Mechanisms of action of hydrophilic hormones on target cells. The role of thyroid hormones in the processes of growth, mental development and metabolism Scheme of action on target cells of steroid hormones
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Mechanisms of action of hormones on target cells
Depending on the structure of the hormone, there are two types of interaction. If the hormone molecule is lipophilic (for example, steroid hormones), then it can penetrate the lipid layer of the outer membrane of target cells. If the molecule is large or polar, then its penetration into the cell is impossible. Therefore, for lipophilic hormones, the receptors are located inside the target cells, and for hydrophilic hormones, the receptors are located in the outer membrane.
To obtain a cellular response to a hormonal signal in the case of hydrophilic molecules, an intracellular signal transduction mechanism operates. This occurs with the participation of substances called second messengers. Hormone molecules are very diverse in shape, but “second messengers” are not.
The reliability of signal transmission is ensured by the very high affinity of the hormone for its receptor protein.
What are the intermediaries that are involved in the intracellular transmission of humoral signals?
These are cyclic nucleotides (cAMP and cGMP), inositol triphosphate, calcium-binding protein - calmodulin, calcium ions, enzymes involved in the synthesis of cyclic nucleotides, as well as protein kinases - protein phosphorylation enzymes. All these substances are involved in the regulation of the activity of individual enzyme systems in target cells.
Let us examine in more detail the mechanisms of action of hormones and intracellular mediators.
There are two main ways of transmitting a signal to target cells from signaling molecules with a membrane mechanism of action:
adenylate cyclase (or guanylate cyclase) systems;
phosphoinositide mechanism.
Before finding out the role of the cyclase system in the mechanism of action of hormones, let's consider the definition of this system. The cyclase system is a system consisting of adenosine cyclophosphate, adenylate cyclase and phosphodiesterase contained in the cell, which regulates the permeability of cell membranes, is involved in the regulation of many metabolic processes of a living cell, and mediates the action of some hormones. That is, the role of the cyclase system is that they are second intermediaries in the mechanism of action of hormones.
The adenylate cyclase - cAMP system. The membrane enzyme adenylate cyclase can be found in two forms - activated and non-activated. Activation of adenylate cyclase occurs under the influence of a hormone-receptor complex, the formation of which leads to the binding of guanyl nucleotide (GTP) to a special regulatory stimulating protein (GS protein), after which the GS protein causes the addition of magnesium to adenylate cyclase and its activation. This is how the hormones activating adenylate cyclase act: glucagon, thyrotropin, parathyrin, vasopressin, gonadotropin, etc. Some hormones, on the contrary, suppress adenylate cyclase (somatostatin, angiotensin-P, etc.).
Under the influence of adenylate cyclase, cAMP is synthesized from ATP, which causes activation of protein kinases in the cell cytoplasm, which ensure the phosphorylation of numerous intracellular proteins. This changes the permeability of membranes, i.e. causes metabolic and, accordingly, functional changes typical for the hormone. The intracellular effects of cAMP are also manifested in their influence on the processes of proliferation, differentiation, and the availability of membrane receptor proteins to hormone molecules.
"Guanylate cyclase - cGMP" system. Activation of membrane guanylate cyclase occurs not under the direct influence of the hormone-receptor complex, but indirectly through ionized calcium and oxidative membrane systems. This is how atrial natriuretic hormone, atriopeptide, a tissue hormone of the vascular wall, realizes its effects. In most tissues, the biochemical and physiological effects of cAMP and cGMP are opposite. Examples include stimulation of cardiac contractions under the influence of cAMP and inhibition of them by cGMP, stimulation of contractions of intestinal smooth muscles by cGMP and inhibition of cAMP.
In addition to the adenylate cyclase or guanylate cyclase systems, there is also a mechanism for transmitting information within the target cell with the participation of calcium ions and inositol triphosphate.
Inositol triphosphate is a substance that is a derivative of a complex lipid - inositol phosphatide. It is formed as a result of the action of a special enzyme - phospholipase "C", which is activated as a result of conformational changes in the intracellular domain of the membrane receptor protein.
This enzyme hydrolyzes the phosphoester bond in the phosphatidyl-inositol 4,5-bisphosphate molecule to form diacylglycerol and inositol triphosphate.
It is known that the formation of diacylglycerol and inositol triphosphate leads to an increase in the concentration of ionized calcium inside the cell. This leads to the activation of many calcium-dependent proteins inside the cell, including the activation of various protein kinases. And here, as with the activation of the adenylate cyclase system, one of the stages of signal transmission inside the cell is protein phosphorylation, which leads to a physiological response of the cell to the action of the hormone.
A special calcium-binding protein, calmodulin, takes part in the phosphoinositide signaling mechanism in the target cell. This is a low molecular weight protein (17 kDa), 30% consisting of negatively charged amino acids (Glu, Asp) and therefore capable of actively binding Ca+2. One calmodulin molecule has 4 calcium-binding sites. After interaction with Ca+2, conformational changes occur in the calmodulin molecule and the “Ca+2-calmodulin” complex becomes capable of regulating the activity (allosterically inhibiting or activating) many enzymes - adenylate cyclase, phosphodiesterase, Ca+2,Mg+2-ATPase and various protein kinases.
In different cells, when the Ca+2-calmodulin complex acts on isoenzymes of the same enzyme (for example, different types of adenylate cyclase), in some cases activation is observed, and in others inhibition of the cAMP formation reaction is observed. These different effects occur because the allosteric centers of the isoenzymes may include different amino acid radicals and their response to the action of the Ca+2-calmodulin complex will be different.
Thus, the role of “second messengers” for transmitting signals from hormones in target cells can be:
cyclic nucleotides (c-AMP and c-GMP);
complex "Ca-calmodulin";
diacylglycerol;
inositol triphosphate.
The mechanisms for transmitting information from hormones inside target cells using the listed intermediaries have common features:
one of the stages of signal transmission is protein phosphorylation;
cessation of activation occurs as a result of special mechanisms initiated by the process participants themselves - there are negative feedback mechanisms.
Hormones are the main humoral regulators of the physiological functions of the body, and their properties, biosynthesis processes and mechanisms of action are now well known. Hormones are highly specific substances in relation to target cells and have very high biological activity.
The human body exists as a single whole thanks to a system of internal connections that ensures the transfer of information from one cell to another in the same tissue or between different tissues. Without this system, it is impossible to maintain homeostasis. Three systems take part in the transfer of information between cells in multicellular living organisms: the CENTRAL NERVOUS SYSTEM (CNS), the ENDOCRINE SYSTEM (ENDOCRINE GLANDS) and the IMMUNE SYSTEM.
The methods of transmitting information in all of these systems are chemical. SIGNAL molecules can be intermediaries in the transfer of information.
These signaling molecules include four groups of substances: ENDOGENOUS BIOLOGICALLY ACTIVE SUBSTANCES (immune response mediators, growth factors, etc.), NEUROMEDIATORS, ANTIBODIES (immunoglobulins) and HORMONES.
B I O C H I M I A G O R M O N O V
HORMONES are biologically active substances that are synthesized in small quantities in specialized cells of the endocrine system and are delivered through circulating fluids (for example, blood) to target cells, where they exert their regulatory effect.
Hormones, like other signaling molecules, share some common properties.
GENERAL PROPERTIES OF HORMONES.
1) are released from the cells that produce them into the extracellular space;
2) are not structural components of cells and are not used as a source of energy.
3) are able to specifically interact with cells that have receptors for a given hormone.
4) have very high biological activity - they effectively act on cells in very low concentrations (about 10 -6 - 10 -11 mol/l).
MECHANISMS OF ACTION OF HORMONES.
Hormones have an effect on target cells.
TARGET CELLS are cells that specifically interact with hormones using special receptor proteins. These receptor proteins are located on the outer membrane of the cell, or in the cytoplasm, or on the nuclear membrane and other organelles of the cell.
BIOCHEMICAL MECHANISMS OF SIGNAL TRANSMISSION FROM A HORMONE TO A TARGET CELL.
Any receptor protein consists of at least two domains (regions) that provide two functions:
- “recognition” of the hormone;
Conversion and transmission of the received signal into the cell.
How does the receptor protein recognize the hormone molecule with which it can interact?
One of the domains of the receptor protein contains a region that is complementary to some part of the signal molecule. The process of receptor binding to a signaling molecule is similar to the process of formation of an enzyme-substrate complex and can be determined by the value of the affinity constant.
Most receptors have not been sufficiently studied because their isolation and purification are very difficult, and the content of each type of receptor in cells is very low. But it is known that hormones interact with their receptors through physical and chemical means. Electrostatic and hydrophobic interactions are formed between the hormone molecule and the receptor. When the receptor binds to the hormone, conformational changes in the receptor protein occur and the complex of the signaling molecule with the receptor protein is activated. In its active state, it can cause specific intracellular reactions in response to a received signal. If the synthesis or ability of receptor proteins to bind to signaling molecules is impaired, diseases occur - endocrine disorders. There are three types of such diseases:
1. Associated with insufficient synthesis of receptor proteins.
2. Associated with changes in the structure of the receptor - genetic defects.
3. Associated with blocking receptor proteins by antibodies.
Steroid hormones (Fig. 6.3) have two pathways of action on cells: 1) classic genomic or slow and 2) fast non-genomic. Genomic mechanism of action
The genomic mechanism of action on target cells begins with the transmembrane transfer of steroid hormone molecules into the cell (due to their solubility in the lipid bilayer of the cell membrane), followed by binding of the hormone to the cytoplasmic receptor protein.
This connection with the receptor protein is necessary for the entry of the steroid hormone into the nucleus, where it interacts with the nuclear receptor. Subsequent interaction of the hormone-nuclear receptor complex with the chromatin acceptor, specific acidic protein and DNA entails: activation of the transcription of specific mRNAs, synthesis of transport and ribosomal RNAs, processing of primary RNA transcripts and transport of mRNA into the cytoplasm, translation of mRNA with a sufficient level of transport RNA with the synthesis of proteins and enzymes in ribosomes. All these phenomena require a long-term (hours, days) presence of the hormone-receptor complex in the nucleus. Non-genomic mechanism of action
The effects of steroid hormones appear not only after several hours, which is required for nuclear influence, but some of them appear very quickly, within a few minutes. These are effects such as increased membrane permeability, increased transport of glucose and amino acids, release of lysosomal enzymes, and shifts in mitochondrial energy. The rapid non-genomic effects of steroid hormones include, for example, an increase within 5 minutes after administration of aldosterone to a person in total peripheral vascular resistance and blood pressure, a change in sodium transport through the membrane of erythrocytes (generally devoid of a nucleus) under the influence of aldosterone in in vitro experiments, rapid entry of Ca2+ into endometrial cells under the influence of estrogens, etc. The mechanism of non-genomic action of steroid hormones consists of binding to specific receptors on the plasma membrane of the cell and activation of cascade reactions of secondary messenger systems, for example, phospholipase C, inositol-3-phosphate, ionized Ca2+, protein kinase C. Under the influence of steroid hormones, the content of cAMP and cGMP in the cell may increase. Non-genomic effect of steroid hormones
Rice. 6.3. Scheme of the pathways of action of steroid hormones.
1 - classic genomic pathway of action (the hormone penetrates through the cell membrane and cytoplasm into the nucleus, where, after interacting with the nuclear receptor, it affects target genes, activating them). 2a and 26 - non-genomic pathways of action through membrane receptors: 2a - pathways associated with a membrane enzyme and the formation of a second messenger leading to the activation of protein kinases. The latter, through phosphorylation of the coactivator protein (BKA) in the nucleus, activate target genes; 26 - pathways associated with ion channels of the cell membrane, as a result of which the hormone-receptor complex activates ion channels, changing the excitability of the cell. 3 - alternative non-genomic pathway of action (the hormone molecule, penetrating through the membrane into the cytoplasm, interacts with the cytosolic receptor, which leads to the activation of cytosolic kinases.
can be realized after their binding to cytoplasmic receptors. Some of the non-genomic effects of steroid hormones occur due to their interaction with receptors associated with the gating mechanism of ion channels in the membranes of nerve cells, thereby being modulators, for example, of glycine-, serotonin-, or gamma-aminobutyrergic neurons. Finally, by dissolving in the lipid bilayer of the membrane, steroid hormones can change the physical properties of the membrane, such as its fluidity or permeability to hydrophilic molecules, which is also a non-genomic effect.
Thus, the mechanisms of action of hormones of different chemical structures have not only differences, but also common features. Like steroids, peptide hormones have the ability to selectively influence gene transcription in the cell nucleus. This effect of peptide hormones can be realized not only from the cell surface during the formation of second messengers, but also by the entry of peptide hormones into the cell due to the internalization of the hormone-receptor complex.
More on the topic The mechanism of action of steroid hormones:
- Chemical nature and general mechanisms of action of hormones
- Regulatory functions of hormones of cells that combine hormone production and non-endocrine functions Regulatory functions of placental hormones
Structure
Steroids are derivatives of cholesterol.
The structure of female sex hormones
Synthesis
Female hormones: estrogens synthesized in ovarian follicles progesterone- in the yellow body. Hormones can be partially formed in adipocytes as a result of aromatization of androgens.
Scheme of synthesis of steroid hormones (complete scheme)
Regulation of synthesis and secretion
Activate: estrogen synthesis - luteinizing and follicle-stimulating hormones, progesterone synthesis - luteinizing hormone.
Reduce: sex hormones through a negative feedback mechanism.
- At the beginning of the cycle, several follicles begin to increase in size in response to FSH stimulation. Then one of the follicles begins to grow faster.
- Under the influence of LH, the granulosa cells of this follicle synthesize estrogens, which suppress the secretion of FSH and promote regression of other follicles.
- The gradual accumulation of estrogen towards the middle of the cycle stimulates the secretion of FSH and LH before ovulation.
- A sharp increase in LH concentration may also be due to the gradual accumulation of progesterone (under the influence of the same LH) and the activation of a positive feedback mechanism.
- After ovulation, the corpus luteum forms, producing progesterone.
- High concentrations of steroids suppress the secretion of gonadotropic hormones, as a result the corpus luteum degenerates and the synthesis of steroids decreases. This reactivates FSH synthesis and the cycle repeats.
- When pregnancy occurs, the corpus luteum is stimulated by human chorionic gonadotropin, which begins to be synthesized two weeks after ovulation. The concentrations of estrogen and progesterone in the blood during pregnancy increase tenfold.
Hormonal changes during the menstrual cycle
Targets and effects
Estrogens
1. At puberty estrogens activate the synthesis of protein and nucleic acids in the reproductive organs and ensure the formation of sexual characteristics: accelerated growth and closure of the epiphyses of long bones, determine the distribution of fat on the body, skin pigmentation, stimulate the development of the vagina, fallopian tubes, uterus, development of the stroma and ducts of the mammary glands, growth of axillary and pubic hair.
2. In the body of an adult woman:
Biochemical effects |
Other effects |
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Progesterone
Progesterone is the main hormone in the second half of the cycle and its task is to ensure the onset and maintenance of pregnancy.
Biochemical effects |
Other effects |
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Pathology
Hypofunction
Congenital or acquired hypofunction of the gonads inevitably leads to osteoporosis. Its pathogenesis is not entirely understood, although it is known that estrogens slow down bone resorption in women of childbearing age.
Hyperfunction
Women. Promotion progesterone may manifest as uterine bleeding and menstrual irregularities. Promotion estrogen may manifest as uterine bleeding.
Men. High concentrations estrogen lead to underdevelopment of the genital organs (hypogonadism), atrophy of the prostate and spermatogenic epithelium of the testicles, female obesity and growth of the mammary glands.
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