The mechanism of action of hormones. Hormone classifications

Hormones are involved in the regulation of metabolism. in the following way. State flow internal environment body and changes associated with external influences goes to nervous system, the response signal is processed and formed there. It enters the effector organs in the form of nerve impulses along the cetrigeus nerves and indirectly through the endocrine system.

The point where the flows of nervous and endocrine information merge is the hypothalamus - here come nerve impulses from different parts of the brain. They determine the production and secretion of hypothalamic hormones, which in turn, through the pituitary gland, influence the production of hormones by the peripheral endocrine glands. The hormones of the peripheral glands, in particular the adrenal medulla, control the secretion of the hypothalamic. Ultimately, the content of the hormone in the bloodstream is maintained according to the principle of self-regulation. A high level of the hormone turns off or weakens its formation through the negative feedback mechanism, low level enhances production.

Hormones act selectively on tissues, due to the unequal sensitivity of tissues to them. Organs and cells most sensitive to influence certain hormone, commonly called the target of the hormone (target organ or target cell).

Target tissue concept. A target tissue is a tissue in which a hormone causes a specific physiological (biochemical) response. General reaction target tissues for the action of the hormone determines whole line factors. First of all, this is the local concentration of the hormone near the target tissue, which depends on:

1. the rate of synthesis and secretion of the hormone;

2. anatomical proximity of the target tissue to the source of the hormone;

3. binding constants of the hormone with a specific carrier protein (if one exists);

4. the rate of transformation of an inactive or inactive form of the hormone into an active one;

5. the rate of disappearance of the hormone from the blood as a result of decay or excretion.

The actual tissue response is determined by:

Relative activity and (or) degree of occupancy of specific receptors

The state of sensitization - desentation of the cell.

The specificity of hormones in relation to target cells is due to the presence in cells specific r-receptors.

All hormone receptors can be divided into 2 types:

1) localizedࠠon outer surface cell membrane;

2) cells located in the cytoplasm.

Receptor properties:

Clear substrate specificity;

Saturability;

Affinity for the hormone in the limit of biological concentrations of the hormone;

reversibility of action.

Depending on where in the cell information is transmitted, the following can be distinguished: variants of hormone action:

1) Membrane (local).

2) Membrane-intracellular or mediated.

3) Cytoplasmic (direct).

Membrane type action is realized at the site of binding of the hormone to the plasma membrane and consists in a selective change in its permeability. According to the mechanism of action, the hormone in this case acts as an allosteric effector. transport systems membranes. So, for example, transmembrane transfer of glucose is provided under the action of insulin, amino acids and some ions. Usually the membrane type of action is combined with membrane-intracellular.

Membrane-intracellular action hormones is characterized by the fact that the hormone does not penetrate the cell, but affects the exchange in it through an intermediary, which is, as it were, a representative of the hormone in the cell - a secondary intermediary (the primary intermediary is the hormone itself). Cyclic nucleotides (cAMP, cGMP) and calcium ions act as secondary messengers.

Regulation is a complex complex mechanism that responds to various kinds the impact of a change in metabolism and maintaining the constancy of the internal environment.

Regulation via cAMP or cGMP. The enzyme is embedded in the cytoplasmic membrane of the cell adenylate cyclase, consisting of 3 parts - recognizing(a set of receptors located on the surface of the membrane), conjugating(N-protein occupying the lipid bilayer of the membrane intermediate position between the receptor and the catalytic part) and catalytic(actually an enzymatic protein, the active center of which is turned inside the cell). The catalytic protein has separate sites for the binding of cAMP and cGMP.

The transfer of information, the source of which is the hormone, occurs as follows:

The hormone binds to the receptor;

The hormone-receptor complex interacts with the N-protein, changing its configuration;

The change in configuration results in the conversion of GDP (present in the inactive protein) to GTP;

The protein-GTP complex activates adenylate cyclase itself;

Active adenylate cyclase generates cAMP inside the cell (ATP ¾® cAMP + H 4 P 2 O 7)

Adenylate cyclase works as long as the hormone-receptor complex is preserved, so one molecule of the complex has time to form from 10 to 100 cAMP molecules.

Synthesis of cGMP is triggered in the same way, with the only difference that the hormone-receptor complex activates guanylate cyclase, which produces cGMP from GTP.

Cyclic nucleotides activate protein kinases (cAMP-dependent or cGMP-dependent);

Activated protein kinases phosphorylate various proteins at the expense of ATP;

Phosphorylation is accompanied by a change in the functional activity (activation or inhibition) of these proteins.

Cyclic nucleotides (cAMP and cGMP) act on different proteins, so the effect depends on the membrane receptor that binds the hormone. The nature of the receptor determines whether the activity of cAMP- or cGMP-dependent enzyme proteins will be changed. Often these nucleotides have opposite effects. Therefore, biochemical processes in the cell under the influence of one hormone can be activated or inhibited, depending on which receptors the cell has. For example, adrenaline can bind to b- and a-receptors. The former include adenylate cyclase and the formation of cAMP, the latter include guanylate cyclase and the formation of cGMP. Cyclic nucleotides activate different proteins, so the nature metabolic changes in the cell does not depend on the hormone, but on the receptors that the cell has.

The influence of cyclic nucleotides on metabolism is stopped by the enzymes phosphodiesterases.

Thus, the process controlled through the adenylate cyclase system depends on the ratio between the rate of production of cAMP or cGMP and the rate of their decay.

The mechanism of action of hormones, including the adenylate cyclase system, is inherent in hormones of protein and polypeptide nature, as well as catecholamines (adrenaline, norepinephrine).

The cytoplasmic mechanism of action is inherent in hormones of a steroid nature.

Steroid hormone receptors are located in the cytoplasm of the cell. These hormones (possessing lipophilic properties), penetrating into the cell, interact with receptors to form a hormone-receptor complex, which, after molecular rearrangement leading to its activation, enters the cell nucleus, where it interacts with chromatin. In this case, gene activation occurs and subsequently a chain of processes develops, accompanied by increased RNA synthesis, including informational ones. This leads to the induction of the corresponding enzymes during the translation process, which entails a change in the rate and direction of metabolic processes in the cell.

Thus, in this case, the hormonal effect is realized at the level of the genetic apparatus of the target cell.

The biological effects of hormones that affect the genetic apparatus of the cell are manifested mainly in the effect on the growth and differentiation of tissues and organs.

mixed type transmission of information is characteristic of iodothyronines(thyroid hormones), which in terms of lipophilic properties occupy an intermediate position between water-soluble and lipophilic (steroid) hormones. This group of hormones realizes its effect both by membrane-intracellular and cytosolic mechanisms.

Initially, the term "hormone" denoted chemicals that are secreted by the endocrine glands into the lymphatic or blood vessels, circulate in the blood and act on various organs and tissues located at a considerable distance from the place of their formation. However, it turned out that some of these substances (for example, norepinephrine), circulating in the blood as hormones, perform the function of a neurotransmitter (neurotransmitter), while others (somatostatin) are both hormones and neurotransmitters. In addition, certain chemicals are secreted by the endocrine glands or cells in the form of prohormones and only on the periphery are converted into biologically active hormones (testosterone, thyroxine, angiotensinogen, etc.).

hormones, in broad sense words are biologically active substances and carriers of specific information, through which communication is carried out between various cells and tissues, which is necessary for the regulation of numerous body functions. The information contained in hormones reaches its destination due to the presence of receptors that translate it into a post-receptor action (influence), accompanied by a certain biological effect.

Currently, the following options for the action of hormones are distinguished:

1) hormonal, or hemocrine, i.e. action at a considerable distance from the place of formation;

2) isocrine, or local, when a chemical synthesized in one cell has an effect on a cell located in close contact with the first, and the release of this substance is carried out into the interstitial fluid and blood;

3) neurocrine, or neuroendocrine (synaptic and non-synaptic), action, when the hormone, being released from nerve endings, performs the function of a neurotransmitter or neuromodulator, i.e. a substance that alters (usually enhances) the action of a neurotransmitter;

4) paracrine - a kind of isocrine action, but at the same time, the hormone formed in one cell enters the intercellular fluid and affects a number of cells located in close proximity;

5) juxtacrine - a kind of paracrine action, when the hormone does not enter the intercellular fluid, and the signal is transmitted through the plasma membrane of a nearby other cell;

6) autocrine action, when a hormone released from a cell affects the same cell, changing it functional activity;

7) solinocrine action, when a hormone from one cell enters the lumen of the duct and thus reaches another cell, having a specific effect on it (for example, some gastrointestinal hormones).

The synthesis of protein hormones, like other proteins, is under genetic control, and typical mammalian cells express genes that code for between 5,000 and 10,000 various proteins, and some highly differentiated cells - up to 50,000 proteins. Any protein synthesis begins with the transposition of DNA segments, followed by transcription, post-transcriptional processing, translation, post-translational processing, and modification. Many polypeptide hormones are synthesized in the form of large prohormone precursors (proinsulin, proglucagon, proopiomelanocortin, etc.). The conversion of prohormones into hormones is carried out in the Golgi apparatus.

By chemical nature, hormones are divided into protein, steroid (or lipid) and amino acid derivatives.

Protein hormones are divided into peptide hormones: ACTH, somatotropic (STH), melanocyte-stimulating (MSH), prolactin, parathyroid hormone, calcitonin, insulin, glucagon, and proteid - glucoproteins: thyrotropic (TSH), follicle-stimulating (FSH), luteinizing (LH), thyroglobulin. Hypophysiotropic hormones and hormones of the gastrointestinal tract belong to oligopeptides, or small peptides. Steroid (lipid) hormones include corticosterone, cortisol, aldosterone, progesterone, estradiol, estriol, testosterone, which are secreted by the adrenal cortex and gonads. Vitamin D sterols, calcitriol, also belong to this group. Arachidonic acid derivatives are, as already mentioned, prostaglandins and belong to the group of eicosanoids. Adrenaline and norepinephrine, synthesized in the adrenal medulla and other chromaffin cells, as well as thyroid hormones, are derivatives of the amino acid tyrosine. Protein hormones are hydrophilic and can be transported by the blood both in a free state and in a partially bound state with blood proteins. Steroid and thyroid hormones are lipophilic (hydrophobic), characterized by low solubility, most of them circulate in the blood in a protein-bound state.

Hormones carry out their biological action by complexing with receptors - informational molecules that transform a hormonal signal into a hormonal action. Most hormones interact with receptors located on the plasma membranes of cells, while other hormones interact with receptors localized intracellularly, i.e. with cytoplasmic and nuclear.

Protein hormones, growth factors, neurotransmitters, catecholamines, and prostaglandins belong to a group of hormones for which receptors are located on the plasma membranes of cells. Plasma receptors, depending on the structure, are divided into:

1) receptors, the transmembrane segment of which consists of seven fragments (loops);

2) receptors, the transmembrane segment of which consists of a single fragment (loop or chain);

3) receptors, the transmembrane segment of which consists of four fragments (loops).

Hormones whose receptor consists of seven transmembrane fragments include: ACTH, TSH, FSH, LH, chorionic gonadotropin, prostaglandins, gastrin, cholecystokinin, neuropeptide Y, neuromedin K, vasopressin, adrenaline (a-1 and 2, b-1 and 2), acetylcholine (M1, M2, M3 and M4), serotonin (1A, 1B, 1C, 2), dopamine (D1 and D2), angiotensin, substance K, substance P, or neurokinin types 1, 2 and 3, thrombin , interleukin-8, glucagon, calcitonin, secretin, somatoliberin, VIP, pituitary adenylate cyclase-activating peptide, glutamate (MG1 - MG7), adenine.

The second group includes hormones that have one transmembrane fragment: growth hormone, prolactin, insulin, somatomammotropin, or placental lactogen, IGF-1, nerve growth factors, or neurotrophins, hepatocyte growth factor, atrial natriuretic peptide types A, B and C, oncostatin, erythropoietin, ciliary neurotrophic factor, leukemic inhibitory factor, tumor necrosis factor (p75 and p55), nerve growth factor, interferons (a, b and g), epidermal growth factor, neurodifferentiating factor, fibroblast growth factors, platelet growth factors A and B, macrophage colony-stimulating factor, activin, inhibin, interleukins-2, 3, 4, 5, 6 and 7, granulocyte-macrophage colony-stimulating factor, granulocyte colony-stimulating factor, low-density lipoprotein, transferrin, IGF-2, urokinase plasminogen activator.

The hormones of the third group, the receptor of which has four transmembrane fragments, include acetylcholine (nicotinic muscle and nerve), serotonin, glycine, g-aminobutyric acid.

Membrane receptors are integral components of plasma membranes. The connection of the hormone with the corresponding receptor is characterized by high affinity, i.e. a high degree of affinity of the receptor for this hormone.

The biological effect of hormones interacting with receptors localized on the plasma membrane is carried out with the participation of a “second messenger”, or transmitter.

Depending on what substance performs its function, hormones can be divided into the following groups:

1) hormones that have a biological effect with the participation of cyclic adenosine monophosphate (cAMP);

2) hormones that carry out their action with the participation of cyclic guanidine monophosphate (cGMP);

3) hormones that mediate their action with the participation of ionized calcium or phosphatidylinositides (inositol triphosphate and diacylglycerol) or both compounds as an intracellular second messenger;

4) hormones that exert their effect by stimulating the cascade of kinases and phosphatases.

The mechanisms involved in the formation of second messengers operate through the activation of adenylate cyclase, guanylate cyclase, phospholipase C, phospholipase A2, tyrosine kinases, Ca2+ channels, etc.

Corticoliberin, somatoliberin, VIP, glucagon, vasopressin, LH, FSH, TSH, chorionic gonadotropin, ACTH, parathyroid hormone, prostaglandins type E, D and I, b-adrenergic catecholamines have a hormonal effect through receptor activation through stimulation of the adenylate cyclase - cAMP system. At the same time, another group of hormones, such as somatostatin, angiotensin II, acetylcholine (muscarinic effect), dopamine, opioids and a2-adrenergic catecholamines, inhibit the adenylate cyclase-cAMP system.

In the formation of second messengers for such hormones as gonadoliberin, thyroliberin, dopamine, A2 thromboxanes, endoperoxides, leukotrienes, aggiotensin II, endothelin, parathyroid hormone, neuropeptide Y, a1-adrenergic catecholamines, acetylcholine, bradykinin, vasopressin, the phospholipase C system, inositol triphosphate are involved , Ca2+-dependent protein kinase C. Insulin, macrophage colony-stimulating factor, platelet-derived growth factor mediate their action through tyrosine kinase, and atrial natriuretic hormone, histamine, acetylcholine, bradykinin, endothelium-derived factor, or nitric oxide, which in turn mediates the vasodilator action of bradykinin , and acetylcholine through guanylate cyclase. It should be noted that the division of hormones according to the principle of activating systems or one or another second messenger is conditional, since many hormones, after interacting with the receptor, simultaneously activate several second messengers.

Most hormones that interact with plasma receptors, having 7 transmembrane fragments, activate second messengers through binding to guanylate nucleotide proteins or G-proteins or regulatory proteins (G-proteins), which are heterotrimeric proteins consisting of a-, b-, g-subunits . More than 16 genes encoding the a-subunit, several genes for the b- and g-subunits have been identified. Different types of a-subunits have non-identical effects. So, a-s-subunit inhibits adenylate cyclase and Ca2+ channels, a-q-subunit inhibits phospholipase C, a-i-subunit inhibits adenylate cyclase and Ca2+ channels and stimulates phospholipase C, K+ channels and phosphodiesterase; the b-subunit stimulates phospholipase C, adenylate cyclase, and Ca2+ channels, while the g-subunit stimulates K+ channels, phosphodiesterase, and inhibits adenylate cyclase. The exact function of other subunits of regulatory proteins has not yet been established.

Hormones complexing with a receptor having one transmembrane fragment activate intracellular enzymes (tyrosine kinase, guanylate cyclase, serine-threonine kinase, tyrosine phosphatase). Hormones, the receptors of which have 4 transmembrane fragments, carry out the transmission of a hormonal signal through ion channels.

Research recent years It has been shown that secondary messengers are not one of the listed compounds, but a multistage (cascade) system, the final substrate (substance) of which can be one or more biologically active compounds. Thus, hormones interacting with receptors having 7 transmembrane fragments and activating G-protein then stimulate adenylate cyclase, phospholipase, or both enzymes, which leads to the formation of several second messengers: cAMP, inositol triphosphate and diacylglycerol. To date, this group is represented by the largest number (more than 100) of receptors, which include peptidergic, dopaminergic, adrenergic, cholinergic, serotonergic and other receptors. In these receptors, 3 extracellular fragments (loops) are responsible for the recognition and binding of the hormone, 3 intracellular fragments (loops) bind the G-protein. The transmembrane (intramembrane) domains are hydrophobic, while the extra- and intracellular fragments (loops) are hydrophilic. The C-terminal cytoplasmic end of the receptor polypeptide chain contains sites where, under the influence of activated G-proteins, phosphorylation occurs, characterizing the active state of the receptor with the simultaneous formation of secondary messengers: cAMP, inositol triphosphate and diacylglycerol.

The interaction of a hormone with a receptor having one transmembrane fragment leads to the activation of enzymes (tyrosine kinase, phosphate tyrosine phosphatase, etc.) that phosphorylate tyrosine residues on protein molecules.

The complexation of the hormone with a receptor belonging to the third group and having 4 transmembrane fragments leads to the activation of ion channels and the entry of ions, which in turn either stimulates (activates) serine-threonine kinases mediating the phosphorylation of certain protein regions, or leads to membrane depolarization. Signal transmission by any of the listed mechanisms is accompanied by effects characteristic of the action of individual hormones.

The history of the study of second messengers begins with the studies of Sutherland et al. (1959), who showed that the breakdown of liver glycogen under the influence of glucagon and adrenaline occurs through the stimulating effect of these hormones on the activity of the cell membrane enzyme adenylate cyclase, which catalyzes the conversion of intracellular adenosine triphosphate (ATP) to cAMP (scheme 1).

Scheme 1. Conversion of ATP to cAMP.

Adenylate cyclase itself is a glycoprotein with a molecular weight of about 150,000 kDa. Adenylate cyclase is involved with Mg2+ ions in the formation of cAMP, the concentration of which in the cell is about 0.01-1 µg mol/l, while the ATP content in the cell reaches a level of up to 1 µg mol/l.

The formation of cAMP occurs with the help of the adenylate cyclase system, which is one of the components of the receptor. The interaction of a hormone with a receptor of the first group (receptors having 7 transmembrane fragments) includes at least 3 successive steps: 1) receptor activation, 2) hormonal signal transmission, and 3) cellular action.

The first stage, or level, is the interaction of the hormone (ligand) with the receptor, which is carried out through ionic and hydrogen bonds and hydrophobic compounds involving at least 3 membrane molecules of the G-protein or a regulatory protein consisting of a-, b- and g- subunits. This, in turn, activates membrane-bound enzymes (phospholipase C, adenylate cyclase) with the subsequent formation of 3 secondary messengers: inositol triphosphate, diacylglycerol and cAMP.

The adenylate cyclase system of the receptor consists of 3 components: the receptor itself (its stimulatory and inhibitory parts), the regulatory protein with its a-, b-, and g-subunits, and the catalytic subunit (adenylate cyclase itself), which in the normal (i.e., unstimulated) state separated from each other (Scheme 2). The receptor (both of its parts - stimulating and inhibitory) is located on the outer, and the regulatory unit - on the inner surface of the plasma membrane. The regulatory unit, or G protein, is bound by guanosine diphosphate (GDP) in the absence of the hormone. The complexing of the hormone with the receptor causes the dissociation of the G-protein-GDP complex and the interaction of the G-protein, namely its a-subunit with guanosine triphosphate (GTP) and the simultaneous formation of the b/g-subunit complex, which is capable of causing certain biological effects. The GTP-a-subunit complex, as already noted, activates adenylate cyclase and the subsequent formation of cAMP. The latter already activates protein kinase A with the corresponding phosphorylation of various proteins, which also manifests itself in a certain biological effect. In addition, the activated GTP-a-subunit complex in some cases regulates the stimulation of phospholipase C, cGMP, phosphodiesterase, Ca2+ and K+ channels and has an inhibitory effect on Ca2+ channels and adenylate cyclase.

Scheme 2. The mechanism of action of protein hormones by activating cAMP (explanations in the text).

PC is a receptor that binds the stimulating hormone,

St is a stimulating hormone

Ru is a receptor that binds an inhibitory hormone,

Ug - depressant hormone,

Ac - adenylate cyclase,

Gy - hormone-inhibiting protein,

Gc is a hormone-stimulating protein.

The role of the hormone, therefore, is to replace the G-protein-GDP complex with the G-protein-GTP complex. The latter activates the catalytic subunit, converting it into a state with high affinity for the ATP-Mg2+ complex, which is rapidly converted to cAMP. Simultaneously with the activation of adenylate cyclase and the formation of cAMP, the G-protein-GTP complex causes the dissociation of the hormone receptor complex by reducing the affinity of the receptor for the hormone.

The resulting cAMP in turn activates cAMP-dependent protein kinases. They are enzymes that phosphorylate the corresponding proteins, i.e. transfer of a phosphate group from ATP to the hydroxyl group of serine, threonine or tyrosine, which are part of the protein molecule. Proteins phosphorylated in this way directly carry out the biological effect of the hormone.

It has now been established that regulatory proteins are represented by more than 50 different proteins capable of complexing with GTP, which are divided into G-proteins with a small molecular weight (20-25 kDa) and high-molecular G-proteins consisting of 3 subunits (a - c mol mass 39-46 kDa, b - 37 kDa and g-subunit - 8 kDa). The a-subunit is essentially a GTPase that hydrolyzes GTP to GDP and free inorganic phosphate. b- and g-subunits are involved in the formation of the active complex after the interaction of the ligand with the corresponding receptor. By releasing GDP at its binding sites, the a-subunit causes dissociation and deactivation of the active complex, since the re-association of the a-subunit - GDP with b- and g-subunits returns the adenylate cyclase system to the initial state. It has been established that the a-subunit of the G-protein in various tissues is represented by 8, b - 4 and g - 6 forms. The dissociation of G-protein subunits in the cell membrane can lead to the simultaneous formation and interaction of various signals that have biological effects of different strength and quality at the end of the system.

Adenylate cyclase itself is a glycoprotein with a molecular weight of 115-150 kDa. In various tissues, 6 of its isoforms have been identified, which interact with a-, b-, and g-subunits, as well as with Ca2+ calmodulin. In some types of receptors, in addition to the regulatory stimulating (Gs) and regulatory inhibitory (GI) proteins, an additional protein, transducin, has been identified.

The role of regulatory proteins in the transmission of the hormonal signal is great, the structure of these proteins is compared with a “cassette”, and the diversity of the response is associated with the high mobility of the regulatory protein. So, some hormones can simultaneously activate in varying degrees both Gs and Gs. Moreover, the interaction of some hormones with receptor regulatory proteins causes the expression of the corresponding proteins that regulate the level and degree of the hormonal response. Activation, as shown above, of regulatory proteins is a consequence of their dissociation from the hormone-receptor complex. In some receptor systems, up to 20 or more regulatory proteins are involved in this interaction, which, in addition to stimulating the formation of cAMP, simultaneously activate and calcium channels.

A certain number of receptors that belong to the first group, having 7 transmembrane fragments, mediate their action by secondary messengers related to phosphatidylinositol derivatives: inositol triphosphate and diacylglycerol. Inositol triphosphate controls cellular processes by generating intracellular calcium. This messenger system can be activated in two ways, namely through a regulatory protein or phosphotyrosine proteins. In both cases, further activation of phospholipase C occurs, which hydrolyzes the polyphosphoinoside system. This system, as stated above, includes two intracellular second messengers that are derived from a membrane-bound polyphosphoinoside called phosphatidylinositol-4,5-bisphosphate (FIF2). The complexation of the hormone with the receptor causes hydrolysis of PIF2 by phosphorylase, resulting in the formation of these messengers - inositol triphosphate (IP3) and diacylglycerol. IP3 promotes an increase in the level of intracellular calcium, primarily due to the mobilization of the latter from the endoplasmic reticulum, where it is localized in the so-called calciosomes, and then due to the entry of extracellular calcium into the cell. Diacylglycerol, in turn, activates specific protein kinases and, in particular, protein kinase C. The latter phosphorylate certain enzymes responsible for the final biological effect. It is possible that the destruction of PIF2, along with the release of two messengers and an increase in the content of intracellular calcium, also induces the formation of prostaglandins, which are potential stimulators of cAMP.

This system mediates the action of such hormones as histamine, serotonin, prostaglandins, vasopressin, cholecystokinin, somatoliberin, thyroliberin, oxytocin, parathyroid hormone, neuropeptide Y, substance P, angiotensin II, catecholamines, which act through a1-adrenergic receptors, etc.

The phospholipase C enzyme group includes up to 16 isoforms, which in turn are subdivided into b-, g-, and d-phospholipase C. It has been shown that b-phospholipase C interacts with regulatory proteins, and g-phospholipase C interacts with tyrosine kinases.

Inositol triphosphate acts through its own specific tetrameric receptors having a molecular weight of 4x313 kDa. After complexing with such a receptor, the so-called “large” inositol triphosphate receptors or ryanodine receptors were identified, which also belong to tetramers and have a molecular weight of 4x565 kDa. It is possible that intracellular calcium channels of ryanodine receptors are regulated by a new second messenger, cADP-ribose (L. Meszaros et al., 1993). The formation of this messenger is mediated by cGMP and nitric oxide (NO), which activates cytoplasmic guanylate cyclase. Thus, nitric oxide can be one of the elements of the transfer of hormonal action with the participation of calcium ions.

As you know, calcium is inside the cell in a protein-bound state and in free form in the extracellular fluid. Calcium-binding intracellular proteins such as calreticulin and calsequestrin have been identified. Intracellular free calcium, which acts as a second messenger, enters from the extracellular fluid through the calcium channels of the plasma membrane of the cell or is released intracellularly from protein binding. Intracellular free calcium affects the corresponding phosphorylase kinases only when bound to the intracellular calmodulin protein (Scheme 3).

Scheme 3. The mechanism of action of protein hormones through CA2+ (explanations in the text) P - receptor; G - hormone; Ca + protein - intracellular calcium in protein-bound form.

Calmodulin, a receptor protein with high affinity for calcium, consists of 148 amino acid residues and is present in all nucleated cells. Its molecular weight (mol.m.) is 17,000 kDa, each molecule has 4 receptors for calcium binding.

In a state of functional rest, the concentration of free calcium in the extracellular fluid is higher than inside the cell, due to the functioning of the calcium pump (ATPase) and the transport of calcium from the cell to the intercellular fluid. During this period, calmodulin is in an inactive form. The complexing of the hormone with the receptor leads to an increase in the intracellular level of free calcium, which binds to calmodulin, converts it into an active form and affects calcium-sensitive proteins or enzymes responsible for the corresponding biological effect of the hormone.

The increased level of intracellular calcium then stimulates the calcium pump, which “pumps” free calcium into the intercellular fluid, reduces its level in the cell, as a result of which calmodulin passes into an inactive form and the state of functional rest is restored in the cell. Calmodulin also acts on adenylate cyclase, guanylate cyclase, phosphodiesterase, phosphorylase kinase, myosin kinase, phospholipase A2, Ca2+- and Mg2+-ATPase, stimulates the release of neurotransmitters, phosphorylation of membrane proteins. By changing calcium transport, the level and activity of cyclic nucleotides, and indirectly glycogen metabolism, calmodulin is involved in secretory and other functional processes in the cell. It is a dynamic component of the mitotic apparatus; it regulates the polymerization of the microtubular-villous system, the synthesis of actomyosin, and the activation of calcium “pump” membranes. Kalmodulin - analogue muscle protein troponin C, which, by binding calcium, forms a complex of actin and myosin, and also activates myosin-ATPase, which is necessary for the repeated interaction of actin and myosin.

Ca2+-calmodulin complex activates Ca2+-calmodulin-dependent protein kinase, which plays an important role in nerve signal transmission (synthesis and release of neurotransmitters), in stimulation or inhibition of phospholipase A2, activates a specific serine-threonine protein phosphatase called calcineurin, which mediates the action of the T-cell receptor in T-lymphocytes.

Calmodulin-dependent protein kinases are divided into two groups: multifunctional, which are well characterized, and specific, or “special purpose”. The first group includes such as protein kinase A, which mediates the phosphorylation of many intracellular proteins. “Special purpose” protein kinases phosphorylate several substrates, such as myosin light chain kinase, phosphorylase kinase, etc.

Protein kinase C is represented by several isoforms (mol.m. from 67 to 83 kDa), which are encoded by 10 different genes. Classical protein kinase C includes 4 different isoforms (a-, b1-, b2- and g-isoforms); 4 other protein isoforms (delta, epsilon, pi and omega) and 2 atypical protein forms.

Classical protein kinases are activated by calcium and diacylglycerol, new protein kinases are activated by diacylglycerol and phorbol esters, and one of the atypical protein kinases does not respond to any of the listed activators, but its activity requires the presence of phosphatidylserine.

It was noted above that hormones whose receptors have 7 transmembrane fragments, after the formation of the hormone-receptor complex, bind to G-proteins that have a small molecular weight (20-25 kDa) and perform different function. Proteins that interact with receptor tyrosine kinase are called ras proteins, and proteins involved in vesicle transport are called rab proteins. The activated form is a G protein complexed with GTP; the inactive form of the ras protein is a consequence of its complexing with GDP. A guanine nucleotide releasing protein is involved in the activation of the ras protein, and the inactivation process is carried out by hydrolysis of GTP under the influence of GTPase. Activation of the ras protein, in turn, through phospholipase C, stimulates the formation of second messengers: inositol triphosphate and diacylglycerol. Ras proteins were first described as oncogenes (A.G. Gilman, 1987), since overexpression, or mutation, of these proteins was found in malignant neoplasms. Normally, ras proteins are involved in various regulatory processes, including growth.

Some protein hormones (insulin, IGF I, etc.) carry out their initial action of activating the receptor through a hormone-sensitive tyrosine kinase. Binding of the hormone to the receptor leads to a conformational change or dimerization that causes tyrosine kinase activation and subsequent autophosphorylation of the receptor. After hormone-receptor interaction, autophosphorylation enhances both tyrosine kinase activity in the other dimer and phosphorylation of intracellular substrates. Receptor tyrosine kinase is an allosteric enzyme in which the extracellular domain is the regulatory subunit and the intracellular (cytoplasmic) domain is the catalytic subunit. Tyrosine kinase is activated or phosphorylated via binding to an adapter or SH2 protein, which consists of two SH2 domains and one SH3 domain. SH2 domains bind specific tyrosine kinase receptor phosphotyrosines, and SH3 bind enzymes or signaling molecules. Phosphorylated proteins (phosphotyrosines) are shortened by 4 amino acids, which determines their specific high-affinity binding to SH2 domains.

Complexes (phosphotyrosine peptides - SH2 domains) determine the selectivity of hormonal signal transmission. The final effect of hormonal signal transduction depends on two reactions - phosphorylation and dephosphorylation. The first reaction is controlled by various tyrosine kinases, the second - by phosphotyrosine phosphatases. To date, more than 10 transmembrane phosphotyrosine phosphatases have been identified, which are divided into 2 groups: a) large transmembrane proteins/tendem domains and b) small intracellular enzymes with a single catalytic domain.

Intracellular fragments of phosphotyrosine phosphatases are very diverse. The function of SH2 domain phosphotyrosine phosphatases (types I and II) is believed to be signal reduction through dephosphorylation of phosphorylating sites on the receptor tyrosine kinase or signal enhancement through binding of tyrosine phosphorylating signaling proteins to one or both SH2 domains, as well as signal transduction through the interaction of a single SH2 protein with by another protein or inactivation by the process of dephosphorylation of tyrosine-phosphorylated second messenger molecules, such as phospholipase C-g or src-tyrosine kinase.

In some hormones, hormonal signal transmission occurs by phosphorylation of tyrosine amino acid residues, as well as serine or threonine. Characteristic in this regard is the insulin receptor, in which phosphorylation of both tyrosine and serine can occur, and serine phosphorylation is accompanied by a decrease in the biological effect of insulin. The functional significance of the simultaneous phosphorylation of several amino acid residues of the receptor tyrosine kinase is not well understood. However, this achieves modulation of the hormonal signal, which is schematically referred to as the second level of receptor signaling mechanisms. This level is characterized by the activation of several protein kinases and phosphatases (such as protein kinase C, cAMP-dependent protein kinase, cGMP-dependent protein kinase, calmodulin-dependent protein kinase, etc.), which phosphorylate or dephosphorylate serine, tyrosine or threonine residues, which causes corresponding conformational changes, necessary for the manifestation of biological activity.

It should be noted that enzymes such as phosphorylase, kinase, casein kinase II, acetyl-CoA carboxylase kinase, triglyceride lipase, glycogen phosphorylase, protein phosphatase I, ATP citrate lyase are activated by the phosphorylation process, and glycogen synthase, pyruvate dehydrogenase and pyruvate kinase are activated by the dephosphorylation process.

The third level of regulatory signaling mechanisms in the action of hormones is characterized by an appropriate response at the cellular level and is manifested by a change in metabolism, biosynthesis, secretion, growth or differentiation. This includes the processes of transport of various substances across the cell membrane, protein synthesis, stimulation of ribosomal translation, activation of the microvillous tubular system, and translocation of secretory granules to the cell membrane. Thus, the activation of the transport of amino acids, glucose through the cell membrane is carried out by the corresponding transporter proteins 5-15 minutes after the onset of the action of hormones such as growth hormone and insulin. There are 5 transporter proteins for amino acids and 7 for glucose, of which 2 are sodium glucose symporters or cotransporters.

Second messenger hormones affect gene expression by modifying transcription processes. Thus, cAMP regulates the rate of transcription of a number of genes responsible for the synthesis of hormones. This action is mediated by the cAMP response element activating protein (CREB). The latter protein (CREB) is complexed with specific regions of DNA, being a common transcription factor.

Many hormones that interact with receptors located on the plasma membrane, after the formation of the hormone-receptor complex, undergo the process of internalization, or endocytosis, i.e. translocation, or the transfer of the hormone-receptor complex into the cell. This process occurs in structures called “coated pits” located on the inner surface of the cell membrane, which is lined with the protein clathrin. Hormone-receptor complexes aggregated in this way, which are localized in “covered pits”, are then internalized by invagination of the cell membrane (the mechanism is very similar to the process of phagocytosis), turning into vesicles (endosomes or receptorosomes), and the latter are translocated into the cell.

During translocation, the endosome undergoes a process of acidification (similar to what occurs in lysosomes), which may result in degradation of the ligand (hormone) or dissociation of the hormone-receptor complex. In the latter case, the released receptor returns to the cell membrane, where it re-interacts with the hormone. The process of immersing the receptor, together with the hormone, into the cell and returning the receptor to the cell membrane is called the receptor recycling process. During the functioning of the receptor (the half-life of the receptor ranges from several to 24 hours or more), it manages to carry out from 50 to 150 such “shuttle” cycles. The process of endocytosis is an integral or additional part of the receptor signaling mechanism in the action of hormones.

In addition, with the help of the process of internalization, the degradation of protein hormones (in lysosomes) and cellular desensitization (decrease in cellular sensitivity to the hormone) is carried out by reducing the number of receptors on the cell membrane. It has been established that the fate of the hormone-receptor complex after the process of endocytosis is different. In most hormones (FSH, LH, chorionic gonadotropin, insulin, IGF 1 and 2, glucagon, somatostatin, erythropoietin, VIP, low density lipoproteins), endosomes inside the cell undergo dissociation. The released receptor returns to the cell membrane, and the hormone undergoes a process of degradation in the lysosomal apparatus of the cell.

In other hormones (GH, interleukin-2, epidermal, nerve and platelet growth factors), after dissociation of endosomes, the receptor and the corresponding hormone undergo a degradation process in lysosomes.

Some hormones (transferin, mannose-6-phosphate containing proteins, and a small part of insulin, growth hormone in some target tissues) after dissociation of endosomes return, like their receptors, to the cell membrane. Despite the fact that these hormones undergo an internalization process, there is no consensus on the direct intracellular action of the protein hormone or its hormone-receptor complex.

Receptors for the hormones of the adrenal cortex, sex hormones, calcitriol, retinoic acid, thyroid hormones are localized intracellularly. These hormones are lipophilic, transported by blood proteins, have a long period half-life and their action is mediated by a hormone-receptor complex, which, by binding to specific regions of DNA, activates or inactivates specific genes.

The binding of a hormone to a receptor leads to changes in the physicochemical properties of the latter, and this process is called receptor activation or transformation. The study of receptor transformation in vitro showed that the temperature regime, the presence of heparin, ATP, and other components in the incubation medium change the rate of this process.

Untransformed receptors are a protein with a molecular weight of 90 kDa, which is identical to the stress or temperature shock protein with the same molecular weight (M. Catell et al., 1985). The latter protein occurs in a- and b-isoforms, which are encoded by different genes. A similar situation is observed in relation to steroid hormones.

In addition to the stress protein with a pier. m. 90 kDa, in the untransformed receptor, a protein with a mol. m 59 kDa (M. Lebean et al., 1992), called immunophilin, which is not directly associated with the steroid hormone receptor, but forms complexes with a protein mol. m. 90 kDa. The function of the immunophilin protein is not well understood, although its role in the regulation of steroid hormone receptor function has been proven, as it binds immunosuppressive substances (eg, rapamycin and FK 506).

Steroid hormones are transported in the blood in a protein-bound state and only a small part of them is in the free form. The hormone, which is in free form, is able to interact with the cell membrane and pass through it into the cytoplasm, where it binds to the cytoplasmic receptor, which is highly specific. For example, receptor proteins that bind only glucocorticoid hormones or estrogens have been isolated from hepatocytes. Currently, receptors for estradiol, androgens, progesterone, glucocorticoids, mineralocorticoids, vitamin D, thyroid hormones, as well as retinoic acid and some other compounds (edixon receptor, dioxin receptor, peroxisomal proliferative activator receptor and additional X receptor for retinoic acid) have been identified. . The concentration of receptors in the respective target tissues is 103 to 5104 per cell.

Steroid hormone receptors have 4 domains: the amino-terminal domain, which has significant differences in receptors for the listed hormones and consists of 100-600 amino acid residues; DNA-binding domain, consisting of approximately 70 amino acid residues; a hormone-binding domain of about 250 amino acids; and a carboxyl-terminal domain. As noted, the amino-terminal domain has the greatest differences both in form and in amino acid sequence. It consists of 100-600 amino acids and its smallest dimensions are found in the thyroid hormone receptor, and the largest in the glucocorticoid hormone receptor. This domain determines the characteristics of the receptor response and is highly phosphorylated in most species, although there is no direct correlation between the degree of phosphorylation and the biological response.

The DNA-binding domain is characterized by 3 introns, two of which have so-called “zinc fingers”, or structures containing zinc ions with 4 cysteine ​​bridges. “Zinc fingers” are involved in the specific binding of the hormone to DNA. There is a small region on the DNA-binding domain for specific binding of nuclear receptors, called “hormone response elements,” that modulates the start of transcription. This region is located within another fragment, consisting of 250 nucleotides, responsible for the initiation of transcription. The DNA-binding domain has the highest structure constancy among all intracellular receptors.

The hormone-binding domain is involved in hormone binding, as well as in the processes of dimerization and regulation of the function of other domains. It is directly adjacent to the DNA-binding domain.

The carboxyl terminal domain is also involved in heterodimerization processes and interacts with various transcription factors, including proximal protein promoters.

Along with this, there is evidence that steroids are first bound by specific proteins of the cell membrane, which transport them to the cytoplasmic receptor or, bypassing it, directly to the nuclear receptors. The cytoplasmic receptor consists of two subunits. In the cell nucleus, subunit A, interacting with DNA, triggers (starts) the transcription process, and subunit B binds to non-histone proteins. The effect of the action of steroid hormones does not appear immediately, but after a certain time, which is necessary for the formation of RNA and the subsequent synthesis of a specific protein.

Thyroid hormones (thyroxin-T4 and triiodothyronine-T3), like steroid hormones, easily diffuse through the lipid cell membrane and are bound by intracellular proteins. According to other data, thyroid hormones first interact with the receptor on the plasma membrane, where they are complexed with proteins, forming the so-called intracellular pool of thyroid hormones. The biological action is mainly carried out by T3, while T4 is deiodinated, turning into T3, which binds to the cytoplasmic receptor. If the steroidcytoplasmic complex translocates to the cell nucleus, then the thyroidcytoplasmic complex first dissociates and T3 directly binds to nuclear receptors with high affinity for it. In addition, high-affinity T3 receptors are also found in mitochondria. It is believed that the calorigenic action of thyroid hormones is carried out in mitochondria through the generation of new ATP, for the formation of which adenosine diphosphate (ADP) is used.

Thyroid hormones regulate protein synthesis at the level of transcription and this action, which is detected after 12-24 hours, can be blocked by the introduction of inhibitors of RNA synthesis. In addition to their intracellular action, thyroid hormones stimulate the transport of glucose and amino acids across the cell membrane, directly affecting the activity of some enzymes localized in it.

Thus, the specific action of the hormone is manifested only after its complexing with the corresponding receptor. As a result of the processes of recognition, complexation and activation of the receptor, the latter generates a number of second messengers that cause a sequential chain of post-receptor interactions, ending in the manifestation of a specific biological effect of the hormone.

It follows that the biological action of the hormone depends not only on its content in the blood, but also on the number and functional state of receptors, as well as on the level of functioning of the post-receptor mechanism.

The number of cellular receptors, like other cell components, is constantly changing, reflecting the processes of their synthesis and degradation. The main role in the regulation of the number of receptors belongs to hormones. There is an inverse relationship between the level of hormones in the intercellular fluid and the number of receptors. So, for example, the concentration of the hormone in the blood and intercellular fluid is very low and amounts to 1014-109 M, which is much lower than the concentration of amino acids and other various peptides (105-103 M). The number of receptors is higher and is 1010-108 M, and there are about 1014-1010 M on the plasma membrane, and the intracellular level of second messengers is slightly higher - 108-106 M. The absolute number of receptor sites on the cell membrane ranges from several hundred to 100,000.

Numerous studies have shown that receptors have a characteristic property to enhance the action of the hormone not only by the described mechanisms, but also through the so-called “nonlinear binding”. Another feature is characteristic, which is that the greatest hormonal effect does not mean the greatest binding of the hormone by receptors. So, for example, the maximum stimulation of glucose transport into adipocytes by insulin is observed when only 2% of insulin receptors are bound by the hormone (J. Gliemann et al., 1975). The same relationship has been established for ACTH, gonadotropins and other hormones (M.L. Dufau et al., 1988). This is due to two phenomena: “nonlinear binding” and the presence of so-called “reserve receptors”. One way or another, but the amplification, or enhancement of the action of the hormone, which is a consequence of these two phenomena, performs an important physiological role in the processes of the biological action of the hormone in normal conditions and in various pathological conditions. For example, in hyperinsulinism and obesity, the number of insulin receptors localized on hepatocytes, adipocytes, thymocytes, and monocytes decreases by 50–60%, and, conversely, insulin deficiency states in animals are accompanied by an increase in the number of insulin receptors. Along with the number of insulin receptors, their affinity also changes; the ability to complex with insulin, and the transduction (transmission) of the hormonal signal inside the receptor also changes. Thus, a change in the sensitivity of organs and tissues to hormones is carried out through feedback mechanisms (down regulation). For conditions accompanied by a high concentration of the hormone in the blood, a decrease in the number of receptors is characteristic, which is clinically manifested as resistance to this hormone.

Some hormones can affect the number of not only "own" receptors, but also receptors for another hormone. So, progesterone reduces, and estrogens increase the number of receptors for both estrogen and progesterone at the same time.

A decrease in hormone sensitivity may be due to the following mechanisms: 1) a decrease in receptor affinity due to the influence of other hormones and hormone receptor complexes; 2) a decrease in the number of functioning receptors as a result of their internalization or release from the membrane into the extracellular space; 3) receptor inactivation due to conformational changes; 4) destruction of receptors by increasing the activity of proteases or degradation of the hormone-receptor complex under the influence of lysosome enzymes; 5) inhibition of the synthesis of new receptors.

For each type of hormone, there are agonists and antagonists. The latter are substances that are able to competitively bind the receptor to the hormone, reducing or completely blocking its biological effect. Agonists, on the contrary, complexing with the corresponding receptor, enhance the action of the hormone or completely imitate its presence, and sometimes the half-life of the agonist is hundreds or more times longer than the degradation time of the natural hormone, and, therefore, during this time a biological effect is manifested, which is naturally used in clinical purposes. So, for example, glucocorticoid agonists are dexamethasone, corticosterone, aldosterone, and partial agonists are 11b-hydroxyprogesterone, 17a-hydroxyprogesterone, progesterone, 21-deoxycortisol, and their antagonists are testosterone, 19-nortestosterone, 17-estradiol. Inactive steroids for glucocorticoid receptors include 11a-hydroxyprogesterone, tetrahydrocortisol, androstenedione, 11a-, 17a-methyltestosterone. These relationships are taken into account not only in the experiment when clarifying the action of hormones, but also in clinical practice.

Deciphering the mechanisms of action of hormones in the animal body provides an opportunity to better understand the physiological processes - the regulation of metabolism, protein biosynthesis, tissue growth and differentiation.

This is also important from a practical point of view, in connection with the increasing use of natural and synthetic hormonal drugs in animal husbandry and veterinary medicine.

Currently, there are about 100 hormones that are formed in the endocrine glands, enter the blood and have a versatile effect on metabolism in cells, tissues and organs. It is difficult to determine such physiological processes in the body that would not be under the regulatory influence of hormones. Unlike many enzymes that cause individual, narrowly directed changes in the body, hormones have multiple effects on metabolic processes and other physiological functions. At the same time, none of the hormones, as a rule, completely provides regulation individual functions. This requires the action of a number of hormones in a certain sequence and interaction. So, for example, somatotropin stimulates growth processes only with the active participation of insulin and thyroid hormones. The growth of follicles is mainly provided by follitropin, and their maturation and the process of ovulation is carried out under the regulatory influence of lutropin, etc.

Most of the hormones in the blood are bound to albumins or globulins, which prevents them from being quickly destroyed by enzymes and maintains an optimal concentration metabolically. active hormones in cells and tissues. Hormones have a direct effect on the process of protein biosynthesis. Steroid and protein hormones (sex, triple pituitary hormones) in target tissues cause an increase in the number and volume of cells. Other hormones, such as insulin, glucocorticoids, and mineralocorticoids, affect protein synthesis indirectly.

First link physiological action hormones in animals are receptors on cell membranes. In the same cells, there are in large numbers several types; specific receptors, with the help of which they selectively bind the molecules of various hormones circulating in the blood. For example, fat cells in their membranes they have specific receptors for glucagon, lutropin, thyrotropin, corticotropin.

Due to the large size of their molecules, most hormones of a protein nature cannot penetrate cells, but are located on their surface and, interacting with the corresponding receptors, affect the metabolism inside the cells. So, in particular, the action of thyrotropin is associated with the fixation of its molecules on the surface of thyroid cells, under the influence of which the permeability of cell membranes for sodium ions increases, and in their presence the intensity of glucose oxidation increases. Insulin increases the permeability of cell membranes in tissues and organs for glucose molecules, which helps to reduce its concentration in the blood and pass into tissues. Somatotropin also has a stimulating effect on the synthesis of nucleic acids and proteins by acting on cell membranes.

The same hormones can influence metabolic processes in tissue cells different ways. Along with the change in permeability cell membranes and membranes of intracellular structures for various enzymes and other chemicals, under the influence of the same hormones, the ionic composition of the environment outside and inside the cells, as well as the activity of various enzymes and the intensity of metabolic processes, can change.

Hormones affect the activity of enzymes and the gene apparatus of cells not directly, but with the help of mediators (intermediaries). One of these mediators is cyclic 3′, 5′-adenosine monophosphate (cyclic AMP). Cyclic AMP (cAMP) is formed inside cells from adenosine triphosphoric acid (ATP) with the participation of the enzyme adenyl cyclase located on the cell membrane, which is activated when exposed to the corresponding hormones. On intracellular membranes there is an enzyme phosphodiesterase, which converts cAMP into a less active substance - 5'-adenosine monophosphate, and this stops the action of the hormone.

When a cell is exposed to several hormones that stimulate the synthesis of cAMP in it, the reaction is catalyzed by the same adenylcyclase, but the receptors in cell membranes for these hormones are strictly specific. Therefore, for example, corticotropin affects only the cells of the adrenal cortex, and thyrotropin - on the cells of the thyroid gland, etc.

Detailed studies have shown that the action of most protein and peptide hormones leads to stimulation of the activity of adenylcyclase and an increase in the concentration of cAMP in target cells, which is associated with further transmission of information. hormonal effects with the active participation of a number of protein kinases. cAMP plays the role of an intracellular mediator of the hormone, providing an increase in the activity of protein kinases dependent on it in the cytoplasm and nuclei of cells. In turn, cAMP-dependent protein kinases catalyze the phosphorylation of ribosome proteins, which is directly related to the regulation of protein synthesis in target cells under the influence of peptide hormones.

Steroid hormones, catecholamines, thyroid hormones, due to the small size of the molecules, pass through the cell membrane and enter into contact with cytoplasmic receptors inside the cells. Further steroid hormones in combination with their receptors, which are acidic proteins, they pass into the nucleus of the cell. It is assumed that peptide hormones, as the hormone-receptor complexes are cleaved, also affect specific receptors in the cytoplasm, the Golgi complex, and the nuclear envelope.

Not all hormones stimulate the activity of the enzyme adenylcyclase and increase its concentration in cells. Some peptide hormones, in particular insulin, cytocin, calcitonin, have an inhibitory effect on adenylcyclase. The physiological effect of their action is believed to be due not to an increase in the concentration of cAMP, but to its decrease. At the same time, in cells with specific sensitivity to these hormones, the concentration of another cyclic nucleotide, cyclic guanosine monophosphate (cGMP), increases. The result of the action of hormones in the cells of the body ultimately depends on the effects of both cyclic nucleotides - cAMP and cGMP, which are universal intracellular mediators - mediators of hormones. With regard to the action of steroid hormones, which, in combination with their receptors, penetrate into the cell nucleus, the role of cAMP and cGMP as intracellular mediators is considered doubtful.

Many, if not all, hormones are finite physiological effect manifest indirectly - through a change in the biosynthesis of protein-enzymes. Protein biosynthesis is a complex multi-stage process carried out with the active participation of the gene apparatus of cells.

The regulatory effect of hormones on protein biosynthesis is carried out mainly by stimulating the RNA polymerase reaction with the formation of ribosomal and nuclear types of RNA, as well as messenger RNA, and by influencing the functional activity of ribosomes and other links of protein metabolism. Specific protein kinases in cell nuclei stimulate the phosphorylation of the corresponding protein components and the RNA polymerase reaction with the formation of messenger RNAs encoding protein synthesis in cells and target organs. At the same time, genes are derepressed in the nuclei of cells, which are released from the inhibitory effect of specific repressors - nuclear histone proteins.

Hormones such as estrogens and androgens in the cell nuclei bind to histone proteins that repress the corresponding genes, and thereby bring the cell gene apparatus into active functional state. At the same time, androgens affect the gene apparatus of cells less than estrogens, which is due to a more active connection of the latter with chromatin and a weakening of RNA synthesis in the nuclei.

Together with the activation of protein synthesis in cells, the formation of histone proteins, which are repressors of gene activity, is carried out, and this prevents the metabolic functions of the nuclei and excessive manifestation of growth stimulation. Consequently, the cell nuclei have their own mechanism of genetic and mitotic regulation of metabolism and growth.

Due to the influence of hormones on anabolic processes in the body, retention increases nutrients feed and, consequently, the amount of substrates for interstitial metabolism increases, the regulatory mechanisms of biochemical processes associated with more efficient use nitrogenous and other compounds.

The processes of protein synthesis in cells are influenced by somatotropin, corticosteroids, estrogens, and also thyroxine. These hormones stimulate the synthesis of various messenger RNAs and thereby enhance the synthesis of the corresponding proteins. In the processes of protein synthesis importance also belongs to insulin, which stimulates the binding of messenger RNAs to ribosomes and, consequently, activates protein synthesis. By activating the chromosomal apparatus of cells, hormones affect the increase in the rate of protein synthesis and the concentration of enzymes in the cells of the liver and other organs and tissues. However, the mechanism of the effect of hormones on intracellular metabolism has not yet been studied enough.

The action of hormones, as a rule, is closely related to the functions of enzymes that provide biochemical processes in cells, tissues and organs. Hormones are involved in biochemical reactions as specific activators or inhibitors of enzymes, exerting their influence on enzymes by ensuring their connection with various biocolloids.

Since enzymes are protein bodies, the effect of hormones on their functional activity is manifested primarily by influencing the biosynthesis of enzymes and catabolic coenzyme proteins. One of the manifestations of the activity of hormones is their participation in the interaction of a number of enzymes in various parts of complex reactions and processes. As you know, vitamins play a certain role in the construction of coenzymes. It is believed that hormones also play a regulatory role in these processes. For example, corticosteroids affect the phosphorylation of certain B vitamins.

For prostaglandins, their high physiological activity and very low side effect. It is now known that prostaglandins act inside cells like mediators and play an important role in the implementation of the effect of hormones. At the same time, the processes of synthesis of cyclic adenosine monophosphate (cAMP) are activated, which is capable of transmitting the narrowly directed action of hormones. It is possible to assume that pharmacological substances inside cells act due to the production of specific prostaglandins. Now in many countries the mechanism of action of prostaglandins at the cellular and molecular level is being studied, since a comprehensive study of the action of prostaglandins can make it possible to purposefully influence the metabolism and other physiological processes in the animal body.

Based on the foregoing, it can be concluded that hormones have a complex and versatile effect in the animal body. The complex influence of nervous and humoral regulation ensures the coordinated course of all biochemical and physiological processes. However, in the finest details, the mechanism of action of hormones has not yet been sufficiently studied. This problem is of interest to many scientists and is of great interest for the theory and practice of endocrinology, as well as animal husbandry and veterinary medicine.

Hormones secreted by the endocrine glands bind to plasma transport proteins or, in some cases, are adsorbed on blood cells and delivered to organs and tissues, affecting their function and metabolism. Some organs and tissues are very sensitive to hormones, so they are called target organs or tissues -targets. Hormones affect literally all aspects of metabolism, functions and structures in the body.

According to modern ideas, the action of hormones is based on the stimulation or inhibition of the catalytic function of certain enzymes. This effect is achieved by activating or inhibiting already existing enzymes in cells by accelerating their synthesis by activating genes. Hormones can increase or decrease the permeability of cellular and subcellular membranes for enzymes and other biologically active substances, thereby facilitating or inhibiting the action of the enzyme. hormone organic organism iron

Membrane mechanism . The hormone binds to the cell membrane and at the site of binding changes its permeability to glucose, amino acids and some ions. In this case, the hormone acts as an effector of membrane vehicles. Insulin does this by altering glucose transport. But this type of hormone transport rarely occurs in isolation. Insulin, for example, has both a membrane and a membrane-intracellular mechanism of action.

Membrane-intracellular mechanism . According to the membrane-intracellular type, hormones act that do not penetrate the cell and therefore affect the metabolism through an intracellular chemical mediator. These include protein-peptide hormones (hormones of the hypothalamus, pituitary gland, pancreas and parathyroid glands, thyrocalcitonin of the thyroid gland); derivatives of amino acids (hormones of the adrenal medulla - adrenaline and norepinephrine, thyroid gland - thyroxine, triiodothyronine).

Intracellular (cytosolic) mechanism of action . It is characteristic of steroid hormones (corticosteroids, sex hormones - androgens, estrogens and gestagens). Steroid hormones interact with receptors located in the cytoplasm. The resulting hormone-receptor complex is transferred to the nucleus and acts directly on the genome, stimulating or inhibiting its activity, i.e. acts on DNA synthesis by changing the rate of transcription and the amount of informational (matrix) RNA (mRNA). An increase or decrease in the amount of mRNA affects protein synthesis during translation, which leads to a change in the functional activity of the cell.

Currently, the following options for the action of hormones are distinguished:

1. hormonal or haemocrine those. action at a considerable distance from the place of formation;
2. isocrine, or local, when a chemical substance synthesized in one cell has an effect on a cell located in close contact with the first, and the release of this substance is carried out into the interstitial fluid and blood;
3. neurocrine, or neuroendocrine (synaptic and non-synaptic), an action when the hormone, being released from the nerve endings, performs the function of a neurotransmitter or neuromodulator, i.e. a substance that alters (usually enhances) the action of a neurotransmitter;
4. paracrine- a kind of isocrine action, but at the same time, the hormone formed in one cell enters the intercellular fluid and affects a number of cells located in close proximity;
5. juxtacrine- a kind of paracrine action, when the hormone does not enter the intercellular fluid, and the signal is transmitted through the plasma membrane of a nearby other cell;
6. autocrine action, when a hormone released from a cell affects the same cell, changing its functional activity;
7. saline action when a hormone from one cell enters the lumen of the duct and thus reaches another cell, affecting it specific impact(eg, some gastrointestinal hormones).

The synthesis of protein hormones, like other proteins, is under genetic control, and typical mammalian cells express genes that encode between 5,000 and 10,000 different proteins, and some highly differentiated cells up to 50,000 proteins. All protein synthesis begins with transposition of DNA segments, then transcription, post-transcriptional processing, translation, post-translational processing and modification. Many polypeptide hormones are synthesized in the form of large precursors - prohormones(proinsulin, proglucagon, proopiomelanocortin, etc.). The conversion of prohormones into hormones is carried out in the Golgi apparatus.

There are two main mechanisms of action of hormones at the cellular level:
1. Implementation of the effect from the outer surface of the cell membrane.
2. Implementation of the effect after the penetration of the hormone into the cell.

1) Implementation of the effect from the outer surface of the cell membrane

In this case, the receptors are located on the cell membrane. As a result of the interaction of the hormone with the receptor, a membrane enzyme, adenylate cyclase, is activated. This enzyme contributes to the formation of adenosine triphosphoric acid (ATP) of the most important intracellular mediator for the implementation of hormonal effects - cyclic 3,5-adenosine monophosphate (cAMP). cAMP activates the cellular enzyme protein kinase, which implements the action of the hormone. It has been established that hormone-dependent adenylate cyclase is a common enzyme that is affected by various hormones, while hormone receptors are multiple and specific to each hormone. secondary intermediaries in addition to cAMP, there may be cyclic 3,5-guanosine monophosphate (cGMP), calcium ions, inositol triphosphate. This is how peptide, protein hormones, tyrosine derivatives - catecholamines act. characteristic feature The action of these hormones is the relative speed of the response, which is due to the activation of previous already synthesized enzymes and other proteins.

Hormones carry out their biological action by complexing with receptors - informational molecules that transform a hormonal signal into a hormonal action. Most hormones interact with receptors located on plasma membranes cells, and other hormones - with receptors localized intracellularly, i.e. With cytoplasmic And nuclear.

Plasma receptors, depending on the structure, are divided into:

1. seven fragments(loops);
2. receptors, the transmembrane segment of which consists of one fragment(loops or chains);
3. receptors, the transmembrane segment of which consists of four fragments(loops).

Hormones whose receptor consists of seven transmembrane fragments include:
ACTH, TSH, FSH, LH, chorionic gonadotropin, prostaglandins, gastrin, cholecystokinin, neuropeptide Y, neuromedin K, vasopressin, epinephrine (a-1 and 2, b-1 and 2), acetylcholine (M1, M2, M3 and M4) , serotonin (1A, 1B, 1C, 2), dopamine (D1 and D2), angiotensin, substance K, substance P, or neurokinin types 1, 2 and 3, thrombin, interleukin-8, glucagon, calcitonin, secretin, somatoliberin, VIP, pituitary adenylate cyclase-activating peptide, glutamate (MG1 – MG7), adenine.

The second group includes hormones that have one transmembrane fragment:
STH, prolactin, insulin, somatomammotropin or placental lactogen, IGF-1, nerve growth factors or neurotrophins, hepatocyte growth factor, atrial natriuretic peptide types A, B and C, oncostatin, erythropoietin, ciliary neurotrophic factor, leukemic inhibitory factor, factor tumor necrosis factors (p75 and p55), nerve growth factor, interferons (a, b and g), epidermal growth factor, neurodifferentiating factor, fibroblast growth factors, platelet growth factors A and B, macrophage colony stimulating factor, activin, inhibin, interleukins-2 , 3, 4, 5, 6 and 7, granulocyte-macrophage colony-stimulating factor, granulocyte colony-stimulating factor, low density lipoprotein, transferrin, IGF-2, urokinase plasminogen activator.

The hormones of the third group, the receptor of which has four transmembrane fragments, include:
acetylcholine (nicotinic muscle and nerve), serotonin, glycine, g-aminobutyric acid.

The coupling of the receptor with effector systems is carried out through the so-called G-protein, the function of which is to ensure the repeated conduction of the hormonal signal at the level of the plasma membrane. G-protein in an activated form stimulates the synthesis of cyclic AMP through adenylate cyclase, which triggers a cascade mechanism for activating intracellular proteins.

The general fundamental mechanism through which the biological effects of "secondary" messengers inside the cell are realized is the process phosphorylation - dephosphorylation proteins with the participation of a wide variety of protein kinases that catalyze the transport of the end group from ATP to the OH groups of serine and threonine, and in some cases, tyrosine of target proteins. The process of phosphorylation is the most important post-translational chemical modification of protein molecules, radically changing both their structure and functions. In particular, it causes a change structural properties(association or dissociation of constituent subunits), activation or inhibition of their catalytic properties, ultimately determining the rate of chemical reactions and, in general, the functional activity of cells.

Adenylate cyclase messenger system

The most studied is the adenylate cyclase pathway of hormonal signal transmission. It involves at least five well-studied proteins:
1)hormone receptor;
2)adenylate cyclase enzyme, which performs the function of synthesis of cyclic AMP (cAMP);
3)G protein, which communicates between adenylate cyclase and the receptor;
4)cAMP-dependent protein kinase, catalyzing the phosphorylation of intracellular enzymes or target proteins, respectively changing their activity;
5)phosphodiesterase, which causes the breakdown of cAMP and thereby terminates (breaks) the action of the signal

It has been shown that the binding of the hormone to the β-adrenergic receptor leads to structural changes the intracellular domain of the receptor, which in turn ensures the interaction of the receptor with the second protein of the signaling pathway, GTP-binding.

GTP-binding protein - G protein- is a mixture of 2 types of proteins:
active G s (from English stimulatory G)
inhibitory G i
Each of them has three different subunits (α-, β- and γ-), i.e. they are heterotrimers. The β-subunits of G s and G i have been shown to be identical; at the same time, α-subunits, which are products of different genes, turned out to be responsible for the manifestation of activator and inhibitory activity by the G-protein. The hormone receptor complex gives the G-protein the ability not only to easily exchange endogenous bound GDP for GTP, but also to transfer the Gs-protein to an activated state, while the active G-protein dissociates in the presence of Mg 2+ ions into β-, γ-subunits and a complex α-subunit G s in the GTP form; this active complex then moves to the adenylate cyclase molecule and activates it. The complex itself then undergoes self-inactivation due to the decay energy of GTP and reassociation of β- and γ-subunits with the formation of the original GDP form G s .

Retz- receptor; G- G-protein; AC-adenylate cyclase.

It is an integral protein of plasma membranes, its active center is oriented towards the cytoplasm and catalyzes the reaction of cAMP synthesis from ATP:

The catalytic component of adenylate cyclase, isolated from various animal tissues, is represented by a single polypeptide. In the absence of G-proteins, it is practically inactive. It contains two SH-groups, one of which is involved in conjugation with the Gs-protein, and the second is necessary for the manifestation of catalytic activity. Under the action of phosphodiesterase, cAMP is hydrolyzed to form inactive 5 "-AMP.

protein kinase is an intracellular enzyme through which cAMP realizes its effect. Protein kinase can exist in 2 forms. In the absence of cAMP, protein kinase is present as a tetrameric complex consisting of two catalytic (C2) and two regulatory (R2) subunits; in this form, the enzyme is inactive. In the presence of cAMP, the protein kinase complex reversibly dissociates into one R 2 subunit and two free C catalytic subunits; the latter have enzymatic activity, catalyzing the phosphorylation of proteins and enzymes, thus changing the cellular activity.

The activity of many enzymes is regulated by cAMP-dependent phosphorylation; accordingly, most hormones of a protein-peptide nature activate this process. However, a number of hormones have an inhibitory effect on adenylate cyclase, respectively, reducing the level of cAMP and protein phosphorylation. In particular, the hormone somatostatin, by combining with its specific receptor, the inhibitory G-protein (Gi, which is a structural homologue of the Gs-protein), inhibits adenylate cyclase and cAMP synthesis, i.e. causes an effect directly opposite to that caused by adrenaline and glucagon. In a number of organs, prostaglandins (in particular, PGE 1) also have an inhibitory effect on adenylate cyclase, although in the same organ (depending on the cell type) the same PGE 1 can activate cAMP synthesis.

The mechanism of activation and regulation of muscle glycogen phosphorylase, which activates the breakdown of glycogen, has been studied in more detail. There are 2 forms:
catalytically active phosphorylase a And
inactive - phosphorylase b.

Both phosphorylases are built from two identical subunits, in each the serine residue at position 14 undergoes the process of phosphorylation–dephosphorylation, activation and inactivation, respectively.

Under the action of phosphorylase b kinase, whose activity is regulated by cAMP-dependent protein kinase, both subunits of the molecule of the inactive form of phosphorylase b undergo covalent phosphorylation and are converted into active phosphorylase a. Dephosphorylation of the latter under the action of a specific phosphatase phosphorylase a leads to enzyme inactivation and a return to its original state.

IN muscle tissue open 3 types regulation of glycogen phosphorylase.
First type – covalent regulation based on hormone-dependent phosphorylation-dephosphorylation of phosphorylase subunits.
Second type – allosteric regulation. It is based on the adenylation–deadenylation reactions of glycogen phosphorylase b subunits (activation–inactivation, respectively). The direction of the reactions is determined by the ratio of the concentrations of AMP and ATP, which are attached not to the active center, but to the allosteric center of each subunit.

In the working muscle, the accumulation of AMP, due to the consumption of ATP, causes adenylation and activation of phosphorylase b. At rest, on the contrary, high concentrations of ATP, displacing AMP, lead to allosteric inhibition of this enzyme by deadenylation.
Third type – calcium regulation, based on the allosteric activation of phosphorylase b kinase by Ca 2+ ions, the concentration of which increases with muscle contraction, thereby contributing to the formation of active phosphorylase a.

Guanylate cyclase messenger system

Enough for a long time cyclic guanosine monophosphate (cGMP) was considered as the antipode of cAMP. He was credited with functions opposite to cAMP. To date, a lot of evidence has been obtained that cGMP plays an independent role in the regulation of cell function. In particular, in the kidneys and intestines, it controls ion transport and water exchange, in the heart muscle it serves as a signal of relaxation, etc.

The biosynthesis of cGMP from GTP is carried out under the action of specific guanylate cyclase, by analogy with the synthesis of cAMP:

Adrenaline receptor complex: AC- adenylate cyclase, G- G-protein; C and R- catalytic and regulatory subunits of protein kinase, respectively; KF- phosphorylase b kinase; F- phosphorylase; Glk-1-P- glucose-1-phosphate; Glk-6-P- glucose-6-phosphate; UDF-Glk- uridine diphosphate glucose; HS- glycogen synthase.

Four different forms of guanylate cyclase are known, three of which are membrane-bound and one soluble is open in the cytosol.

Membrane-bound forms are composed of 3 plots:
receptor, localized on outer surface plasma membrane;
intramembrane domain And
catalytic component, the same for different forms enzyme.
Guanylate cyclase is open in many organs (heart, lungs, kidneys, adrenal glands, intestinal endothelium, retina, etc.), which indicates its wide participation in the regulation of intracellular metabolism mediated through cGMP. The membrane-bound enzyme is activated through the corresponding receptors by short extracellular peptides, in particular, the hormone atrial natriuretic peptide (ANP), a thermostable toxin of gram-negative bacteria, etc. ANF, as is known, is synthesized in the atrium in response to an increase in blood volume, enters the kidneys with blood, activates guanylate cyclase (correspondingly increases the level of cGMP), promoting the excretion of Na and water. Smooth muscle cells blood vessels also contain a similar receptor-guanylate cyclase system, through which the ANF associated with the receptor has a vasodilating effect, helping to reduce blood pressure. IN epithelial cells intestine as an activator of the receptor-guanylate cyclase system can serve bacterial endotoxin, which leads to a slowdown in the absorption of water in the intestines and the development of diarrhea.

The soluble form of guanylate cyclase is a heme-containing enzyme consisting of 2 subunits. Nitrovasodilators are involved in the regulation of this form of guanylate cyclase, free radicals products of lipid peroxidation. One of the well-known activators is endothelial factor (EDRF) causing vascular relaxation. The active component, natural ligand, of this factor is nitric oxide NO. This form of the enzyme is also activated by some nitrosovasodilators (nitroglycerin, nitroprusside, etc.) used for heart disease; the breakdown of these drugs also releases NO.

Nitric oxide is formed from the amino acid arginine with the participation of a complex Ca 2+ -dependent enzyme system with a mixed function called NO-synthase:

Nitric oxide, when interacting with the heme of guanylate cyclase, contributes to rapid education cGMP, which reduces the force of heart contractions by stimulating ion pumps that function at low concentrations of Ca 2+ . However, the action of NO is short-lived, several seconds, localized - near the site of its synthesis. A similar effect, but longer, is provided by nitroglycerin, which releases NO more slowly.

Evidence has been obtained that most of the effects of cGMP are mediated through a cGMP-dependent protein kinase called protein kinase G. This enzyme, which is widespread in eukaryotic cells, was obtained in pure form. It consists of 2 subunits - a catalytic domain with a sequence similar to the C-subunit of protein kinase A (cAMP-dependent), and a regulatory domain similar to the R-subunit of protein kinase A. However, protein kinases A and G recognize different protein sequences, regulating, respectively phosphorylation of the OH group of serine and threonine of various intracellular proteins and thereby exerting various biological effects.

Level of cyclic cAMP nucleotides and cGMP in the cell is controlled by the corresponding phosphodiesterases, which catalyze their hydrolysis to 5'-nucleotide monophosphates and differ in their affinity for cAMP and cGMP. A soluble calmodulin-dependent phosphodiesterase and a membrane-bound isoform not regulated by Ca2+ and calmodulin have been isolated and characterized.

Ca 2+ messenger system

Ca 2+ ions play a central role in the regulation of many cellular functions. A change in the concentration of intracellular free Ca 2+ is a signal for the activation or inhibition of enzymes, which in turn regulate metabolism, contractile and secretory activity, adhesion and cell growth. Sources of Ca 2+ can be intra- and extracellular. Normally, the concentration of Ca 2+ in the cytosol does not exceed 10 -7 M, and its main sources are the endoplasmic reticulum and mitochondria. Neurohormonal signals lead to a sharp increase in Ca 2+ concentration (up to 10–6 M), which comes both from the outside through the plasma membrane (more precisely, through voltage-gated and receptor-gated calcium channels) and from intracellular sources. One of essential mechanisms conducting a hormonal signal in the calcium-messenger system is the launch of cellular reactions (responses) by activating a specific Ca 2+ -calmodulin-dependent protein kinase. The regulatory subunit of this enzyme turned out to be Ca 2+ -binding protein calmodulin. With an increase in Ca 2+ concentration in the cell in response to incoming signals, a specific protein kinase catalyzes the phosphorylation of many intracellular target enzymes, thereby regulating their activity. Phosphorylase b kinase activated by Ca 2+ ions, like NO-synthase, was shown to contain calmodulin as a subunit. Calmodulin is part of many other Ca 2+ -binding proteins. With an increase in calcium concentration, the binding of Ca 2+ to calmodulin is accompanied by its conformational changes, and in this Ca 2+ -bound form, calmodulin modulates the activity of many intracellular proteins (hence its name).

The intracellular system of messengers also includes derivatives of phospholipids of eukaryotic cell membranes, in particular, phosphorylated derivatives of phosphatidylinositol. These derivatives are released in response to a hormonal signal (for example, from vasopressin or thyrotropin) under the action of a specific membrane-bound phospholipase C. As a result of successive reactions, two potential second messengers are formed - diacylglycerol and inositol-1,4,5-triphosphate.

The biological effects of these second messengers are realized in different ways. The action of diacylglycerol, as well as free Ca 2+ ions, is mediated through membrane-bound Ca-dependent enzyme protein kinase C, which catalyzes the phosphorylation of intracellular enzymes, changing their activity. Inositol-1,4,5-triphosphate binds to a specific receptor on the endoplasmic reticulum, facilitating the release of Ca 2+ ions from it into the cytosol.

Thus, the presented data on second messengers indicate that each of these systems of intermediaries hormonal effect corresponds to a certain class of protein kinases, although the possibility of a close relationship between these systems cannot be ruled out. The activity of type A protein kinases is regulated by cAMP, protein kinase G is regulated by cGMP; Ca 2+ -calmodulin-dependent protein kinases are under the control of intracellular [Ca 2+ ], and protein kinase type C is regulated by diacylglycerol in synergy with free Ca 2+ and acidic phospholipids. An increase in the level of any second messenger leads to the activation of the corresponding class of protein kinases and subsequent phosphorylation of their protein substrates. As a result, not only the activity changes, but also the regulatory and catalytic properties of many cell enzyme systems: ion channels, intracellular structural elements and genetic apparatus.

2) Implementation of the effect after the penetration of the hormone into the cell

In this case, the receptors for the hormone are located in the cytoplasm of the cell. The hormones of this mechanism of action, due to their lipophilicity, easily penetrate the membrane into the target cell and bind in its cytoplasm with specific receptor proteins. The hormone-receptor complex enters the cell nucleus. In the nucleus, the complex breaks down, and the hormone interacts with certain sections of nuclear DNA, resulting in the formation of a special messenger RNA. Messenger RNA leaves the nucleus and promotes the synthesis of a protein or protein-enzyme on the ribosomes. This is how steroid hormones and tyrosine derivatives act - thyroid hormones. Their action is characterized by a deep and long-term restructuring of cellular metabolism.

It is known that the effect of steroid hormones is realized through the genetic apparatus by changing gene expression. The hormone after delivery with blood proteins into the cell penetrates (by diffusion) through the plasma membrane and then through the nuclear membrane and binds to the intranuclear receptor-protein. The steroid–protein complex then binds to the DNA regulatory region, the so-called hormone-sensitive elements, promoting transcription of the corresponding structural genes, induction of de novo protein synthesis, and alteration of cell metabolism in response to a hormonal signal.

It should be emphasized that the main and distinctive feature of the molecular mechanisms of action of the two main classes of hormones is that the action of peptide hormones is realized mainly through post-translational (post-synthetic) modifications of proteins in cells, while steroid hormones (as well as thyroid hormones, retinoids, vitamin D3 hormones) act as regulators of gene expression.

Inactivation of hormones occurs in effector organs, mainly in the liver, where hormones undergo various chemical changes by binding to glucuronic or sulfuric acid, or as a result of the action of enzymes. Some of the hormones are excreted in the urine unchanged. The action of some hormones can be blocked due to the secretion of hormones that have an antagonistic effect.