Basic mechanisms of hormone action. Membrane-intracellular mechanism of action of hormones
There are three possible options mechanism of action of hormones.
Membrane or local mechanism- lies in the fact that the hormone at the site of binding with cell membrane changes its permeability to metabolites, for example, glucose, amino acids, and some ions. The supply of glucose and amino acids, in turn, affects biochemical processes in the cell, and changing the distribution of ions on both sides of the membrane affects the electrical potential and function of the cells. The membrane type of hormone action is rarely found in isolated form. For example, insulin has both membrane (causes local changes transport of ions, glucose and amino acids), and membrane-intracellular type of action.
Membrane-intracellular the type of action (or indirect) is characteristic of hormones that do not penetrate the cell and therefore affect metabolism through an intracellular chemical messenger, which is the authorized representative of the hormone inside the cell. The hormone, through membrane receptors, affects the function of signaling systems (usually enzymes) that trigger the formation or entry of intracellular mediators. And the latter, in turn, affect the activity and quantity different enzymes and thereby change the metabolism in the cell.
Cytosolic mechanism action is characteristic of lipophilic hormones that are able to penetrate through the lipid layer of the membrane into the cell, where they enter into a complex with cytosolic receptors. This complex regulates the number of enzymes in the cell, selectively influencing the activity of nuclear chromosome genes, and thereby changing the metabolism and functions of the cell. This type of hormone action is called direct, in contrast to the membrane-intracellular action, when the hormone regulates metabolism only indirectly, through intracellular intermediaries.
Hormones of the thyroid and parathyroid glands
Hormones thyroid gland
Thyroid gland secretes two groups of hormones with different influence on metabolism. The first group is iodothyronines: thyroxine and triiodothyronine. These hormones regulate energy metabolism and influence cell division and differentiation, determining the development of the body. Iodothyronines act on many tissues of the body, but in to the greatest extent on the tissue of the liver, heart, kidneys, skeletal muscles and to a lesser extent on adipose and nervous tissue.
With hyperfunction of the thyroid gland (hyperthyroidism), excessive formation of iodothyronines is observed. A characteristic feature thyrotoxicosis is the accelerated breakdown of carbohydrates and fats (mobilized from fat depots). Fast combustion fatty acids, glycerol and glycolysis products require high oxygen consumption. Mitochondria increase in size, swell, and their shape changes. Therefore, thyrotoxicosis is sometimes called “mitochondrial disease.” Externally, hyperthyroidism manifests itself as the following symptoms: increased basal metabolism, increased body temperature (increased heat production), weight loss, severe tachycardia, increased nervous excitability, bulging eyes, etc. These disorders can be relieved either by surgical removal of part of the thyroid gland, or with the help of drugs that inhibit its activity.
With hypofunction (hypothyroidism) of the thyroid gland there is a lack of iodothyronines. Hypothyroidism in early childhood called cretinism or myxedema in children, and in adults simply myxedema. Cretinism is characterized by pronounced physical and mental retardation. This is explained by a decrease in the effect of iodothyronines on cell division and differentiation, which entails slow and abnormal growth bone tissue, impaired differentiation of neurons. In adults, myxedema manifests itself in a decrease in basal metabolism and body temperature, memory impairment, and impaired skin(dryness, peeling), etc. In the tissues of the body, the metabolism of carbohydrates and fats and all energy processes are reduced. Hypothyroidism is eliminated by treatment with iodothyronine drugs.
The second group includes calciotonin (a protein with a molecular weight of 30,000), it regulates phosphorus-calcium metabolism, its action is discussed below.
Mechanisms of action of hormones.
Please note that the mechanism of action of hormones depends on its chemical nature and properties - solubility in water or fats. According to the mechanism of action, hormones can be divided into two groups: direct and distant action.
1. Hormones direct action. This group includes lipophilic (fat-soluble) hormones - steroids and iodothyronines. These substances are slightly soluble in water and therefore form complex compounds with plasma proteins in the blood. These proteins include both specific transport proteins (for example, transcortin, which binds hormones of the adrenal cortex) and nonspecific ones (albumin).
Direct-acting hormones, due to their lipophilicity, are able to diffuse through the lipid bilayer of target cell membranes. Receptors for these hormones are located in the cytosol. The resulting complex of the hormone with the receptor moves to the cell nucleus, where it binds to chromatin and affects DNA. As a result, the rate of RNA synthesis on the DNA matrix (transcription) and the rate of formation of specific enzymatic proteins on the RNA matrix (translation) change. This leads to a change in the amount of enzymatic proteins in target cells and a change in their direction chemical reactions(see Figure 2).
Figure 2. The mechanism of influence of direct-acting hormones on the cell.
As you already know, regulation of protein synthesis can be carried out using mechanisms of induction and repression.
Induction of protein synthesis occurs as a result of stimulation of the synthesis of the corresponding messenger RNA. At the same time, the concentration of a certain enzyme protein in the cell increases and the rate of chemical reactions catalyzed by it increases.
Repression of protein synthesis occurs by suppressing the synthesis of the corresponding messenger RNA. As a result of repression, the concentration of a certain enzyme protein in the cell is selectively reduced and the rate of chemical reactions catalyzed by it is reduced. Keep in mind that the same hormone can induce the synthesis of some proteins and repress the synthesis of other proteins. The effect of direct-acting hormones usually appears only 2 to 3 hours after penetration into the cell.
2. Hormones of distant action. Distant-acting hormones include hydrophilic (water-soluble) hormones - catecholamines and hormones of protein-peptide nature. Since these substances are lipid insoluble, they cannot penetrate cell membranes. Receptors for these hormones are located on outer surface plasma membrane target cells. Distant-acting hormones exert their effect on the cell with the help of a secondary messenger, which most often is cyclic AMP (cAMP).
Cyclic AMP is synthesized from ATP by the action of adenylate cyclase:
The mechanism of distant action of hormones is shown in Figure 3.
Figure 3. The mechanism of influence of distant-acting hormones on the cell.
The interaction of a hormone with its specific receptor leads to the activation of the G protein of the cell membrane. G protein binds GTP and activates adenylate cyclase.
Active adenylate cyclase converts ATP into cAMP, cAMP activates protein kinase.
Inactive protein kinase is a tetramer that consists of two regulatory (R) and two catalytic (C) subunits. As a result of interaction with cAMP, the tetramer dissociates and the active center of the enzyme is released.
Protein kinase phosphorylates enzyme proteins using ATP, either activating them or inactivating them. As a result of this, the rate of chemical reactions in target cells changes (in some cases increases, in others decreases).
Inactivation of cAMP occurs with the participation of the enzyme phosphodiesterase.
Hormones secreted by glands internal secretion, 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 have very high sensitivity to hormones, which is why they are called target organs or fabrics -targets. Hormones affect literally every aspect of metabolism, function and structure in the body.
According to modern ideas, the action of hormones is based on stimulation or inhibition of the catalytic function of certain enzymes. This effect is achieved by activating or inhibiting existing enzymes in cells by accelerating their synthesis through gene activation. Hormones can increase or decrease the permeability of cellular and subcellular membranes to enzymes and other biological active substances, due to which the action of the enzyme is facilitated or inhibited. hormone organic body iron
Diaphragm 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 vehicles membranes. Insulin has this effect by changing glucose transport. But this type of hormone transport rarely occurs in isolated form. Insulin, for example, has both a membrane and membrane-intracellular mechanism of action.
Membrane-intracellular mechanism . Hormones act according to the membrane-intracellular type, which do not penetrate the cell and therefore affect metabolism through an intracellular chemical intermediary. 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 noradrenaline, of the 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, changing the rate of transcription and the amount of messenger RNA (mRNA). An increase or decrease in the amount of mRNA affects protein synthesis during translation, which leads to changes functional activity cells.
The action of hormones is based on stimulation or inhibition of the catalytic function of certain enzymes in the cells of target organs. This action can be achieved by activating or inhibiting already existing enzymes. Moreover important role belongs cyclic adenosine monophosphate(cAMP) which is here secondary intermediary(the role of the primary
the hormone itself acts as an intermediary). It is also possible to increase the concentration of enzymes by accelerating their biosynthesis through gene activation.
The mechanism of action of peptide and steroid hormones different. Amines and peptide hormones do not penetrate into the cell, but attach to specific receptors in the cell membrane on its surface. Receptor bound to enzyme adenylate cyclase. The hormone-receptor complex activates adenylate cyclase, which breaks down ATP to form cAMP. The action of cAMP is realized through a complex chain of reactions leading to the activation of certain enzymes through their phosphorylation, they carry out the final effect of the hormone (Fig. 2.3).
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Rice. 2.4 Mechanism of action steroid hormones I - the hormone enters the cell and binds to a receptor in the cytoplasm; II - the receptor transports the hormone into the nucleus; III - the hormone interacts reversibly with the DNA of chromosomes; IV - the hormone activates the gene on which messenger RNA (mRNA) is formed; V-mRNA leaves the nucleus and initiates protein synthesis (usually an enzyme) on ribosomes; the enzyme realizes the final hormonal effect; 1 - cell membrane, 2 - hormone, 3 - receptor, 4 - nuclear membrane, 5 - DNA, 6 - mRNA, 7 - ribosome, 8 - protein (enzyme) synthesis. |
Steroid hormones and also Tk And T 4(thyroxine and triiodothyronine) are fat soluble, so they penetrate the cell membrane. The hormone binds to a receptor in the cytoplasm. The resulting hormone-receptor complex is transported to the cell nucleus, where it enters into a reversible interaction with DNA and induces the synthesis of a protein (enzyme) or several proteins. By turning on specific genes on a certain DNA section of one of the chromosomes, matrix (messenger) RNA (mRNA) is synthesized, which passes from the nucleus to the cytoplasm, attaches to ribosomes and induces protein synthesis here (Fig. 2.4).
Unlike enzyme-activating peptides, steroid hormones cause the synthesis of new enzyme molecules. In this regard, the effects of steroid hormones appear much more slowly than the effects of peptide hormones, but usually last longer.
2.2.5. Classification of hormones
Based on functional criteria, they distinguish three groups of hormones: 1) hormones that directly affect the target organ; these hormones are called effector 2) hormones, the main function of which is the regulation of the synthesis and release of effector hormones;
these hormones are called tropic 3) hormones produced nerve cells And regulating the synthesis and release of adenohypophysis hormones; These hormones are called releasing hormones, or liberins, if they stimulate these processes, or inhibitory hormones, statins, if they have the opposite effect. Close connection between the central nervous system and endocrine system carried out mainly with the help of these hormones.
In a complex system hormonal regulation organisms are distinguished more or less long chains regulation. Main line of interactions: CNS → hypothalamus → pituitary gland → peripheral endocrine glands. All elements of this system are combined feedback. The function of some endocrine glands is not under the regulatory influence of adenohypophysis hormones (for example, parathyroid glands, pancreas, etc.).
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 have a very high sensitivity to hormones, which is why they are called target organs or fabrics–targets. Hormones affect literally every aspect of metabolism, function and structure in the body.
According to modern concepts, the action of hormones is based on stimulation or inhibition of the catalytic function of certain enzymes. This effect is achieved by activating or inhibiting existing enzymes in cells by accelerating their synthesis through gene activation. Hormones can increase or decrease the permeability of cellular and subcellular membranes to enzymes and other biologically active substances, thereby facilitating or inhibiting the action of the enzyme.
The following types of mechanism of action of hormones are distinguished: membrane, membrane-intracellular and intracellular (cytosolic).
Diaphragm 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 transport. Insulin has this effect by changing glucose transport. But this type of hormone transport rarely occurs in isolated form. Insulin, for example, has both a membrane and membrane-intracellular mechanism of action.
Membrane-intracellular mechanism . Hormones act according to the membrane-intracellular type, which do not penetrate the cell and therefore affect metabolism through an intracellular chemical intermediary. 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 hormones - thyroxine, triiodothyronine).
The functions of intracellular chemical messengers of hormones are performed by cyclic nucleotides - cyclic 3 ׳ ,5׳ – adenosine monophosphate (cAMP) and cyclic 3 ׳ ,5׳ – guanosine monophosphate (cGMP), calcium ions.
Hormones influence the formation of cyclic nucleotides: cAMP - through adenylate cyclase, cGMP - through guanylate cyclase.
Adenylate cyclase is built into the cell membrane and consists of 3 interconnected parts: receptor (R), represented by a set of membrane receptors located outside the membrane, conjugating (N), represented by a special N protein located in the lipid layer of the membrane, and catalytic (C), which is an enzymatic protein, that is, adenylate cyclase itself, which converts ATP (adenosine triphosphate) into cAMP.
Adenylate cyclase works according to the following scheme. As soon as the hormone binds to the receptor (R) and the hormone-receptor complex is formed, the N–protein–GTP (guanosine triphosphate) complex is formed, which activates the catalytic (C) part of adenylate ceclase. Activation of adenylate cyclase leads to the formation of cAMP inside the cell on the inner surface of the membrane from ATP.
Even one molecule of the hormone that binds to the receptor causes adenylate cyclase to work. In this case, for one molecule of bound hormone, 10-100 molecules of cAMP are formed inside the cell. Adenylate cyclase remains active as long as the hormone-receptor complex exists. Guanylate cyclase works in a similar way.
Inactive protein kinases are found in the cell cytoplasm. Cyclic nucleotides - cAMP and cGMP - activate protein kinases. There are cAMP-dependent and cGMP-dependent protein kinases that are activated by their cyclic nucleotide. Depending on the membrane receptor that binds a particular hormone, either adenylate ceclase or guanylate ceclase is switched on, and accordingly, either cAMP or cGMP is formed.
Most hormones act through cAMP, and only oxytocin, thyrocalcitonin, insulin and adrenaline act through cGMP.
With the help of activated protein kinases, two types of regulation of enzyme activity are carried out: activation of existing enzymes by covalent modification, that is, phospholation; changing the amount of enzyme protein due to changes in the rate of its biosynthesis.
The influence of cyclic nucleotides on biochemical processes ceases under the influence of a special enzyme, phosphodiesterase, which destroys cAMP and cGMP. Another enzyme, phosphoprotein phosphase, destroys the result of the action of protein kinase, that is, it splits off phosphoric acid from enzyme proteins, as a result of which they become inactive.
There are very few calcium ions inside the cell; there are more outside the cell. They enter from the extracellular environment through calcium channels in the membrane. In the cell, calcium interacts with the calcium-binding protein calmodulin (CM). This complex changes the activity of enzymes, which leads to changes in the physiological functions of cells. The hormones oxytocin, insulin, and prostaglandin F 2α act through calcium ions. Thus, the sensitivity of tissues and organs to hormones depends on membrane receptors, and their specific regulatory effect is determined by an intracellular mediator.
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, changing the rate of transcription and the amount of messenger 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.
