the following are described: adenylate cyclase, guanylate cyclase, phospholipase C, D and A2, tyrosine kinase, phosphattyrosine phosphatase, phosphoinositide-3-OH-kinase, serine-threonine-N-kinase and other synthase. formed under the influence of these membrane enzymes are: 1) cyclic adenosine monophosphate (cAMP); 2) cyclic guanosine monophosphate (cGMP); 3) inositol-3-phosphate (IPZ); 4) diacylglycerol; 5) oligo (A) (2,5-oligoisoadenylate); 6) Ca2 + (ionized calcium); 7) phosphatidic acid; 8) cyclic adenosine diphosphate ribose; 9) NO (nitric oxide). Many hormones, forming ligand-receptor complexes, simultaneously activate several membrane enzymes and, accordingly, secondary mediators.

Mechanisms of action of peptide, protein hormones and catecholamines. Ligand. A significant part of hormones and biologically active substances interact with a family of receptors associated with G-proteins of the plasma membrane (andrenaline, norepinephrine, adenosine, angiotensin, endothelium, etc.).

The main systems of secondary intermediaries.

Adenylate cyclase - cAMP system... The membrane enzyme adenylate cyclase can be in two forms - activated and non-activated. Activation of adenylate cyclase occurs under the influence of a hormone-receptor complex, the formation of which leads to the binding of a guanyl nucleotide (GTP) with a special regulatory stimulating protein (GS-protein), after which the GS-protein causes the addition of Mg to adenylate cyclase and its activation. This is how hormones that activate adenylate cyclase - glucagon, thyrotropin, parathyrin, vasopressin (via V-2 receptors), gonadotropin, etc. act. A number of hormones, on the contrary, inhibit adenylate cyclase - somatostatin, angiotensin-II, etc. Hormone receptor complexes interact in these hormones the cell membrane with another regulatory inhibitory protein (GI protein), which causes hydrolysis of guanosine triphosphate (GTP) to guanosine diphosphate (HDP) and, accordingly, suppression of the activity of adenylate cyclase. Adrenaline activates adenylate cyclase through β-adrenergic receptors, and suppresses it through alpha1-adrenergic receptors, which largely determines the differences in the effects of stimulation of different types of receptors. Under the influence of adenylate cyclase, cAMP is synthesized from ATP, which causes the activation of two types of protein kinases in the cytoplasm of the cell, leading to the phosphorylation of numerous intracellular proteins. This increases or decreases the permeability of membranes, the activity and the amount of enzymes, i.e., it causes metabolic and, accordingly, functional changes in the vital activity of the cell, typical for the hormone. Table 6.2 shows the main effects of activation of cAMP-dependent protein kinases.

The transmethylase system provides methylation of DNA, all types of RNA, chromatin and membrane proteins, a number of hormones at the tissue level, and membrane phospholipids. This contributes to the implementation of many hormonal influences on the processes of proliferation, differentiation, the state of membrane permeability and the properties of their ion channels, and, which is important to emphasize, affects the availability of membrane receptor proteins to hormone molecules. The termination of the hormonal effect realized through the adenylate cyclase - cAMP system is carried out with the help of a special enzyme phosphodiesterase cAMP, which causes hydrolysis of this secondary mediator with the formation of adenosine-5-monophosphate. However, this hydrolysis product is converted in the cell to adenosine, which also has the effects of a secondary messenger, since it suppresses methylation processes in the cell.

Guanylate cyclase-cGMP system. Activation of membrane guanylate cyclase occurs not under the direct influence of the hormone-receptor complex, but indirectly through ionized calcium and oxidant membrane systems. The stimulation of guanylate cyclase activity, which determines the effects of acetylcholine, is also carried out indirectly through Ca2 +. Through the activation of guanylate cyclase, the effect is also realized on the atrial triuretic hormone - atriopeptide. By activating peroxidation, it stimulates guanylate cyclase, the endothelial hormone of the vascular wall, nitric oxide, a relaxing endothelial factor. Under the influence of guanylate cyclase, cGMP is synthesized from GTP, which activates cGMP-dependent protein kinases, which reduce the rate of phosphorylation of myosin light chains in the smooth muscles of the vascular walls, leading to their relaxation. In most tissues, the biochemical and physiological effects of cAMP and cGMP are opposite. Examples include stimulation of cardiac contractions under the influence of cAMP and inhibition of their cGMP, stimulation of intestinal smooth muscle contraction with cGMP, and suppression of cAMP. cGMP provides hyperpolarization of the retinal receptors under the influence of light photons. Enzymatic hydrolysis of cGMP, and hence the cessation of the hormonal effect, is carried out using a specific phosphodiesterase.

System phospholipase C - inositol-3-phosphate. The hormone-receptor complex with the participation of the regulatory G-protein leads to the activation of the membrane enzyme phospholipase C, which causes hydrolysis of membrane phospholipids with the formation of two secondary mediators: inositol-3-phosphate and diacylglycerol. Inositol-3-phosphate causes the release of Ca2 + from intracellular stores, mainly from the endoplasmic reticulum, ionized calcium binds to a specialized protein calmodulin, which activates protein kinases and phosphorylation of intracellular structural proteins and enzymes. In turn, diacylglycerol contributes to a sharp increase in the affinity of protein kinase C for ionized calcium, the latter activates it without the participation of calmodulin, which also ends with the processes of protein phosphorylation. Diacylglycerol simultaneously implements another way of mediating the hormonal effect by activating phospholipase A-2. Under the influence of the latter of the membrane phospholipids, arachidonic acid is formed, which is a source of substances powerful in metabolic and physiological effects - prostaglandins and leukotrienes. In different cells of the body, one or the other way of formation of secondary mediators prevails, which ultimately determines physiological effect hormone. Through the considered system of secondary mediators, the effects of adrenaline (in connection with the alpha-adrenergic receptor), vasopressin (in connection with the V-1 receptor), angiotensin-I, somatostatin, oxytocin are realized.

Calcium-calmodulin system... Ionized calcium enters the cell after the formation of a hormone-receptor complex either from the extracellular environment due to the activation of slow calcium channels of the membrane (as happens, for example, in the myocardium), or from intracellular stores under the influence of inositol-3-phosphate. In the cytoplasm of non-muscle cells, calcium binds to a special protein, calmodulin, and in muscle cells, the role of calmodulin is played by troponin C. Calmodulin bound to calcium changes its spatial organization and activates numerous protein kinases that provide phosphorylation, and therefore change the structure and properties of proteins. In addition, the calcium-calmodulin complex activates cAMP phosphodiesterase, which suppresses the effect of the cyclic compound as a secondary messenger. A short-term increase in calcium in the cell and its binding to calmodulin caused by a hormonal stimulus is a triggering stimulus for numerous physiological processes - muscle contraction, hormone secretion and release of mediators, DNA synthesis, changes in cell motility, transport of substances through membranes, changes in enzyme activity.

Secondary intermediary relationships Several secondary messengers are present or can form simultaneously in the cells of the body. In this regard, various relationships are established between the secondary mediators: 1) equal participation, when different mediators are necessary for a full hormonal effect; 2) one of the intermediaries is the main one, and the other only contributes to the realization of the effects of the first; 3) mediators act sequentially (for example, inositol-3-phosphate provides calcium release, diacylglycerol facilitates the interaction of calcium with protein kinase C); 4) intermediaries duplicate each other to ensure redundancy in order to ensure the reliability of regulation; 5) mediators are antagonists, i.e. one of them turns on the reaction, and the other inhibits (for example, in the smooth muscles of blood vessels inositol-3-phosphate and calcium realize their contraction, and cAMP - relaxation).