Basic mechanisms of action of hormones. 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 to cell membrane changes its permeability to metabolites, such as glucose, amino acids, some ions. The intake of glucose, amino acids, in turn, affects biochemical processes in the cell, and a change in the distribution of ions on both sides of the membrane affects the electrical potential and function of the cells. The membrane type of action of hormones is rarely found in isolated form. For example, insulin has both a 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 the metabolism through an intracellular chemical mediator, 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 can penetrate through the lipid layer of the membrane into the cell, where they enter into a complex with cytosolic receptors. This complex regulates the amount of enzymes in the cell, selectively influencing the activity of nuclear chromosome genes, and thereby change the metabolism and functions of the cell. This type of action of the hormone is called direct, in contrast to the membrane-intracellular, when the hormone regulates metabolism only indirectly, through intracellular mediators.
Thyroid and parathyroid hormones
Hormones thyroid gland
Thyroid secretes two types of hormones various influences for 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 organism. Iodothyronines act on many tissues of the body, but in most on the tissues of the liver, heart, kidneys, skeletal muscle and, to a lesser extent, adipose and nervous tissue.
With hyperfunction of the thyroid gland (hyperthyroidism), there is an excessive formation of iodothyronines. characteristic feature thyrotoxicosis is an accelerated breakdown of carbohydrates and fats (mobilized from fat depots). fast combustion fatty acids, glycerol and glycolysis products require a large consumption of oxygen. Mitochondria increase in size, swell, change their shape. Therefore, sometimes thyrotoxicosis is called "mitochondrial disease." Externally, hyperthyroidism manifests itself in the form the following symptoms: an increase in basal metabolism, an increase in body temperature (increased heat production), weight loss, severe tachycardia, increased nervous excitability, bulging eyes, etc. These disorders are removed either by surgical removal of a part of the thyroid gland, or with the help of drugs that depress its activity.
With hypofunction (hypothyroidism) of the thyroid gland, there is a lack of iodothyronines. Hypothyroidism in early childhood is called cretinism or myxedema in children, and in adults it is simply myxedema. Cretinism is characterized by pronounced physical and mental retardation. This is due to a decrease in the action of iodothyronines on cell division and differentiation, which leads to 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, 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 iodothyronines.
The second group includes calciotonin (a protein with a molecular weight of 30,000), it regulates phosphorus-calcium metabolism, its operation is discussed below.
Mechanisms of action of hormones.
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 poorly 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 non-specific ones (albumins).
Hormones of direct action, due to their lipophilicity, are able to diffuse through the double lipid layer of target cell membranes. Receptors for these hormones are found in the cytosol. The resulting complex of the hormone with the receptor moves to the cell nucleus, where it binds to chromatin and acts on DNA. As a result, the rate of RNA synthesis on the DNA template (transcription) and the rate of formation of specific enzymatic proteins on the RNA template (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. Mechanism of influence on the cell of hormones of direct action.
As you already know, the regulation of protein synthesis can be carried out using the mechanisms of induction and repression.
The 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 protein-enzyme 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 protein-enzyme in the cell selectively decreases and the rate of chemical reactions catalyzed by it decreases. 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 after 2 - 3 hours after penetration into the cell.
2. Distant hormones. Distant hormones include hydrophilic (water-soluble) hormones - catecholamines and hormones of a protein-peptide nature. Since these substances are insoluble in lipids, they cannot penetrate cell membranes. Receptors for these hormones are located on outer surface plasma membrane target cells. Long-range hormones realize their effect on the cell with the help of a second messenger, which most often acts as cyclic AMP (cAMP).
Cyclic AMP is synthesized from ATP by adenylate cyclase:
The mechanism of distant action of hormones is shown in Figure 3.
Figure 3. Mechanism of influence of long-range hormones on the cell.
The interaction of the hormone with its specific receptor leads to the activation of the G-protein of the cell membrane. The G protein binds GTP and activates adenylate cyclase.
Active adenylate cyclase converts ATP to cAMP, cAMP activates protein kinase.
An 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 at the expense of ATP, either activating them or inactivating them. As a result of this, the rate of chemical reactions in target cells changes (in some cases it increases, in others it 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 are very high sensitivity hormones, which is why 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 to 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 Vehicle membranes. 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 functional activity cells.
The action of hormones is based on the 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 existing enzymes. And important role belongs cyclic adenosine monophosphate(cAMP) which is here secondary intermediary(role of primary
the mediator is performed by the hormone itself). It is also possible to increase the concentration of enzymes by accelerating their biosynthesis by activating genes.
Mechanism of action of peptide and steroid hormones different. Amines and peptide hormones do not penetrate into the cell, but join on its surface to specific receptors in the cell membrane. Receptor bound to an enzyme adenylate cyclase. The complex of the hormone with the receptor 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 by their phosphorylation, and 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 to the nucleus; III - the hormone interacts reversibly with the DNA of chromosomes; IV - the hormone activates the gene on which matrix (information) RNA (mRNA) is formed; V-mRNA leaves the nucleus and initiates the synthesis of a protein (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, as well as Tz 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 in a certain DNA region of one of the chromosomes, matrix (informational) RNA (mRNA) is synthesized, which passes from the nucleus to the cytoplasm, attaches to ribosomes and induces protein synthesis here (Fig. 2.4).
Unlike peptides that activate enzymes, steroid hormones cause the synthesis of new enzyme molecules. In this regard, the effects of steroid hormones appear much more slowly than the action of peptide hormones, but usually last longer.
2.2.5. Classification of hormones
Based on functional criteria, there are 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 relationship between the CNS 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 → peripheral endocrine glands. All elements of this system are combined feedback. The function of part of the 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 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 concepts, 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.
There are the following types of the mechanism of action of hormones: membrane, membrane-intracellular and intracellular (cytosolic).
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, 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 affect 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, actually adenylate cyclase, 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 a hormone-receptor complex is formed, the formation of the N-protein-GTP (guanosine triphosphate) complex occurs, 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 ATP membrane.
Even one molecule of the hormone bound to the receptor causes adenylate cyclase to work. In this case, 10-100 cAMP molecules are formed inside the cell per molecule of the bound hormone. Adenylate cyclase remains active as long as the hormone-receptor complex exists. Guanylate cyclase works in a similar way.
In the cytoplasm of the cell are inactive protein kinases. Cyclic nucleotides, cAMP and GMP, 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 certain hormone, either adenylate ceclase or guanylate ceclase is switched on, and either cAMP or cGMP is formed, respectively.
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 already existing enzymes by covalent modification, that is, by phosphorylation; change in the amount of enzymatic protein due to a change in the rate of its biosynthesis.
The influence of cyclic nucleotides on biochemical processes is terminated 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 cleaves phosphoric acid from enzymatic proteins, as a result of which they become inactive.
There are very few calcium ions inside the cell, but there are more of them outside the cell. They come 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 a change in the physiological functions of cells. Through calcium ions, the hormones oxytocin, insulin, prostaglandin F 2α act. 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 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.
