General Mechanisms of Cell Damage

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The specific mechanisms of cell damage.

The first event, which ultimately leads to cell damage - is damaging agent interaction with target-molecules. Thus, targets may be UV aromatic groups of proteins, enzymes and receptors or nucleotides in the DNA and RNA molecules. The target for carbon monoxide are various heme-containing enzymes. The target of the action of hypoxia are the mitochondria, which are no longer store energy in the form of ATP, etc.

Interaction target damaging factor c can lead to damage of the target itself that occurs, for example, under the action of ultraviolet rays on the cells. In other cases, the target is not damaged by the actions of agents, but temporarily ceases to function. That is, this leads ultimately to cell damage in general. For example, turn off the function of cytochrome oxidase, which in this case serves as a target for the action of the poison cyanide. But the enzyme is not damaged: if you remove cyanide from the environment, cytochrome oxidase function is restored. The cause of cell death is subsequent damage to cell structures, caused by prolonged cessation of power supply.

Thus, between the point of interaction with the target damaging agent and certain process damage cell structures may occur entire chain of events.

Acting agents	The main target	Primary process
Toxins	Active center enzymes and receptors Ionic channel	Inactivation of enzymes, receptors and ion channel blockade
Ultraviolet radiation	Nucleic acids and proteins	nucleotides and amino acids of certain photochemical reactions
Microwave millimeter wave	water molecules	Accelerating, limited diffusion in an aqueous medium
hypoxia	Mitochondria	Reduced ATP synthesis
hyperkalemia	cell membranes	The decline in membrane potential, excitement

Non-specific mechanisms of cell damage

I. Violation of energy supply of the processes occurring in the cell:

- Reduction of intensity and (or) the efficiency of ATP resynthesis process.

- Violation of the transport of ATP energy.

- Violation of using the energy of ATP.

II. Damage to the membrane device and enzyme systems of the cell:

1. Excessive intensification of free radical reactions and FRPOL.

2. Significant activation of hydrolases (lysosomal, membrane-free).

3. Introduction of amphiphilic compounds in the lipid phase of membranes and their detergent effect.

4. Slowdown of resynthesis of damaged membrane components and (or) the synthesis of them again.

5. Violation of the conformation of protein molecules, lipoproteins, phospholipids.

6. Hyperextension and rupture of the membranes swollen cells and (or) their organelles.

III. Ions and fluid imbalance, change of electrophysiological properties of cells:

- Changes in the ratio of individual ions in hyaloplasm.

- Changes in transmembrane ion ratio.

- Hyperhydration cells.

- Dehydration cells.

IV. Violation of the genetic program of cells and (or) the mechanisms for its implementation:

A. Violation of the genetic program:

- Changes in the biochemical structure of genes.

- De-repression of pathogenic genes.

- Repression "vitally important" genes.

- Introduction of foreign DNA into the genome fragments with the pathogenic properties.

B. Violation of the implementation of the genetic program:

1. Breakdown of mitosis:

a) damage to chromosomes,

b) damage to structures providing the mitotic cycle,

c) violation of the cytokinesis process.

2. Violation of meiosis.

V. The breakdown of intracellular mechanisms regulating cell functions:

- Violation of reception of regulatory impacts.

- Violation of the Second Education intermediaries.

- Violation of protein phosphorylation.

I. Violation of the energy supply of the processes occurring in the cell.

The energy supply of cells at the expense of ATP produced mostly in the mitochondria. Among the many functions performed by mitochondria are the most important oxidation in the Krebs cycle, electron transport phosphorylation of ADP, conjugation of oxidation and phosphorylation.

Oxidation in the Krebs cycle. Unlike the anaerobic glycolysis in which one molecule of glucose form two molecules of pyruvate, Krebs cycle requires the involvement of oxygen. Glycolysis occurs in the cytosol and the resulting pyruvate is supplied via its carrier to the mitochondria in exchange for OH. The matrix of the mitochondria contain enzymes that oxidize acetyl-CoA to CO2. The end products of the tricarboxylic acid cycle (CO2, leaving the cells and NADH) - an electron source portable respiratory chain.

Transport of electrons. Electrons move through the respiratory chain localized in the inner mitochondrial membrane and containing four large enzyme complex (mainly cytochrome) chain electron transport.

Chemiosmotic conjugation. Pairing electron transport and ATP synthesis provides a proton gradient. The inner mitochondrial membrane is impermeable to the anions and cations. But with the passage of electrons in the respiratory chain H + ions are pumped from the matrix into the intermembrane space. The energy used by the electrochemical proton gradient for ATP synthesis and transport of inorganic ions and metabolites in the matrix.

The phosphorylation of ADP. Christa mitochondria contain ATP synthase, conjugating oxidation in the Krebs cycle, and phosphorylation of ADP to ATP. ATP synthesized by the reverse current of protons into the matrix through the channel in the ATP-synthesizing complex.

Pair of oxidation and phosphorylation. As a result, coupling of these processes the energy released by the oxidation of substrates stored in the energy-rich bonds of ATP. The liberation of the energy stored in ATP, further ensures that numerous cell functions (e.g., muscle contraction, flagellum motility of the sperm, pumping H + out of the parietal cells in the gastric glands to maintain acidic conditions). The efficiency of oxidative phosphorylation in mitochondria higher effectiveness of glycolysis in the cytosol. From one molecule of glucose formed in the first case 38 ATP molecules, and only two in the second.

Violation of re-synthesis of ATP. Resynthesis of ATP is disturbed as a result of oxygen deficiency and (or) substrate metabolism, reducing the activity of enzymes of tissue respiration and glycolysis, mitochondrial damage and destruction, in which the reaction of the Krebs cycle and the electron transfer to molecular oxygen, coupled with phosphorylation of ADP.

Disorders of energy transport. Encased in a high-energy bonds of ATP energy is normally delivered from places of its synthesis (from mitochondria and hyaloplasm) to effector structures (myofibrils, membrane ion "pumps" and OE) with the participation of the enzyme systems: ADP - ATP translocase (adeninnukleotidtransferazy) and creatine phosphokinase (CPK). Adeninnukleotidtransferaza provides energy transportation macroergic phosphate bond of ATP from mitochondrial matrix across their inner membrane and CPK - Creatine further to form creatine phosphate, which enters the cytosol. CK effector cell structures transports creatine phosphate group to ADP to form ATP, which is used in the processes of cell activity. Enzyme energy transport systems can also be damaged by a variety of pathogenic agents, in connection with which, even against the background of the high total content of ATP in the cell, can develop its deficit energoraskhoduyuschih structures.

Breakdown of energy utilization. Violation of energy cells and their metabolic disorder can develop in conditions of sufficient production and normal transport of ATP energy. This damage can result from recycling energy mechanisms mainly by reducing the ATPase activity (actomyosin ATPase, K +, Na + - dependent ATPase plasmolemma, Mg2 + -dependent ATPase "calcium pump" etc. sarcoplasmic reticulum.). Therefore, disorder of cell activity can occur even under conditions of normal or high content of ATP in the cell.

Violation of energy supply, in turn, may be a factor in disorders of cell membrane device functions, their enzyme systems, the balance of ions and fluid, and cell regulation mechanisms.

II. Damage to the membrane device and enzyme systems of the cell.

This mechanism plays an important role in the breakdown of cell activity, as well as reversible transition changes in it irreversible. This is because the basic properties of cells depend to a large extent on the condition and its membrane enzymes.

According to the model of the cell membrane, and the proposed S.Singer G.Nicolson (1972), it is a viscous semi-liquid mosaic pattern. Its basis molecules comprise phospholipids (lipid phase of the membrane), polar (ionic) "head" which is directed to an aqueous environment, i.e. hydrophilic membrane surfaces and non-polar parts ( "tails") - inside them (hydrophobic zone). Phospholipid suspended in medium protein molecules, some of which are fully immersed in the membrane and penetrates its thickness (so-called integral proteins) located on a portion of their surface ("peripheral" proteins). Peripheral proteins do not penetrate into the thickness of the membrane and are retained at the surface mainly by electrostatic forces. Protein molecules can change the positions they hold in the lipid phase of the membrane, which affects the intensity and character of the catalyzed reactions. In addition, the membrane lipids often provide optimal conditions for the enzymatic processes. For example, oxidative phosphorylation requires anhydrous environment that prevents "spontaneous" ATP hydrolysis.

In recent years the idea of the structure of membranes complemented position that its components (proteins, glycoproteins, glycosaminoglycans, glycolipids) interact with each other and with the microfilaments, microtubules, epitheliofibril cytoplasm of cells, forming a complete dynamic system - tverdoelastichny frame. This frame "mounted" in the liquid phase of the lipid membranes. Having frame provides a relatively stable position on (in) membrane antigens, receptors, enzymes, and other components, and prevents aggregation of the membrane proteins, which would be unavoidable with the free movement of the molecules in the liquid lipid environment.

Elements of biological membranes, damage-prone: 1 - lipid bilayer; 2 - a monolayer of lipid molecules; 3 - glycolipids; 4 - glycoproteins; 5 - microfilaments; 6 - microtubules; 7 - an ion channel; 8 - ion pump

The main mechanisms of cell membrane damage include: 1) excessive intensification of free radical reactions (FRR) and free-radical lipid peroxidation (FRPOL) membranes; 2) a significant activation of hydrolases (lysosomal, membrane-free); 3) introduction of amphiphilic compounds (mainly FRPOL products and lipolysis) in the lipid membranes and detergent phase (destructive) action; 4) inhibition processes resynthesis of damaged membranes and components (or) their re-synthesis (de novo); 5) violation of the conformation of macromolecules; 6) hyperextension and rupture of the membranes swollen cells and (or) their organelles. It is important that all of these mechanisms directly or indirectly cause damage conformational change and (or) the kinetic properties of the cell enzymes, many of which are associated with membranes.

Free-radical reactions. One of the most important mechanisms of enzymes and membrane damage is excessive activation of free radical reactions and FRPOL. These reactions occur in the cells and in normal, being a necessary element of vital processes, such as electron transport chain respiratory enzymes, the synthesis of prostaglandins and leukotrienes, proliferation and maturation of cells, phagocytosis, catecholamine metabolism and others. Reactions FRPOL involved in the processes of the lipid composition of the regulation biomembranes and enzyme activity. The latter is a result of both the direct products lipoperoksidnyh reactions to enzymes and indirectly - through a change in the state of membranes, which are associated with many enzymes.

FRPOL intensity is regulated by the relation of factors, activating (pro-oxidants) and suppress (antioxidants), this process. Among the most active pro-oxidants are easily oxidized compounds inducing free radicals, such as naphthoquinones, vitamins A and D, reducing: NADFH2, NADH2, lipoic acid, products of metabolism of prostaglandins and catecholamines.

The peroxidation reaction may involve the connection of different biochemical composition: lipids, proteins, nucleic acids. However, the leading role among them are phospholipids. This is determined by the fact that they are a major component of membranes and readily undergo oxygenase reaction.

FRPOL process can be divided into three stages:

1) initiation of oxygen ("oxygen" stage)

2) formation of free radicals of inorganic and organic ("free radical" stage)

3) formation of lipid peroxides and other compounds ("peroxy" stage). An initial link peroxy free radical reactions in the cell is damaged, as a rule, in the formation of so-called oxygenase reaction of active oxygen species: singlet (O2), oxygen radical superoxide (O2-, hydrogen peroxide (H2O2), hydroxyl radical (OH-).

Superoxide radical O2- generated leukocytes (especially intense during phagocytosis) in mitochondria during oxidative reactions in tissues in metabolic transformation catecholamine synthesis of prostaglandins and other compounds.

H2O2 is produced by reacting (dismutation) O2 hyaloplasm radicals in cells, and mitochondrial matrix. This process can be catalyzed by the enzyme superoxide dismutase (SOD)

O2 + O2 + 2H + → H2O2 + O2

O2 and H2O2 have a damaging effect in and of themselves. However, under the influence of iron ions present in hyaloplasm cells and in biological fluids (extracellular blood plasma, lymph) O- and H2O2 may be "transformed" into a very "aggressive", which has a high pathogenic action of hydroxyl radical OH-:

H2O2 + Fe2 → Fe3 + + OH + OH-;

O2 + H2O2 → O2 + OH + OH.

OH active radicals react with organic compounds, mainly lipids and nucleic acids and proteins. As a result, formation of active radicals and peroxides. This reaction can buy Chain "avalanche" character. However, this does not always happen. Excessive activation of free-radical reactions and peroxide factors inhibit antioxidant protect cells.

Antioxidant protection of cells. The cells flow processes and are factors that limit or even stop free radical and peroxide reactions, ie, has an antioxidant effect. One such process is, in particular, radicals and interaction between a lipid hydroperoxide that leads to the formation of a "non-radical" compounds. The leading role in the antioxidant defense system cells play mechanisms of enzymatic and non-enzymatic nature.

Links antioxidant system and some of the factors

Links antioxidant system	Factors	Mechanisms of action
I. «Antioxigen»	Retinol, carotenoids, riboflavin	Decrease O2 content in the cell, for example, by activation of its utilization, increase conjugation of oxidation and phosphorylation
II. «Antiradical»	Superoxide dismutase, tocopherols, mannitol	Translation of active radicals in the "non-radical" compounds, "quenching" free radicals with organic compounds
III. «Antiperoxide»	Glutathione peroxidase, catalase, serotonin	Inactivation of lipid hydroperoxides, for example by restoring

Excessive intensification of free radical and peroxide reactions is one of the main factors of damage to membranes and cell enzymes. The leading role in this process are the following:

1) a change of physicochemical properties of lipid membranes, reducing the content of phospholipid, cholesterol, fatty acids. This conformation causes a violation of lipoprotein complexes and therefore decrease in activity of proteins and enzyme systems providing reception humoral effects transmembrane transport of ions and molecules, the structural integrity of the membrane;

2) changing the physical and chemical properties of the protein micelles performing structural and enzymatic functions in the cell;

3) the formation of structural defects in the membrane - the so-called elementary channels (clusters) due to the introduction of products in them FRPOL. In particular, the accumulation of lipid hydroperoxides in the membrane leads to their association in micelles creating transmembrane channels permeability, which is possible uncontrolled current cations and other organic and inorganic molecules in the compounds and from the cage. Increased education FRPOL products and in parallel with these clusters may lead to fragmentation of the membrane (this process is known as detergent action FRPOL products), and cell death. These processes, in turn, are responsible for the violation of important vital processes of cells - excitability and generation of the nerve impulse, metabolism, perception and implementation of control interventions, intercellular interaction and others.

Activation of hydrolases. Normally, the composition and condition of the membranes are modified not only lipoperoxide and free radical processes, but also membrane-bound, free (solubilized) and lysosomal enzymes, lipases, phospholipases, proteases. Under the influence of pathogens or their activity hyaloplasm content in cells can be significantly increased (in particular, due to the development of acidosis, enzymes promoting increased yield of lysosomes and their subsequent activation). In this regard, intensive and glycerophospholipids undergo hydrolysis of membrane proteins, enzymes and cells. This is accompanied by a significant increase in membrane permeability and a decrease in the kinetic properties of enzymes.

The detergent effects of amphiphiles. As a result of the activation reactions and lipoperoxide hydrolases (especially the lipases and phospholipases) are accumulated in the cell lipid hydroperoxides, free fatty acid, lysophospholipids, especially glycerophospholipids, phosphatidylcholines, phosphate diletanolaminy, phosphatidylserines. These compounds are called amphiphilic due to their ability to penetrate into and be fixed on both (as in the hydrophobic or in the hydrophilic) environments cell membranes (from the Greek. Ampho «two", "two", in two ways). With a relatively small level in the cell amphiphilic compounds are penetrating into the biological membrane, alter the normal sequence of glycerophospholipids, violate the structure of lipoprotein complexes, increased permeability, as well as changing the configuration of the membrane due to the "wedge-shaped" form lipid micelles. Accumulation of a large number of amphiphiles is accompanied by massive introduction of a membrane, as well as lipid hydroperoxides and excess, it leads to the formation of clusters and micro-breaks in them.

Disorders reactions membranes updates. Potentiation of damage to cell membranes due to braking processes update their components and elimination of defects in them also contributes to the disorder of energy "security" of plastic processes in the cell. This is due to a violation of reparative reactions resynthesis of damaged or lost lipid, protein, lipoprotein, glycoprotein and other membrane molecules, as well as their re-synthesis.

Violations of the conformation of macromolecules. Significant changes in physical and chemical state of cell membranes can be caused by a modification of the conformation (spatial structure, shape) of protein macromolecules, lipoproteins, glycoproteins, and other compounds. The reason for this may be the dephosphorylation ("deenergization"), these molecules are mainly due to the violation of the processes of power supply cells. At the same time there is a change of the secondary and tertiary structure of proteins, conformation of lipoproteins, as well as suppression of catalytic activity of enzymes.

Hyperextension and rupture of membranes. membrane damage causes cell swelling (including their organelles) in connection with their overhydration. A significant increase in cell volume and subcellular structures (mitochondria, endoplasmic reticulum, nucleus, and others.) Causes hyperextension and often breaks their membranes. The latter is the consequence of increasing the oncotic and osmotic pressure in the cells. This in turn is due to an excess of hydrophilic molecules are organic compounds (lactic acid, pyruvic acid, albumin, glucose, etc.), As well as ions.

Thus, it is seen that the membrane damage and cell enzyme is one of the most frequent causes of disturbances and the major cell activity.

III. Ions and fluid imbalance, change of electrophysiological properties of cells.

Ions and water imbalance in the cell, usually develops after or simultaneously with disorders of energy supply and damaged membranes and enzymes. As a result, significantly changed the transmembrane transport of many ions. To the greatest extent it relates to K +, Na +, Ca2 +, Mg2 +, Cl-, ie ions, which are involved in such vital processes as arousal, conduct action potentials (AP), electro-mate and others.

Ion imbalance characterized by the change in the ratio of individual ions in the cytosol and the violation of the transmembrane ion ratios on both sides of a plasmolemma and intracellular membranes.

Manifestation of ion imbalance. Manifestations of ion imbalance are varied. Most important for the functioning and existence of cell changes in the ionic composition, determined by different membrane ATPase and membrane defects.

Cations. Due to the disruption of Na +, K + -ATPase plasmolemma occurs:

- Cytosolic accumulation of excess Na + cells;

- The loss of the cell K +.

Because disruption of Na + -Ca2 + -ionoobmennogo plasmolemma mechanism (sharing two Na +, outside the cell, one of Ca2 + exiting from it), and Ca2 + -ATPase is an increase in the content of Ca2 + in the cytosol.

Anions. Violations of the transmembrane distribution of cations soprovozhdaetmya change the content in the cell and anions Cl-, OH-, HCO3-, and others.

The effects of ion imbalance. Important posldstviyami ionic imbalances are changes in cell volume and cell oragnoidov (hypo- and hyperhydration), as well as violations electrogenesis in excitable cellular elements (eg, cardiomyocytes, neurons, skeletal muscle fiber, smooth muscle cells - MMC).

Hyperhydration cells. The main cause of fluid overload - increase in the content of Na + and Ca2 + in damaged cells. This is accompanied by an increase in their osmotic pressure, and water accumulation. Cells with the swell, their volume increases, combined with stretching and often with micro- breaks tsitolemmy and organelle membranes.

Hypohydratation cells. Hypohydratation cells is observed, for example, fever, hyperthermia, polyuria, infectious diseases (cholera, typhoid, dysentery). Such conditions lead to loss of body water, accompanied by fluid exiting the cells and dissolved therein proteins (including enzymes), as well as other water-dissolved organic and inorganic compounds. Intracellular hypohydration often combined with the wrinkling of the core, the disintegration of mitochondria and other organelles.

Violation electrogenesis. Violation electrogenesis as changes in membrane potential and action potential characteristics are essential, as they are often one of the most important signs of the existence and nature of cell damage. Examples include changes in ECG at myocardial cell injury, an electroencephalogram in violation of the structure and function of brain neurons, electromyogram with changes in muscle cells.

IV. Violation of the genetic program of cells and (or) the mechanisms for its implementation.

The main processes, leading to changes in the cell genetic information, are changing the biochemical structure of genes (mutations); derepression of pathogenic genes (e.g., oncogenes); suppression of vital activity of genes (for example, programming the synthesis of enzymes); introducing into the genome a foreign DNA fragment encoding the pathogenic properties (e.g., DNA oncogenic viruses, abnormal area other cell DNA).

In addition to changes in the genetic program, an important mechanism of cell metabolism disorder is a violation of the implementation of this program, mainly in the process of cell division during mitosis or meiosis. Data about the pathology of meiosis (during germ cell development) to date is not enough. This is due, in particular, the difficulty of obtaining biopsies of testicles or ovaries. More questions are designed mitosis pathology.

There are three groups of disorders of mitosis: 1) change in the chromosomal apparatus; 2) damage to structures for mitosis process; 3) violation of the division of the cytoplasm and cytolemmy (cytokinesis). For group 1 mitosis disorders include changes in the structure and number of chromosomes. Examples of group 2 disorders may be multipolar or formation monocentric mitosis at metaphase chromosomes dispersion, that is, in particular, a consequence of the spindle abnormalities. Violations of the cytoplasm and plasmolemma fission appear premature or delayed cytokinesis, and the lack of it (group 3 mitosis disorders).

Action on the genetic apparatus of the cell-damaging factors, the different nature of very high intensity can cause the death of her. Among the most important processes causing cell death are as follows: 1) the destruction of the structure of DNA by direct action of a superstrong pathogens, most chemical or physical nature (in particular, high doses of ionizing radiation, alkylating agents, free radicals, hydroperoxides lipids); 2) by hydrolytic cleavage of the DNA with nucleases significant activation (pre-existing or synthesized de novo), 3) activation transferases, causing degradation of the DNA by transfer from a phosphoric acid residue the carbon atom of ribose its mononucleotide one to another, which is accompanied by rupture of the internucleotide bond; 4) changes in the structure of DNA.

It is believed that the cells have a special program, which leads to irreversible destruction of genetic material and cell death. It is believed that the cell death program is linked to the presence in its genome of gene specific "killer." These genes were formed in the early stages of the evolution of multicellular organisms to eliminate irreversibly damaged and (or) abnormally functioning cells that represent a real or potential danger for the life of the whole organism. Thus eliminate normal cells were replaced in connection with the division of neighboring cells intact. This ensured the stability of the structure and functioning of tissues, organs and generally in a multicellular organism as a system.

The presence of the genetic program of cell death explains many phenomena: regular change of cells during embryogenesis; physiological death "grown old" cells as the final stage of their differentiation needed to change their "young" cells; removal of damaged and (or) of abnormal cells that threaten the existence of the whole organism (eg, tumor cells)

V. The breakdown of intracellular mechanisms regulating cell function.

Disorders of cell activity may be a result of disorders of one or more levels of implementation of regulatory mechanisms.

Intercellular information signals. All kinds of information described in the cell-cell interactions within the concept of "response signal", which laid the foundations of Paul Ehrlich. Intercellular informational interactions fit into the following scheme:

Signal → receptor → (second intermediary) → answer.

Signals. Signaling from cell to cell signaling molecule is performed (first intermediary) generated in some cells and specifically affecting the other - of a target cell. The specificity of the effects of signaling molecules determine the receptors of the target cell binding ligands only their own. All signaling molecules (ligands) - depending on their physical and chemical nature - divided into polar (or rather - hydrophilic) and apolar (fat-soluble). Hydrophilic molecules (e.g., neurotransmitters, cytokines, peptide hormones, antigens) can not penetrate the plasma membrane and bind to receptors plasmolemma (membrane receptor). The fat-soluble molecules (for example, thyroid hormones and steroilnic) plasmolemma penetrate and bind to intracellular receptors (nuclear receptor).

Receptors. Three classes of cellular receptors are described: membrane, nuclear and orphans.

Membrane receptors - glycoproteins. They control the permeability plasmolemma by changing the conformation of the ion channel proteins (eg, N-acetylcholine receptor). Regulates the flow of molecules into a cell (e.g., using LDL cholesterol receptors), extracellular matrix molecules bind to cytoskeletal components (e.g., integrins). Record the presence of information signals (e.g. neurotransmitters light quanta olfactory molecules. Antigens, cytokines, peptide hormones). Membrane receptors recorded arriving to cell signal and transmit it to the intracellular chemical compounds mediating the final effect (second messengers). Functional membrane receptors are divided into catalytic associated with ion channels and operates through G - protein.

Nuclear receptors - proteins of steroid hormone receptors (mineral and glucocorticoids, estrogen, progesterone, testosterone), retinoids, thyroid hormone, bile acids, vitamin D3. Each receptor has a ligand-binding domain and a portion that interacts with specific DNA sequences. In other words, the nuclear receptor - ligand-activated transcription factors.

Orphan receptors. The human genome has more than 30 nuclear receptors, ligands which are on the identification step.

Second intermediaries. The intracellular signaling molecules (second messengers) transmit information with the membrane receptors on the effectors (actuators molecule) mediating cell response to the signal. Stimuli such as light, the molecules of different substances, hormones and other chemical signals (ligands) initiate a response of the target cell, changing it in the intracellular level (second) mediators. Second mediators presented numerous class of compounds. These include cyclic nucleotides (cAMP and cGMP), inositol triphosphate, diglycerol Ca2 +.

Responses target cells. cell function are the result of realization of genetic information (e.g., transcription, post-translational modification) and highly diverse (e.g., changes in the nature of the operation, the stimulation ilipodavlenie activity reprogramming syntheses, etc.).

Disorders BAS interaction with receptors. Intercellular signals in the form of character information BAS (hormones, neurotransmitters, cytokines, etc.) Implement regulatory effects of BAS after interaction with cellular receptors.

The reasons are diverse regulatory signal distortion. The most important are:

- Changes in receptor sensitivity;

- Deviation of the number of receptors;

- Violations of the receptor conformation of macromolecules;

- Changes in the lipid environment of membrane receptors.

These deviations can significantly modify the nature of the cellular response to the control stimulus. Since the accumulation of toxic products when Spolli myocardial ischemia alters the physical and chemical properties of the membranes. It is associated with the cardiac responses to norepinephrine and atsitilholin, perceives the corresponding receptors of the plasma membrane of cardiomyocytes.

Frustration at the level of the second mediators. At the second level of intracellular mediators (messengers) - cyclic nucleotides: adenosine monophosphate (cAMP) and guanosine monophosphate (cGMP) and other generated in response to the primary intermediaries - hormones and neurotransmitters that numerous disorders. An example would be a violation of the formation of the membrane potential of cardiomyocytes with excess accumulation of cAMP in them. This is one of the possible causes of cardiac arrhythmias.

Frustration at the level of response to the signal. At the level of metabolic processes regulated second messengers, or other intracellular factors are also capable of numerous disorders. For violation of the activation of cellular enzymes, for example in connection with a deficit of cAMP or cGMP, can greatly change the intensity of metabolic reactions, and as a result - lead to the breakdown of cell activity.