Transmission of excitement in autonomic synapses. Vegetative synapses and their properties

text_fields

text_fields

arrow_upward

Preganglionic synapses are formed by the nerve processes of the intercalary neurons of the autonomic centers on the nerve cells of the autonomic ganglia. The number of neurons in the autonomic ganglion is very large and 2-30 times higher than the number of preganglionic conductors entering the ganglion. Therefore, each preganglionic fiber branches and forms synapses on several neurons of the ganglion. At the same time, on each neuron of the ganglion there are numerous synapses of different preganglionic fibers. These features provide ganglion neurons with a high ability for spatial and temporal summation of excitations.

Preganglionic synapses have three features:

1) significant synaptic conduction delay, about 5 times longer than in central synapses,
2) significantly longer duration of EPSP,
3) the presence of pronounced and prolonged trace hyperpolarization of ganglion neurons. Due to these features, preganglionic synapses have low lability and ensure the transformation of the rhythm of excitations with an impulse frequency in the postganglionic fiber of no more than 15 / s.

A mediator in all preganglionic synapses of both sympathetic and parasympathetic divisions of the autonomic nervous system is acetylcholine. The chemical cellular receptors of the postsynaptic membrane that bind acetylcholine are called cholinergic receptors and are referred to in preganglionic synapses as nicotine-sensitive, since they are activated by nicotine (H-cholinergic receptors). Specific blockers of these receptors are curare and curare-like substances (benzohexonium, ditilin, etc.), which are part of the ganglion blockers group. In addition to the main H-cholinergic receptors involved in the transmission of excitation, preganglionic synapses also have M-cholinergic receptors (activated by the alkaloid muscarin - muscarinic-sensitive), the role of which, apparently, is reduced to the regulation of the release of the mediator and the sensitivity of H-cholinergic receptors

Postganglionic or peripheral synapses

text_fields

text_fields

arrow_upward

Postganglionic or peripheral synapses formed by the efferent conductor on the effector differ in the two described divisions of the autonomic nervous system.

2.1. Sympathetic synapses

Sympathetic synapses are formed not only in the area of ​​numerous terminal branches of the sympathetic nerve, as in all other nerve fibers, but also in the membranes varicose veins- numerous extensions of the peripheral areas of sympathetic fibers in the area of ​​innervated tissues. Varicose veins also contain synaptic vesicles with a transmitter, albeit in lower concentrations than the terminal endings.

a) Mediator of sympathetic synapses - norepinephrine

The main mediator of sympathetic synapses is norepinephrine and such synapses are called adrenergic. The receptors that bind the adrenergic mediator are called adrenergic receptors. There are two types of adrenergic receptors - alpha and beta, each of which is divided into two subtypes - 1 and 2. A small part of the sympathetic synapses use the neurotransmitter acetylcholine and such synapses are called cholinergic, and receptors - cholinergic receptors. Cholinergic synapses of the sympathetic nervous system are found in the sweat glands. In adrenergic synapses, in addition to norepinephrine, adrenaline and dopamine, also referred to as catecholamines, are contained in significantly smaller amounts, therefore, the mediator substance in the form of a mixture of three compounds was previously called sympathine.

The synthesis of norepinephrine from the amino acid tyrosine using three enzymes - tyrosine hydroxylase, DOPA decarboxylase and dopamine beta-hydroxylase - occurs in all parts of the postganglionic neuron: its body, axon, varicose veins and terminal synaptic endings. However, less than 1% of norepinephrine comes from the body with the current of axoplasm, while the main part of the mediator is synthesized in the peripheral parts of the axon and is stored in the granules of synaptic vesicles. Norepinephrine contained in granules is in two funds or pools (storage forms) - stable or reserve (85-90%) and labile, mobilized into the synaptic cleft during the transmission of excitation. Norepinephrine of the labile fund is slowly replenished from the stable pool if necessary. The replenishment of norepinephrine reserves, in addition to the synthesis processes, is carried out by its powerful reverse uptake from the synaptic cleft by the presynaptic membrane (up to 50% of the amount released into the synaptic cleft), after which the captured mediator partially enters the vesicles, and not entering the vesicles is destroyed by the enzyme monoamine oxidase (MAO) ...

b) Mechanisms of norepinephrine release into the synaptic cleft

The release of the transmitter into the synaptic cleft occurs in quanta under the influence of an excitation pulse, while the number of quanta is proportional to the frequency of nerve impulses. The release of the mediator proceeds by exocytosis and is Ca-dependent.

The release of norepinephrine into the synaptic cleft is regulated by several special mechanisms:

1) binding of norepinephrine in the synaptic cleft with alpha-2-adrenergic receptors of the presynaptic membrane (Figure 3.10), which plays the role of negative feedback and inhibits the release of the transmitter;

2) the binding of norepinephrine to presynaptic beta-adrenergic receptors, which plays the role of positive feedback and enhances the release of the transmitter.
Moreover, if the portions of the released norepinephrine are small, then the mediator interacts with beta-adrenergic receptors, which increases its release, and at high concentrations, the mediator binds to the alpha-2 ~ adrenergic receptor, which suppresses its further release;

3) the formation of effector cells and the release into the synaptic cleft of group E prostaglandins, which suppress the release of the mediator through the presynaptic membrane;

4) entry into the synaptic cleft of the adrenergic synapse from a nearby cholinergic synapse of acetylcholine, which binds to the M-cholinergic receptor of the presynaptic membrane and causes suppression of the release of norepinephrine.

c) The fate of norepinephrine released into the synaptic cleft

The fate of the mediator released into the synaptic cleft depends on four processes:

1) binding to receptors of post- and pre-synaptic membranes,

2) reuptake by the presynaptic membrane,

3) destruction in the region of the receptors of the postsynaptic membrane by the enzyme catechol-O-methyltransferase (COMT),

4) diffusion from the synaptic cleft into the bloodstream, from where norepinephrine is actively captured by the cells of many tissues.

Diffusing to the postsynaptic membrane, norepinephrine binds to two types of adrenergic receptors located on it - alpha-1 and beta, forming a mediator-receptor complex (Figure 3.10).

The number of alpha-1 and beta-adrenergic receptors in different tissues is not the same, for example, alpha-adrenergic receptors prevail in the smooth muscles of the arterial vessels of the internal organs, and beta-adrenergic receptors prevail in myocardial cells. Activation of alpha-1-adrenergic receptors by the mediator leads to depolarization and the formation of EPSP, which is flatter, low-amplitude and prolonged than the EPSP of nerve cells and the EPP of skeletal muscles. Stimulation of alpha-adrenergic receptors also causes a shift in metabolism in the cell membrane and the formation of specific molecules called secondarynym mediators of the mediator effect. Secondary mediators of alpha-adrenergic receptor stimulation are inositol-3-phosphate and ionized calcium. The systems of secondary mediators will be discussed in more detail in the section on humoral regulation of functions.

Beta-adrenergic receptors, as well as alpha, they are divided into 2 subtypes: beta 1 and beta 2.
Beta-1-adrenergic receptors are located in the heart muscle and their stimulation ensures the activation of the basic physiological properties of the myocardium (automation, excitability, conduction and contractility).
Beta-2-adrenergic receptors are located in the smooth muscles of arterial vessels, especially skeletal muscles, coronary arteries, bronchi, uterus, bladder, and their stimulation causes an inhibitory effect in the form of smooth muscle relaxation.

Although in this case hyperpolarization of the postsynaptic membrane occurs, TPSP cannot be detected due to a very slow process and extremely low amplitudes of hyperpolarization. Stimulation of beta-adrenergic receptors activates another system of secondary mediators - adenylate cyclase-cAMP, and it is believed that the beta-adrenergic receptor is either associated with adenylate cyclase, or is generally this protein-enzyme.

The sympathetic nervous system is the most important regulator of metabolism in the body. It is associated with the metabolic effects of the sympathetic nervous system. trophic action on the fabric. Classic experimental confirmation trophic influence of the sympathetic nervous system is the Orbeli-Ginetsinsky phenomenon, the essence of which is as follows. The amplitude of contractions of the frog's gastrocnemius muscle is recorded during stimulation of the anterior roots of the spinal cord that innervate it. Fatigue develops gradually and the amplitude of contractions falls. If at this moment to produce stimulation of the sympathetic borderline trunk in this area, then the amplitude of the contractions is restored, i.e. fatigue disappears

2.2. Parasympathetic synapses

a) Mediator of sympathetic synapses - acetylcholine

Parasympathetic postganglionic or peripheral synapses use acetylcholine as a mediator, which is located in the axoplasm and synaptic vesicles of presynaptic terminals in three main pools or funds. It,
At first, a stable, tightly bound to the protein, not ready for release, the pool of the mediator;
Secondly, mobilization, less firmly bound and fit for release, pool;
third pool ready to be released spontaneously or actively. In the presynaptic terminal, pools are constantly moving in order to replenish the active pool, and this process is also carried out by moving the synaptic vesicles to the presynaptic membrane, since the mediator of the active pool is contained in those vesicles that are directly adjacent to the membrane. The release of the mediator occurs in quanta, the spontaneous release of single quanta is replaced by an active one upon the arrival of excitation impulses that depolarize the presynaptic membrane. The release of neurotransmitter quanta, as in other synapses, is calcium-dependent.

b) The mechanism of regulation of the release of acetylcholine into the synaptic cleft

Regulation of the release of acetylcholine into the synaptic cleft is provided by the following mechanisms:

1) Binding of acetylcholine with M-cholinergic receptors of the presynaptic membrane, which has an inhibitory effect on the release of acetylcholine - negative feedback;
2) Binding of acetylcholine with the H-cholinergic receptor, which enhances the release of the mediator - positive feedback;
3) The entry into the synaptic cleft of the parasympathetic synapse of norepinephrine from the nearby sympathetic synapse, which has an inhibitory effect on the release of acetylcholine;
4) Isolation into the synaptic shell under the influence of acetylcholine from the postsynaptic cell of a large number ATP molecules, which bind to the purinergic receptors of the presynaptic membrane and inhibit the release of the mediator - a mechanism called retro-inhibition.(Figure 3.11)

Figure 3.11. Parasympathetic synapse and its regulation.

1 - presynaptic ending, 2 - synaptic vesicle, 3 - synaptic cleft with quanta of acetypcholine (AX), 4 - postsynaptic membrane of the effector cell, 5 - adjacent adrenergic synapse. M - muscarinic cholinergic receptor, H - nicotinic cholinergic receptor, ChE - cholinesterase, HC-cGMP - secondary mediator system: guanylate cyclase - cyclic guanosine monophosphate, NA - norepinephrine, (+) - stimulation of the release of the mediator, (-) - suppression of the release of the pick.

c) The fate of acetylcholine released into the synaptic cleft

Acetylcholine released into the synaptic cleft is removed from it in several ways:

At first, part of the mediator binds to the cholinergic receptors of the post- and presynaptic membrane;
secondly, the mediator is destroyed by acetylcholinesterase to form choline and acetic acid which undergo reuptake by the presynaptic membrane and are again used for the synthesis of acetylcholine;
third, the mediator is carried out by diffusion into the intercellular space and blood, and this process occurs after the mediator binds to the receptor. When the mediator is removed by the latter route, almost half of the released acetylcholine is inactivated.

On the postsynaptic membrane, acetylcholine binds to cholinergic receptors belonging to the M (muscarinic) type.

The formation of a mediator-reeptor complex on the membrane leads to common different types cell reactions:

At first, to the activation of receptor-guided ion channels and a change in the membrane charge;
Secondly, to the activation of systems of secondary messengers in cells.

In the smooth muscle and secretory cells of the gastrointestinal tract, urinary bladder and ureter, bronchi, coronary and pulmonary vessels, the acetylcholine-M-choline-receptor complex activates Na-channels, leads to depolarization and the formation of EPSP, as a result of which cells are excited and smooth muscle contraction occurs or secretion of digestive juices. The same effect is promoted by the activation of secondary mediators - inositol-tri-phosphate and ionized calcium. At the same time, in the cells of the conducting system of the heart, smooth muscles of the vessels of the genital organs, the acetylcholine-M-cholinergic receptor complex activates the K-channels and the outgoing current K +, leading to hyperpolarization and inhibitory effects - a decrease in automation, conductivity and excitability in the myocardium, expansion of the genital arteries. organs. At the same time, a system of secondary mediators, guanylate cyclase-cyclic guanosine monophosphate, is activated in these cells. The multidirectional effects of parasympathetic regulation during the formation of an acetylcholine-M-cholinergic receptor complex on the membranes of different cells suggests the presence of two types of M-cholinergic receptors on the postsynaptic membrane of postganglionic synapses, similar to the types of adrenergic receptors described above. At the same time, all M-cholinergic receptors are blocked by atropine, which removes both parasympathetic stimulation of smooth muscle contraction and parasympathetic inhibition of the heart.

The efficiency of synaptic transmission depends on the number of active receptors on the postsynaptic membrane, which reflects the functions of an effector cell that synthesizes membrane receptors. The effector cell regulates the number of membrane receptors depending on the intensity of the synapse, i.e. selection of a mediator in it. So, when the vegetative nerve is cut (cessation of the release of the mediator), the sensitivity of the tissue innervated by it to the corresponding mediator increases due to an increase in the number of membrane receptors capable of binding the mediator. Sensitization of denervated structures or tissue sensitization is an example of self-regulation at the effector level.

Relationship between sympathetic and parasympathetic regulation of functions

text_fields

text_fields

arrow_upward

Since most of the effects of sympathetic and parasympathetic nervous regulation are opposite, their relationship is sometimes characterized as antagonistic. At the same time, the existing relationships between the higher autonomic centers and even at the level of postganglionic synapses in tissues receiving double innervation make it possible to apply the concept of reciprocal regulation. An example of a reciprocal relationship at the effector level is accentuated antagonism or mutually reinforcing opposition.

Structural and functional features of the autonomic nervous system

All body functions are conventionally divided into somatic and vegetative. The former are associated with the activity of the muscular system, the latter are performed by internal organs, blood vessels, blood, endocrine glands, etc. However, this division is arbitrary, since such a vegetative function as metabolism is inherent in skeletal muscles. On the other hand, motor activity is accompanied by changes in the functions of internal organs, blood vessels, and glands.

The autonomic nervous system is a collection of nerve cells of the spinal cord, brain and autonomic ganglia, which innervate the internal organs and blood vessels.

The arc of the autonomic reflex differs in that its efferent link has a two-neuronal structure, i.e. from the body of the first efferent neuron, located in the central nervous system, there is a preganglionic fiber, which ends on the neurons of the autonomic ganglion, located outside the central nervous system. From this second efferent neuron, postganglionic fiber goes to the executive organ. Nerve impulses along autonomic reflex arcs propagate much more slowly than along somatic ones. First, this is due to the fact that even the simplest autonomic reflex is polysynaptic, and most autonomic nerve centers include a huge number of neurons and synapses. Secondly, preganglionic fibers belong to group "B", and postganglionic ones - "C". The speed of the excitation is the smallest. All autonomic nerves have significantly less selectivity (for example, n. Vagus) than somatic ones.

The autonomic nervous system is divided into 2 sections: sympathetic and parasympathetic. The bodies of preganglionic sympathetic neurons lie in the lateral horns of the thoracic and lumbar segments of the spinal cord. The axons of these neurons emerge as part of the anterior roots and end in the paravertebral ganglia of the sympathetic chains. From the ganglia there are postganglionic fibers that innervate the smooth muscles of the organs and blood vessels of the head, chest, abdominal cavities of the small pelvis, as well as the digestive glands. There is sympathetic innervation not only of arteries and veins, but also of arterioles. In general, the function of the sympathetic nervous system is to mobilize the body's energy resources through dissimilation processes, to increase its activity, including the nervous system.

The bodies of preganglionic parasympathetic neurons are located in the sacral part of the spinal cord, the medulla oblongata and the midbrain in the region of the nuclei III, VII, IX and X pairs of cranial nerves. The preganglionic fibers coming from them end on the neurons of the parasympathetic ganglia. They are located near the innervated organs (paraorganically) or in their thickness (intramurally). Therefore, postganglionic fibers are very short. The parasympathetic nerves, starting from the stem centers, also innervate organs and a small number of vessels of the head, neck, as well as the heart, lungs, smooth muscles and glands of the gastrointestinal tract (GIT). There are no parasympathetic endings in the central nervous system. Nerves extending from the sacral segments innervate the pelvic organs and blood vessels. The general function of the parasympathetic department is to provide recovery processes in organs and tissues, by increasing assimilation. Thus, homeostasis is maintained.

The highest centers of regulation of autonomic functions are located in the hypothalamus. However, the cerebral cortex also affects the vegetative centers. This influence is determined by the limbic system and the centers of the hypothalamus. Many internal organs are double, i.e. sympathetic and parasympathetic innervation. This is the heart, organs of the digestive tract, small pelvis and others. In this case, the influence of the divisions of the autonomic nervous system is antagonistic. For example, sympathetic nerves enhance the work of the heart, inhibit the motility of the digestive system, contract the sphincters of the excretory ducts of the digestive glands, and relax the bladder. The parasympathetic nerves affect the functions of these organs in the opposite way. Therefore, under physiological conditions, the functional state of these organs is determined by the predominance of the influence of one or another department of the autonomic nervous system. However, for the body, their effect is synergistic. For example, such functional synergy occurs when vascular baroreceptors are excited when blood pressure rises. As a result of their excitation, the activity of the parasympathetic centers increases and the sympathetic centers decreases. Parasympathetic nerves reduce the frequency and strength of heart contractions, and inhibition of the sympathetic centers leads to relaxation of blood vessels. Blood pressure drops to normal. In many organs that have dual autonomic innervation, the regulatory influences of the parasympathetic nervous system constantly predominate. These are the glandular cells of the gastrointestinal tract, the bladder and others. There are organs that have only one innervation. For example, most blood vessels are innervated only by the sympathetic nerves, which constantly maintain them in a constricted state, i.e. toned.

In the 80s A.D. Nozdrachev formulated the concept of the metasympathetic nervous system. According to her, the intramural ganglia of the autonomic nervous system, which form the nerve plexuses, are simple neural networks, analogous to the nuclei of the central nervous system. In these small neural clusters, mainly located in the wall of the digestive canal organs, the perception of irritation, information processing and transmission to the efferent neurons, and then to the executive organs, take place. They are smooth muscle cells of the alimentary canal, uterus, cardiomyocytes, i.e. ganglia are quite autonomous from the central nervous system. However, the signals from them enter the central nervous system, are processed in it, and then through the extramural parasympathetic nerves are transmitted to the efferent neurons of the ganglion, and from it to the executive organ, i.e. ganglion efferent neurons are a common terminal pathway for both extramural parasympathetic nerves and other ganglion neurons.

In the wall of the esophagus, stomach, intestines there are 3 interconnected plexuses: sub-serous, intermuscular (Auerbach), submucosal (Meissner). The cells that make up the plexus are classified according to the classification of A.S. Dogel to three types:

Type I - neurons with numerous short dendrites and long axons. The axon ends on smooth muscle cells and glandular cells of the alimentary canal. These neurons are effector neurons.

Type II - larger neurons with several dendrites and a short axon that forms a synapse on type I neurons. The end of the dendrites is located in the submucosa and mucous membranes, i.e. these cells are sensitive.

Type III - are used to transmit signals between other neurons in the ganglia. They can be considered associative, i.e. interneurons. There are fewer of them than others.

In addition, the so-called generator neurons are isolated in the plexuses. They are automatic and set the frequency of rhythmic activity of the smooth muscles of the gastrointestinal tract.

Thus, a distinctive feature of the metasympathetic nervous system is that its efferent neurons are always located intramurally and regulate the frequency of rhythmic contractions of the heart, intestines, uterus, etc. Therefore, even after cutting all the extramural nerves going to these organs, their normal function is preserved.

The presence of the metasympathetic system contributes to the release of the central nervous system from unnecessary information, since metasympathetic reflexes are closed in the intramural ganglia. It ensures the maintenance of homeostasis by controlling the work of those internal organs that have it.

The regulation of the functions of the autonomic nervous system is carried out according to the reflex principle, i.e. irritation of peripheral receptors leads to the emergence of nerve impulses, which, after analysis and synthesis in the vegetative centers, enter the efferent neurons, and then the executive organs. Therefore, all autonomic reflexes, depending on the site of the receptor and efferent link, are divided into the following groups:

1. Viscero-visceral. These are reflexes that arise as a result of irritation of the interoreceptols of internal organs and are manifested by changes in their functions. For example, with mechanical irritation of the peritoneum or abdominal organs, there is a decrease and weakening of heart contractions (Goltz reflex).

2. Viscero-dermal. Irritation of the interoreceptors of internal organs, leads to changes in sweating, the lumen of the vessels of the skin, skin sensitivity.

3. Somato-visceral. The action of an irritant on somatic receptors, for example, skin receptors, leads to a change in the activity of internal organs. This group includes reflexes of Danini-Aschner (slowing of the heartbeat when pressing on the eyeballs).

4. Viscero-somatic. Irritation of interoreceptors causes changes in motor functions. Excitation of the vascular chemoreceptors by carbon dioxide helps to increase the contractions of the intercostal respiratory muscles. If the mechanisms of autonomic regulation are disturbed, changes in visceral functions occur. In particular, psychosomatic diseases.

Mechanisms of synaptic transmission in the autonomic nervous system

The synapses of the autonomic nervous system are generally the same structure as the central ones. However, there is a significant diversity of postsynaptic membrane chemoreceptors.

The transmission of nerve impulses from the preganglionic fibers to the neurons of all autonomic ganglia is carried out by H-cholinergic synapses, i.e. synapses, on the postsynaptic membrane of which nicotine-sensitive cholinergic receptors are located.

Postganglionic cholinergic fibers form M-cholinergic synapses on the cells of the executive organs (glands, smooth muscle cells of the digestive system, blood vessels, etc.). Their postsynaptic membrane contains muscarinic receptors (blocker - atropine).

In both those and other synapses, the transmission of excitation is carried out by acetylcholine. M-cholinergic synapses have an exciting effect on the smooth muscles of the alimentary canal, urinary system (except for sphincters), and gastrointestinal glands. However, they reduce the excitability, conduction and contractility of the heart muscle and cause relaxation of some vessels in the head and pelvis.

Postganglionic synaptic fibers form 2 types of adrenergic synapses on effectors: alpha-adrenergic and beta-adrenergic. The postsynaptic membrane of the former contains beta1 and beta2 adrenergic receptors.

When norepinephrine affects alpha-1-adrenergic receptors, the arteries and arterioles of the internal organs and skin are narrowed, the muscles of the uterus, the sphincters of the gastrointestinal tract contract, but at the same time other smooth muscles of the alimentary canal are relaxed.

Postsynaptic beta-adrenergic receptors are also classified into beta1 and beta2 types. Beta1-adrenergic receptors are located in the cells of the heart muscle. Under the action of norepinephrine on them, the excitability, conductivity and contractility of cardiomyocytes increase. The activity of beta2-adrenergic receptors leads to vasodilation of the lungs, heart and skeletal muscles, relaxation of the smooth muscles of the bronchi, bladder, inhibition of the motility of the digestive system.

In addition, postganglionic fibers were found, which form histaminergic, seretoninergic, purinergic (ATP) synapses on the cells of internal organs.



A synapse is a specific area of ​​contact between the processes of nerve cells and other non-excitable and excitable cells, which provide the transmission of an information signal. A synapse is morphologically formed by contacting membranes of 2 cells. The membrane related to the process is called the presynaptic membrane of the cell, into which the signal enters, its second name is postsynaptic. Together with the belonging of the postsynaptic membrane, a synapse can be interneuronal, neuromuscular and neurosecretory. The word synapse was introduced in 1897 by Charles Sherrington (English physiologist).

What is a synapse?

A synapse is a special structure that ensures the transmission of a nerve impulse from a nerve fiber to another nerve fiber or nerve cell, and for the effect on the nerve fiber from a receptor cell (the area of ​​contact with each other of nerve cells and another nerve fiber), two nerve cells are required ...

A synapse is a small section at the end of a neuron. With its help, information is transmitted from the first neuron to the second. The synapse is located in three areas of nerve cells. Also, synapses are located in the place where a nerve cell enters into connection with various glands or muscles of the body.

What does a synapse consist of?

The structure of the synapse is simple. It is formed from 3 parts, in each of which certain functions are carried out during the transfer of information. Thus, such a structure of the synapse can be called suitable for transmission. Two main cells directly affect the process: the receiving and transmitting cells. At the end of the axon of the transmitting cell is the presynaptic ending (the initial part of the synapse). It can affect the launch of neurotransmitters in the cell (this word has several meanings: neurotransmitters, mediators or neurotransmitters) - determined by which the transmission of an electrical signal is realized between 2 neurons.

The synaptic cleft is the middle part of the synapse - this is the gap between 2 interacting nerve cells. Through this gap, an electrical impulse comes from the transmitting cell. The final part of the synapse is the receiving part of the cell, which is the postsynaptic terminal (the contacting fragment of the cell with different sensitive receptors in its structure).

Synapse mediators

Mediator (from Latin Media - transmitter, mediator or middle). Such synapse mediators are very important in the transmission process.

The morphological difference between inhibitory and excitatory synapses is that they do not have a transmitter release mechanism. A mediator at inhibitory synapse, motor neuron, and other inhibitory synapse is considered the amino acid glycine. But the inhibitory or excitatory nature of the synapse is determined not by their mediators, but by the property of the postsynaptic membrane. For example, acetylcholine has a stimulating effect in the neuromuscular synapse of the terminals (vagus nerves in the myocardium).

Acetylcholine serves as an excitatory mediator in cholinergic synapses (the end of the spinal cord of the motor neuron plays the presynaptic membrane in it), in the synapse on Ranshaw cells, in the presynaptic terminal of sweat glands, adrenal medulla, in the intestinal synapse and in the nervous ganglia. Acetylcholi nesterase and acetylcholine were also found in a fraction of different parts of the brain, sometimes in a large number, but apart from the cholinergic synapse on Ranshaw cells, they have not yet been able to identify the rest of the cholinergic synapses. According to scientists, the mediator excitatory function of acetylcholine in the central nervous system is very likely.

Catelchomines (dopamine, norepinephrine, and adrenaline) are considered adrenergic mediators. Epinephrine and norepinephrine are synthesized at the end of the sympathetic nerve, in the cell of the adrenal gland, spinal cord and brain. Amino acids (tyrosine and L-phenylalanine) are considered the starting material, and adrenaline is the final product of the synthesis. The intermediate, which includes norepinephrine and dopamine, also functions as synaptic mediators created at the endings of the sympathetic nerves. This function can be either inhibitory (secretory glands of the intestine, several sphincters and smooth muscle of the bronchi and intestines), or excitatory (smooth muscles of certain sphincters and blood vessels, in the myocardial synapse - norepinephrine, in the subcutaneous nuclei of the brain - dopamine).

When the synapse mediators complete their function, catecholamine is absorbed by the presynaptic nerve ending, and transmembrane transport is turned on. During the absorption of neurotransmitters, synapses are protected from premature depletion of the supply during long and rhythmic work.

Synapse: main types and functions

Langley in 1892 suggested that synaptic transmission in the vegetative ganglion of mammals is not electrical in nature, but chemical. After 10 years, Elliott found that adrenaline is obtained from the adrenal glands from the same effect as the stimulation of the sympathetic nerves.

After that, it was suggested that adrenaline is capable of being secreted by neurons and, when excited, is released by the nerve endings. But in 1921, Levy made an experiment in which he established the chemical nature of transmission in the autonomic synapse among the heart and the vagus nerves. It filled the vessels with saline and stimulated the vagus nerve, causing the heart to slow down. When fluid was transferred from inhibited cardiac pacing to an unstimulated heart, it beat slower. It is clear that the stimulation of the vagus nerve caused the release of the inhibitory substance into the solution. Acetylcholine fully reproduced the effect of this substance. In 1930, the role in the synaptic transmission of acetylcholine in the ganglion was finally established by Feldberg and his co-worker.

Synapse chemical

The chemical synapse is fundamentally different in the transmission of stimulation with the help of a mediator from presynapse to postsynapse. Therefore, differences are formed in the morphology of the chemical synapse. The chemical synapse is more common in the vertebral CNS. It is now known that a neuron is able to secrete and synthesize a pair of mediators (coexisting mediators). Neurons also have neurotransmitter plasticity - the ability to change a major neurotransmitter during development.

Neuromuscular synapse

This synapse carries out the transfer of excitation, however, this connection can be destroyed by various factors. The transmission ends during the blockade of the release of acetylcholine into the synaptic cleft, as well as during the excess of its content in the zone of postsynaptic membranes. Many poisons and drugs affect seizure, an outlet that is associated with the cholinergic receptors of the postsynaptic membrane, then the muscle synapse blocks the transmission of excitation. The body dies during suffocation and stopping the contraction of the respiratory muscles.

Botulinus is a microbial toxin in the synapse; it blocks the transmission of excitation by destroying the syntaxin protein in the presynaptic terminal, which is controlled by the release of acetylcholine into the synaptic cleft. Several toxic warfare agents, pharmacological drugs (neostigmine and proserin), as well as insecticides block the conduction of excitation into the neuromuscular synapse by inactivating acetylcholinesterase, an enzyme that destroys acetylcholine. Therefore, there is an accumulation of acetylcholine in the zone of the postsynaptic membrane, the sensitivity to the mediator decreases, the exit from the postsynaptic membranes and the immersion of the receptor block into the cytosol takes place. Acetylcholine will be ineffective and the synapse will be blocked.

Nervous synapse: features and components

A synapse is the connection of a point of contact between two cells. Moreover, each of them is enclosed in its own electrogenic membrane. The nerve synapse consists of three main components: the postsynaptic membrane, the synaptic cleft, and the presynaptic membrane. The postsynaptic membrane is a nerve ending that travels to the muscle and descends into the muscle tissue. In the presynaptic region there are vesicles - these are closed cavities with a mediator. They are always on the move.

Approaching the membrane of nerve endings, the vesicles merge with it, and the transmitter enters the synaptic cleft. One vesicle contains a quantum of a mediator and mitochondria (they are needed for the synthesis of a mediator - the main source of energy), then acetylcholine is synthesized from choline and, under the influence of the enzyme acetylcholine transferrase, is processed into acetylCoA).

Synaptic cleft among post- and presynaptic membranes

The size of the gap is different in different synapses. filled with intercellular fluid, which contains a mediator. The postsynaptic membrane covers the place of contact of the nerve ending with the innervated cell in the myoneural synapse. At certain synapses, the postsynaptic membrane creates a fold, increasing the contact area.

Additional substances that make up the postsynaptic membrane

The following substances are present in the post-synaptic membrane zone:

Receptor (cholinergic receptor in the myoneural synapse).

Lipoprotein (very similar to acetylcholine). This protein has an electrophilic end and an ionic head. The head enters the synaptic cleft, interacts with the cationic head of acetylcholine. Because of this interaction, the postsynaptic membrane changes, then depolarization occurs, and potentially dependent Na-channels open. Membrane depolarization is not considered a self-reinforcing process;

It is gradual, its potential on the postsynaptic membrane depends on the number of mediators, that is, the potential is characterized by the property of local excitations.

Cholinesterase is considered a protein that has an enzymatic function. In structure, it is similar to the cholinergic receptor and has similar properties to acetylcholine. Cholinesterase destroys acetylcholine, at first the one that is associated with the cholinergic receptor. Under the action of cholinesterase, the cholinergic receptor removes acetylcholine, and repolarization of the postsynaptic membrane is formed. Acetylcholine is broken down to acetic acid and choline, which is necessary for the trophism of muscle tissue.

With the help of active transport, choline is removed to the presynaptic membrane, it is used for the synthesis of a new mediator. Under the influence of a mediator, the permeability in the postsynaptic membrane changes, and under cholinesterase, the sensitivity and permeability return to their initial value. Chemoreceptors are able to interact with new mediators.

Under the vegetative (from Lat. Vegetare - to grow) activity of the body is understood the work of internal organs, which provides energy and other components necessary for the existence of all organs and tissues. V late XIX century French physiologist Claude Bernard (Bernard C.) came to the conclusion that "the constancy of the internal environment of the body is the guarantee of its free and independent life." As he noted back in 1878, the internal environment of the body is subject to strict control, which keeps its parameters within certain limits. In 1929, the American physiologist Walter Cannon (Cannon W.) proposed to designate the relative constancy of the internal environment of the body and some physiological functions by the term homeostasis (Greek homoios - equal and stasis - state). There are two mechanisms for maintaining homeostasis: nervous and endocrine. This chapter will cover the first of these.

11.1. Autonomic nervous system

The autonomic nervous system innervates the smooth muscles of the internal organs, the heart and exocrine glands (digestive, sweat, etc.). Sometimes this part of the nervous system is called visceral (from Lat. Viscera - viscera) and very often - autonomous. The last definition emphasizes an important feature of autonomic regulation: it occurs only reflexively, i.e. is not realized and does not obey voluntary control, thereby fundamentally differing from the somatic nervous system, which innervates skeletal muscles. In the English-language literature, as a rule, the term autonomic nervous system is used, in the domestic it is more often called autonomic.

At the very end of the 19th century, the British physiologist John Langley (Langley J.) divided the autonomic nervous system into three divisions: sympathetic, parasympathetic and enteral. This classification remains generally accepted at the present time (although in the domestic literature the enteral division, consisting of neurons in the intermuscular and submucosal plexuses of the gastrointestinal tract, is often called metasympathetic). This chapter examines the first two divisions of the autonomic nervous system. Cannon drew attention to their different functions: the sympathetic controls the fight or flight reactions (in the English rhyming version: fight or flight), and the parasympathetic is necessary for rest and digest. The Swiss physiologist Walter Hess (Hess W.) suggested calling the sympathetic department ergotropic, i.e. contributing to the mobilization of energy, intense activity, and the parasympathetic - trophotropic, i.e. regulating tissue nutrition, regenerative processes.

11.2. Peripheral division of the autonomic nervous system

First of all, it should be noted that the peripheral part of the autonomic nervous system is extremely efferent, it serves only to conduct excitation to the effectors. If in the somatic nervous system only one neuron (motoneuron) is needed for this, then in the autonomic nervous system, two neurons are used, connecting through a synapse in a special autonomic ganglion (Fig. 11.1).

The bodies of preganglionic neurons are located in the brainstem and spinal cord, and their axons are directed to the ganglia, where the bodies of postganglionic neurons are located. Working organs are innervated by axons of postganglionic neurons.

The sympathetic and parasympathetic divisions of the autonomic nervous system differ primarily in the location of the preganglionic neurons. The bodies of sympathetic neurons are located in the lateral horns of the thoracic and lumbar (two to three upper segments) sections. The preganglionic neurons of the parasympathetic division are located, firstly, in the brain stem, from where the axons of these neurons exit as part of the four cranial nerves: oculomotor (III), facial (VII), glossopharyngeal (IX) and vagus (X). Second, parasympathetic preganglionic neurons are found in the sacral spinal cord (Fig. 11.2).

Sympathetic ganglia are usually divided into two types: paravertebral and prevertebral. The paravertebral ganglia form the so-called. sympathetic trunks, consisting of nodes connected by longitudinal fibers, which are located on either side of the spine from the base of the skull to the sacrum. In the sympathetic trunk, most of the axons of preganglionic neurons transmit excitation to postganglionic neurons. A smaller part of the preganglionic axons pass through the sympathetic trunk to the prevertebral ganglia: cervical, stellate, celiac, superior and inferior mesenteric - in these unpaired formations, as well as in the sympathetic trunk, there are sympathetic postganglionic neurons. In addition, part of the sympathetic preganglionic fibers innervates the adrenal medulla. The axons of preganglionic neurons are thin and, despite the fact that many of them are covered with myelin sheath, the rate of excitation conduction along them is much lower than along the axons of motor neurons.

In the ganglia, the fibers of the preganglionic axons branch and form synapses with the dendrites of many postganglionic neurons (divergence phenomenon), which, as a rule, are multipolar and have, on average, about a dozen dendrites. One preganglionic sympathetic neuron has an average of about 100 postganglionic neurons. At the same time, convergence of many preganglionic neurons to the same postganglionic neurons is also observed in the sympathetic ganglia. Due to this, the summation of the excitation occurs, which means that the reliability of the signal transmission increases. Most of the sympathetic ganglia are located far enough from the innervated organs and therefore postganglionic neurons have rather long axons that are devoid of myelin coating.

In the parasympathetic section, preganglionic neurons have long fibers, some of which are myelinated: they end near the innervated organs or in the organs themselves, where the parasympathetic ganglia are located. Therefore, in postganglionic neurons, the axons are short. The ratio of pre- and postganglionic neurons in the parasympathetic ganglia differs from the sympathetic: here it is only 1: 2. Most internal organs have both sympathetic and parasympathetic innervation, an important exception to this rule is the smooth muscles of the blood vessels, which are regulated only by the sympathetic division. And only the arteries of the genital organs have double innervation: both sympathetic and parasympathetic.

11.3. Autonomic nerve tone

Many autonomic neurons exhibit spontaneous background activity, i.e. the ability to spontaneously generate action potentials under resting conditions. This means that the organs innervated by them, in the absence of any stimulation from the external or internal environment, still receive excitation, usually with a frequency of 0.1 to 4 impulses per second. This low frequency stimulation appears to maintain a constant slight contraction (tone) of the smooth muscle.

After the transection or pharmacological blockade of certain autonomic nerves, the innervated organs are deprived of their tonic influence and such a loss is immediately detected. So, for example, after a one-sided transection of the sympathetic nerve that controls the vessels of the rabbit's ear, a sharp expansion of these vessels is found, and after the transection or blockade of the vagus nerves in the experimental animal, the contractions of the heart become more frequent. Removing the blockade restores normal frequency contractions of the heart. After transection of the nerves, the frequency of heart contractions and vascular tone can be restored if the peripheral segments are artificially stimulated with an electric current, having selected its parameters so that they are close to the natural rhythm of impulses.

As a result of various influences on the vegetative centers (which remains to be considered in this chapter), their tone can change. So, for example, if 2 impulses per second pass along the sympathetic nerves that control the smooth muscles of the arteries, then the width of the arteries is typical for a state of rest and then normal blood pressure is recorded. If the tone of the sympathetic nerves increases and the frequency of nerve impulses entering the arteries increases, for example, up to 4-6 per second, then the smooth muscles of the vessels will contract more strongly, the lumen of the vessels will decrease, and the blood pressure will increase. And vice versa: with a decrease in sympathetic tone, the frequency of impulses entering the arteries becomes less than usual, which leads to vasodilation and a decrease in blood pressure.

The tone of the autonomic nerves is extremely important in the regulation of the activity of internal organs. It is supported due to the arrival of afferent signals to the centers, the action on them of various components of the cerebrospinal fluid and blood, as well as the coordinating influence of a number of brain structures, primarily the hypothalamus.

11.4. Afferent link of autonomic reflexes

Vegetative reactions can be observed when almost any receptive region is irritated, but most often they arise in connection with shifts in various parameters of the internal environment and the activation of interoreceptors. For example, activation of mechanoreceptors located in the walls of hollow internal organs (blood vessels, digestive tract, bladder, etc.) occurs when pressure or volume changes in these organs. Excitation of the chemoreceptors of the aorta and carotid arteries occurs due to an increase in the arterial blood pressure of carbon dioxide or the concentration of hydrogen ions, as well as a decrease in oxygen tension. Osmoreceptors are activated depending on the concentration of salts in the blood or in the cerebrospinal fluid, glucose receptors - depending on the concentration of glucose - any change in the parameters of the internal environment causes irritation of the corresponding receptors and a reflex reaction aimed at maintaining homeostasis. In the internal organs there are also pain receptors, which can be excited with a strong stretching or contraction of the walls of these organs, with their oxygen starvation, with inflammation.

Interoreceptors can belong to one of two types of sensory neurons. First, they can be sensitive endings of the neurons of the spinal ganglia, and then excitation from the receptors is carried out, as usual, into the spinal cord and then, with the help of intercalary cells, to the corresponding sympathetic and parasympathetic neurons. Switching of excitation from sensitive to intercalated, and then efferent neurons often occurs in certain segments of the spinal cord. With segmental organization, the activity of internal organs is controlled by autonomic neurons located in the same segments of the spinal cord, to which afferent information from these organs arrives.

Secondly, the propagation of signals from interoreceptors can be carried out along sensory fibers that are part of the autonomic nerves themselves. So, for example, most of the fibers that form the vagus, glossopharyngeal, celiac nerves belong not to autonomic, but to sensory neurons, whose bodies are located in the corresponding ganglia.

11.5. The nature of sympathetic and parasympathetic influences on the activity of internal organs

Most organs are double, i.e. sympathetic and parasympathetic innervation. The tone of each of these departments of the autonomic nervous system can be balanced by the influence of another department, but in certain situations, increased activity is found, the predominance of one of them, and then the true nature of the influence of this department is manifested. This isolated effect can also be found in experiments with transection or pharmacological blockade of sympathetic or parasympathetic nerves. After such an intervention, the activity of the working organs changes under the influence of the department of the autonomic nervous system that has retained a connection with it. Another way of experimental study is to alternate stimulation of the sympathetic and parasympathetic nerves with specially selected parameters. electric current- this simulates an increase in sympathetic or parasympathetic tone.

The influence of the two divisions of the autonomic nervous system on the controlled organs is most often opposite in the direction of the shifts, which even gives reason to talk about the antagonistic nature of the relationship between the sympathetic and parasympathetic divisions. So, for example, when the sympathetic nerves that control the work of the heart are activated, the frequency and strength of its contractions increase, the excitability of the cells of the conducting system of the heart increases, and with an increase in the tone of the vagus nerves, opposite shifts are recorded: the frequency and strength of heart contractions decrease, the excitability of the elements of the conducting system decreases ... Other examples of the opposite influence of sympathetic and parasympathetic nerves can be seen in table 11.1.

Despite the fact that the influence of the sympathetic and parasympathetic divisions on many organs turns out to be the opposite, they act as synergists, i.e. friendly. With an increase in the tone of one of these departments, the tone of the other decreases synchronously: this means that physiological shifts of any direction are due to coordinated changes in the activity of both departments.

11.6. Transmission of excitation in the synapses of the autonomic nervous system

In the autonomic ganglia of both the sympathetic and parasympathetic divisions, the mediator is the same substance - acetylcholine (Fig. 11.3). The same mediator serves as a chemical mediator for the transmission of excitation from parasympathetic postganglionic neurons to working organs. The main mediator of sympathetic postganglionic neurons is norepinephrine.

Although the same mediator is used in the autonomic ganglia and in the transmission of excitation from parasympathetic postganglionic neurons to the working organs, the cholinergic receptors interacting with it are not the same. In the vegetative ganglia, nicotine-sensitive or H-cholinergic receptors interact with the mediator. If in the experiment the cells of the vegetative ganglia are moistened with a 0.5% solution of nicotine, then they cease to conduct excitation. The same result is obtained by introducing a solution of nicotine into the blood of experimental animals and thereby creating a high concentration of this substance. At low concentrations, nicotine acts like acetylcholine, i.e. excites this type of cholinergic receptors. These receptors are associated with ionotropic channels, and upon their excitation, sodium channels of the postsynaptic membrane open.

The cholinergic receptors located in the working organs and interacting with acetylcholine of postganglionic neurons belong to a different type: they do not respond to nicotine, but they can be excited with a small amount of another alkaloid, muscarine, or blocked with a high concentration of the same substance. Muscarinic-sensitive or M-cholinergic receptors provide metabotropic control, in which secondary mediators are involved, and the reactions caused by the action of the mediator develop more slowly and persist longer than with ionotropic control.

The mediator of sympathetic postganglionic neurons, norepinephrine, can bind to metabotropic adrenergic receptors of two types: a- or b, the ratio of which in different organs is not the same, which determines different physiological responses to the action of norepinephrine. For example, b-adrenergic receptors predominate in the smooth muscles of the bronchi: the action of the mediator on them is accompanied by muscle relaxation, which leads to the expansion of the bronchi. In the smooth muscles of the arteries of internal organs and skin, there are more α-adrenergic receptors, and here the muscles contract under the action of norepinephrine, which leads to a narrowing of these vessels. The secretion of sweat glands is controlled by special, cholinergic sympathetic neurons, the mediator of which is acetylcholine. There is evidence that the arteries of skeletal muscles also innervate sympathetic cholinergic neurons. According to another point of view, the arteries of skeletal muscles are controlled by adrenergic neurons, and norepinephrine acts on them through a-adrenergic receptors. And the fact that during muscular work, always accompanied by an increase in sympathetic activity, the arteries of skeletal muscles expand is explained by the action of the adrenal medulla hormone adrenaline on b-adrenergic receptors

With sympathetic activation, adrenaline is released in large quantities from the adrenal medulla (attention should be paid to the innervation of the adrenal medulla by sympathetic preganglionic neurons), and also interacts with adrenergic receptors. This enhances the sympathetic response, since the blood brings adrenaline to those cells near which there are no endings of sympathetic neurons. Norepinephrine and adrenaline stimulate the breakdown of glycogen in the liver and lipids in adipose tissue, acting there on b-adrenergic receptors. In the heart muscle, b-receptors are much more sensitive to norepinephrine than to adrenaline, while in the vessels and bronchi they are more easily activated by adrenaline. These differences served as the basis for the division of b-receptors into two types: b1 (in the heart) and b2 (in other organs).

The mediators of the autonomic nervous system can act not only on the postsynaptic, but also on the presynaptic membrane, where there are also corresponding receptors. Presynaptic receptors are used to regulate the amount of transmitter released. For example, with an increased concentration of norepinephrine in the synaptic cleft, it acts on presynaptic a-receptors, which leads to a decrease in its further release from the presynaptic terminal (negative feedback). If the concentration of the neurotransmitter in the synaptic cleft becomes low, the b-receptors of the presynaptic membrane interact with it, and this leads to an increase in the release of norepinephrine (positive feedback).

By the same principle, i.e. with the participation of presynaptic receptors, regulation of the release of acetylcholine is carried out. If the endings of sympathetic and parasympathetic postganglionic neurons are close to each other, then the reciprocal influence of their mediators is possible. For example, the presynaptic endings of cholinergic neurons contain a-adrenergic receptors and, if norepinephrine acts on them, the release of acetylcholine will decrease. In the same way, acetylcholine can reduce the release of norepinephrine if it binds to the M-cholinergic receptors of the adrenergic neuron. Thus, the sympathetic and parasympathetic divisions compete even at the level of postganglionic neurons.

Many drugs act on the transmission of excitation in the autonomic ganglia (ganglion blockers, a-blockers, b-blockers, etc.) and therefore are widely used in medical practice to correct various kinds of autonomic regulation disorders.

11.7. Centers of autonomic regulation of the spinal cord and trunk

Many preganglionic and postganglionic neurons are able to activate independently of each other. For example, some sympathetic neurons control sweating, while others control cutaneous blood flow, the secretion of the salivary glands is increased by some parasympathetic neurons, and the secretion of glandular cells of the stomach by others. There are methods for detecting the activity of postganglionic neurons, which make it possible to distinguish vasoconstrictor neurons of the skin from cholinergic neurons that control the vessels of skeletal muscles or from neurons that act on the hair muscles of the skin.

The topographically organized input of afferent fibers from different receptive areas to certain segments of the spinal cord or different areas of the trunk excites interneurons, and they transmit excitation to preganglionic autonomic neurons, thus closing the reflex arc. Along with this, the autonomic nervous system is characterized by integrative activity, which is especially pronounced in the sympathetic division. Under certain circumstances, for example, when experiencing emotions, the activity of the entire sympathetic division can increase, and accordingly, the activity of parasympathetic neurons decreases. In addition, the activity of autonomic neurons is consistent with the activity of motoneurons, on which the work of skeletal muscles depends, but their supply of glucose and oxygen necessary for work is carried out under the control of the autonomic nervous system. The participation of autonomic neurons in integrative activity is provided by the autonomic centers of the spinal cord and trunk.

In the thoracic and lumbar spinal cord are the bodies of sympathetic preganglionic neurons, which form the intermediate-lateral, intercalary and small central vegetative nuclei. Sympathetic neurons that control the sweat glands, blood vessels of the skin and skeletal muscles are located lateral to the neurons that regulate the activity of internal organs. By the same principle, parasympathetic neurons are located in the sacral part of the spinal cord: laterally - innervating the bladder, medially - the large intestine. After separation of the spinal cord from the brain, autonomic neurons are able to discharge rhythmically: for example, sympathetic neurons of twelve segments of the spinal cord, united by intraspinal pathways, can, to a certain extent, reflexively regulate the tone of blood vessels. However, in spinal animals, the number of discharging sympathetic neurons and the frequency of discharges are lower than in intact animals. This means that the spinal cord neurons that control vascular tone are stimulated not only by the afferent input, but also by the centers of the brain.

The brain stem contains the vasomotor and respiratory centers, which rhythmically activate the sympathetic nuclei of the spinal cord. The afferent information from the baro- and chemoreceptors continuously arrives at the trunk and, in accordance with its nature, the autonomic centers determine changes in the tone of not only sympathetic, but also parasympathetic nerves that control, for example, the work of the heart. This is a reflex regulation, in which motor neurons of the respiratory muscles are also involved - they are rhythmically activated by the respiratory center.

In the reticular formation of the brain stem, where the vegetative centers are located, several mediator systems are used that control the most important homeostatic indicators and are in complex relationships with each other. Here, some groups of neurons can stimulate the activity of others, inhibit the activity of others, and at the same time experience the influence of both those and others on themselves. Along with the centers of regulation of blood circulation and respiration, there are neurons that coordinate many digestive reflexes: salivation and swallowing, secretion of gastric juice, gastric motility; we can separately mention the protective gag reflex. Different centers constantly coordinate their activities with each other: for example, when swallowing, the entrance to the airways is reflexively closed and, thanks to this, inhalation is prevented. The activity of the stem centers subordinates the activity of the autonomic neurons of the spinal cord.

11. 8. The role of the hypothalamus in the regulation of autonomic functions

The hypothalamus accounts for less than 1% of the brain volume, but it plays a decisive role in the regulation of autonomic functions. There are several reasons for this. First, the hypothalamus quickly receives information from interoreceptors, the signals from which are sent to it through the brain stem. Secondly, information comes here from the surface of the body and from a number of specialized sensory systems (visual, olfactory, auditory). Thirdly, some hypothalamic neurons have their own osmo-, thermo- and glucose receptors (such receptors are called central). They can respond to shifts in osmotic pressure, temperature, and glucose levels in the cerebrospinal fluid and blood. In this regard, it should be recalled that the properties of the blood-brain barrier are less pronounced in the hypothalamus than in the rest of the brain. Fourthly, the hypothalamus has two-way connections with the limbic system of the brain, the reticular formation and the cerebral cortex, which allows it to coordinate autonomic functions with certain behavior, for example, with the experience of emotions. Fifth, the hypothalamus forms projections onto the autonomic centers of the trunk and spinal cord, which allows it to directly control the activity of these centers. Sixth, the hypothalamus controls the most important mechanisms of endocrine regulation (see chapter 12).

The most important switches for autonomic regulation are carried out by the neurons of the hypothalamic nuclei (Fig. 11.4), in different classifications they number from 16 to 48. In the 40s of the twentieth century, Walter Hess (Hess W.) through electrodes introduced with the help of stereotaxic technique consistently irritated different areas hypothalamus in experimental animals and found different combinations of autonomic and behavioral reactions.

When the posterior region of the hypothalamus and the gray matter adjacent to the aqueduct were stimulated, the blood pressure in the experimental animals increased, the heart rate increased, respiration became more frequent and deepened, the pupils dilated, and the hair also rose, the back was bent and the teeth bared, i.e. vegetative shifts indicated the activation of the sympathetic division, and the behavior was affective-defensive. Irritation of the rostral parts of the hypothalamus and the preoptic region caused feeding behavior in the same animals: they began to eat, even if they were fully fed, while the secretion of saliva increased and the motility of the stomach and intestines increased, and the heart rate and respiration decreased, and muscle blood flow became less. , which is quite typical for an increase in parasympathetic tone. One area of ​​the hypothalamus, with the light hand of Hess, began to be called ergotropic, and the other - trophotropic; they are separated from each other by some 2-3 mm.

From these and many other studies, the idea was gradually formed that the activation of different areas of the hypothalamus triggers an already prepared complex of behavioral and autonomic reactions, which means that the role of the hypothalamus is to assess the information coming to it from different sources and, on its basis, choose one or another option, combining behavior with a certain activity of both parts of the autonomic nervous system. Behavior itself can be considered in this situation as an activity aimed at preventing possible shifts in the internal environment. It should be noted that not only the deviations of homeostasis that have already occurred, but also any event potentially threatening homeostasis can activate the necessary activity of the hypothalamus. So, for example, with a sudden threat of autonomic shifts in a person (an increase in the frequency of heart contractions, an increase in blood pressure etc.) occur faster than he takes flight, i.e. such shifts already take into account the nature of the subsequent muscle activity.

Direct control of the tone of the autonomic centers, and hence the output activity of the autonomic nervous system, is carried out by the hypothalamus with the help of efferent connections with three important areas (Fig. 11.5):

1). The nucleus of the solitary tract in the upper part of the medulla oblongata, which is the main recipient of sensory information from internal organs. It interacts with the nucleus of the vagus nerve and other parasympathetic neurons and is involved in the control of temperature, circulation and respiration. 2). The rostral ventral region of the medulla oblongata, which is critical in increasing the overall output activity of the sympathetic division. This activity manifests itself in an increase in blood pressure, an increase in the heart rate, the secretion of sweat glands, pupil dilation, and contraction of the muscles that lift the hair. 3). Autonomic neurons of the spinal cord, which can be directly influenced by the hypothalamus.

11.9. Vegetative mechanisms of blood circulation regulation

In a closed network of blood vessels and the heart (Fig.11.6), blood is constantly moving, the volume of which averages 69 ml / kg of body weight in adult men and 65 ml / kg of body weight in women (i.e., with a body weight of 70 kg will be respectively 4830 ml and 4550 ml). At rest, from 1/3 to 1/2 of this volume does not circulate through the vessels, but is located in the blood depots: capillaries and veins of the abdominal cavity, liver, spleen, lungs, subcutaneous vessels.

During physical work, emotional reactions, stress, this blood passes from the depot into the general bloodstream. The movement of blood is provided by rhythmic contractions of the ventricles of the heart, each of which expels about 70 ml of blood into the aorta (left ventricle) and pulmonary artery (right ventricle), and with heavy physical exertion in well-trained people this indicator (it is called systolic or stroke volume) can grow up to 180 ml. The heart of an adult beats at rest approximately 75 times per minute, which means that during this time more than 5 liters of blood must pass through it (75´70 = 5250 ml) - this indicator is called the minute volume of blood circulation. With each contraction of the left ventricle, the pressure in the aorta, and then in the arteries, rises to 100-140 mm Hg. Art. (systolic pressure), and by the beginning of the next contraction drops to 60-90 mm (diastolic pressure). In the pulmonary artery, these indicators are less: systolic - 15-30 mm, diastolic - 2-7 mm - this is due to the fact that the so-called. the pulmonary circulation, starting from the right ventricle and delivering blood to the lungs, is shorter than the large one, and therefore has less resistance to blood flow and does not require high pressure. Thus, the main indicators of circulatory function are the frequency and strength of heart contractions (the systolic volume depends on it), systolic and diastolic pressure, which are determined by the volume of fluid in the closed circulatory system, minute volume of blood flow and vascular resistance to this blood flow. The resistance of the vessels changes in connection with the contractions of their smooth muscles: the narrower the vessel lumen becomes, the more resistance to blood flow it has.

The constancy of the volume of fluid in the body is regulated by hormones (see Chapter 12), but how much of the blood will be in the depot, and how much will circulate through the vessels, how much resistance the vessels will have to the blood flow - depends on the control of the vessels by the sympathetic section. The work of the heart, and hence the value of blood pressure, primarily systolic, is controlled by both sympathetic and vagus nerves (although endocrine mechanisms and local self-regulation also play an important role here). The mechanism for tracking changes in the most important parameters of the circulatory system is quite simple; it boils down to continuous recording by baroreceptors of the degree of stretching of the aortic arch and the place of separation of the common carotid arteries into external and internal (this area is called the carotid sinus). This is sufficient, since the stretching of these vessels reflects the work of the heart, and the resistance of the vessels, and the volume of blood.

The more the aorta and carotid arteries are stretched, the more often nerve impulses spread from baroceptors along the sensitive fibers of the glossopharyngeal and vagus nerves to the corresponding nuclei of the medulla oblongata. This leads to two consequences: an increase in the influence of the vagus nerve on the heart and a decrease in the sympathetic effect on the heart and blood vessels. As a result, the work of the heart decreases (the minute volume decreases) and the tone of the vessels that resist blood flow decreases, and this leads to a decrease in the stretching of the aorta and carotid arteries and a corresponding decrease in impulses from baroreceptors. If it begins to decrease, then there will be an increase in sympathetic activity and a decrease in the tone of the vagus nerves, and as a result, the proper value of the most important parameters of blood circulation will again be restored.

The continuous movement of blood is necessary, first of all, in order to deliver oxygen from the lungs to the working cells, and the carbon dioxide formed in the cells to carry away to the lungs, where it is excreted from the body. The content of these gases in the arterial blood is maintained at a constant level, which is reflected by the values ​​of their partial pressure (from the Latin pars - part, i.e., partial from the whole atmospheric): oxygen - 100 mm Hg. Art., carbon dioxide - about 40 mm Hg. Art. If the tissues begin to work more intensively, then they will begin to take more oxygen from the blood and give more carbon dioxide into it, which will lead, respectively, to a decrease in the oxygen content and an increase in carbon dioxide in the arterial blood. These shifts are detected by chemoreceptors located in the same vascular regions as baroreceptors, i.e. in the aorta and forks of the carotid arteries that feed the brain. The receipt of more frequent signals from chemoreceptors in the medulla oblongata will lead to the activation of the sympathetic section and a decrease in the tone of the vagus nerves: as a result, the work of the heart will increase, the tone of the vessels will increase, and under high pressure the blood will circulate faster between the lungs and tissues. At the same time, the increased frequency of impulses from the vascular chemoreceptors will lead to increased and deeper breathing and the rapidly circulating blood will become more oxygenated and free from excess carbon dioxide: as a result, the blood gas composition will normalize.

Thus, the baroreceptors and chemoreceptors of the aorta and carotid arteries immediately respond to shifts in hemodynamic parameters (manifested by an increase or decrease in the stretching of the walls of these vessels), as well as to changes in blood oxygen and carbon dioxide saturation. The vegetative centers, which received information from them, change the tone of the sympathetic and parasympathetic divisions in such a way that the influence they exert on the working organs leads to the normalization of the parameters deviated from the homeostatic constants.

Of course, this is only a part of the complex system of regulation of blood circulation, in which, along with the nervous, there are also humoral and local mechanisms of regulation. For example, any particularly intensively working organ consumes more oxygen and forms more under-oxidized metabolic products, which are capable of expanding the vessels supplying the organ with blood on their own. As a result, he begins to take more from the general blood flow than he took before, and therefore in the central vessels, due to the decreasing blood volume, pressure decreases and it becomes necessary to regulate this shift with the help of nervous and humoral mechanisms.

During physical work, the circulatory system must adapt to muscle contractions, and to increased oxygen consumption, and to the accumulation of metabolic products, and to the changing activity of other organs. With various behavioral reactions, when experiencing emotions in the body, complex changes occur, which are reflected in the constancy of the internal environment: in such cases, the whole complex of such changes that activate different areas of the brain will certainly affect the activity of the hypothalamic neurons, and it already coordinates the mechanisms of autonomic regulation with muscle work , emotional state or behavioral reactions.

11.10. The main links in the regulation of respiration

With calm breathing, about 300-500 cubic meters enter the lungs during inhalation. cm of air and the same volume of air when you exhale goes into the atmosphere - this is the so-called. tidal volume. After a calm inhalation, you can additionally inhale 1.5-2 liters of air - this is the reserve volume of inhalation, and after a normal exhalation, another 1-1.5 liters of air can be expelled from the lungs - this is the reserve volume of exhalation. The sum of the tidal and reserve volumes is the so-called. vital capacity of the lungs, which is usually determined using a spirometer. Adults breathe on average 14-16 times a minute, ventilating 5-8 liters of air through their lungs during this time - this is the minute breathing volume. With an increase in the depth of breathing due to reserve volumes and a simultaneous increase in the frequency of respiratory movements, the minute ventilation of the lungs can be increased several times (on average, up to 90 liters per minute, and trained people are able to double this indicator).

Air enters the alveoli of the lungs - air cells densely braided with a network of blood capillaries that carry venous blood: it is poorly saturated with oxygen and excessively saturated with carbon dioxide (Fig. 11.7).

The very thin walls of the alveoli and capillaries do not interfere with gas exchange: along the partial pressure gradient, oxygen from the alveolar air passes into the venous blood, and carbon dioxide diffuses into the alveoli. As a result, arterial blood flows from the alveoli with a partial pressure of oxygen in it of about 100 mm Hg. Art., and carbon dioxide - no more than 40 mm Hg. Art .. Ventilation of the lungs constantly renews the composition of the alveolar air, and continuous blood flow and diffusion of gases through the pulmonary membrane make it possible to constantly convert venous blood into arterial blood.

Inhalation occurs due to contractions of the respiratory muscles: the external intercostal and diaphragm, which are controlled by the motor neurons of the cervical (diaphragm) and thoracic spinal cord (intercostal muscles). These neurons are activated by pathways descending from the respiratory center of the brainstem. The respiratory center is formed by several groups of neurons of the medulla oblongata and the pons, one of them (dorsal inspiratory group) is spontaneously activated at rest 14-16 times per minute, and this excitation is carried out to the motor neurons of the respiratory muscles. In the lungs themselves, in the pleura covering them and in the airways there are sensitive nerve endings that are excited when the lungs are stretched and air moves along the airways during inhalation. Signals from these receptors go to the respiratory center, which, on their basis, regulates the duration and depth of inspiration.

With a lack of oxygen in the air (for example, in the thin air of mountain peaks) and during physical work, the oxygen saturation of the blood decreases. During physical work, at the same time, the content of carbon dioxide in the arterial blood increases, since the lungs, working as usual, do not have time to purify the blood from it to the required condition. The chemoreceptors of the aorta and carotid arteries react to the shift in the gas composition of arterial blood, the signals from which go to the respiratory center. This leads to a change in the nature of breathing: inhalation occurs more often and is made deeper due to reserve volumes, exhalation, usually passive, becomes forced under such circumstances (the ventral group of neurons of the respiratory center is activated and the internal intercostal muscles begin to act). As a result, the minute volume of respiration increases and greater ventilation of the lungs with a simultaneous increased blood flow through them allows restoring the gas composition of the blood to the homeostatic standard. Immediately after intense physical work the person has shortness of breath and a rapid pulse, which stop when the oxygen debt is repaid.

The rhythm of the activity of the neurons of the respiratory center also adapts to the rhythmic activity of the respiratory and other skeletal muscles, from the proprioceptors of which it continuously receives information. The coordination of respiratory rhythmics with other homeostatic mechanisms is carried out by the hypothalamus, which, interacting with the limbic system and the cortex, changes the breathing pattern during emotional reactions. The cerebral cortex can directly affect the function of breathing, adapting it to talking or singing. Only the direct influence of the cortex makes it possible to arbitrarily change the nature of breathing, deliberately delay it, reduce it or speed it up, but all this is possible only within limited limits. So, for example, a voluntary holding of breath in most people does not exceed a minute, after which it spontaneously resumes due to the excessive accumulation of carbon dioxide in the blood and a simultaneous decrease in oxygen in it.

Summary

The constancy of the internal environment of the body is the guarantor of its free activity. The autonomic nervous system is responsible for the rapid restoration of displaced homeostatic constants. It is also able to prevent possible shifts in homeostasis associated with changes in the external environment. Two divisions of the autonomic nervous system simultaneously control the activity of most internal organs, exerting the opposite effect on them. An increase in the tone of sympathetic centers is manifested by ergotropic reactions, and an increase in parasympathetic tone - trophotropic. The activity of the vegetative centers coordinates the hypothalamus, it coordinates their activity with the work of muscles, emotional reactions and behavior. The hypothalamus interacts with the limbic system of the brain, the reticular formation and the cerebral cortex. Vegetative regulation mechanisms play a major role in the implementation of the vital functions of blood circulation and respiration.

Questions for self-control

165. In what part of the spinal cord are the bodies of parasympathetic neurons?

A. Sheiny; B. Grudnoy; B. Upper segments of the lumbar spine; D. Lower segments of the lumbar spine; D. Sacral.

166. What cranial nerves do not contain fibers of parasympathetic neurons?

A. Trigeminal; B. Oculomotor; B. Facial; D. Wandering; D. Lingopharyngeal.

167. What ganglia of the sympathetic department should be attributed to paravertebral?

A. Sympathetic trunk; B. Sheiny; V. Star; G. Chrevny; B. Inferior mesenteric.

168. Which of the following effectors receives mainly only sympathetic innervation?

A. Bronchi; B. Stomach; B. Intestine; D. Blood vessels; D. Bladder.

169. Which of the following reflects an increase in the tone of the parasympathetic department?

A. Dilation of the pupils; B. Expansion of the bronchi; B. Increase in the frequency of contractions of the heart; D. Increased secretion of the digestive glands; D. Increased secretion of sweat glands.

170. Which of the above is characteristic for increasing the tone of the sympathetic department?

A. Increased secretion of bronchial glands; B. Strengthening gastric motility; B. Increased secretion of the lacrimal glands; D. Contraction of the muscles of the bladder; E. Increased breakdown of carbohydrates in cells.

171. The activity of which endocrine gland is controlled by sympathetic preganglionic neurons?

A. Adrenal cortex; B. Medulla of the adrenal glands; B. Pancreas; D. Thyroid gland; D. Parathyroid glands.

172. What neurotransmitter is used to transmit excitation in the sympathetic autonomic ganglia?

A. Adrenaline; B. Norepinephrine; B. Acetylcholine; G. Dopamine; D. Serotonin.

173. With the help of what mediator parasympathetic postganglionic neurons usually act on effectors?

A. Acetylcholine; B. Adrenaline; B. Norepinephrine; G. Serotonin; D. Substance R.

174. Which of the above characterizes the H-cholinergic receptors?

A. Belong to the postsynaptic membrane of the working organs, regulated by the parasympathetic division; B. Ionotropic; B. Activated by muscarin; D. Refers only to the parasympathetic department; D. Are located only on the presynaptic membrane.

175. What receptors must bind to a mediator for an increased breakdown of carbohydrates in the effector cell?

A. a-adrenergic receptors; B. b-adrenergic receptors; B. H-cholinergic receptors; D. M-cholinergic receptors; D. Ionotropic receptors.

176. What structure of the brain coordinates vegetative functions and behavior?

A. Spinal cord; B. The medulla oblongata; B. Midbrain; G. Hypothalamus; D. Bark of the cerebral hemispheres.

177. What homeostatic shift will have a direct effect on the central receptors of the hypothalamus?

A. Increased blood pressure; B. Increase in blood temperature; B. Increase in blood volume; D. Increase in the partial pressure of oxygen in arterial blood; E. Decrease in blood pressure.

178. What is the value of the minute volume of blood circulation, if the stroke volume is 65 ml, and the heart rate is 78 per minute?

A. 4820 ml; B. 4960 ml; B. 5070 ml; G. 5140 ml; D. 5360 ml.

179. Where are the baroreceptors that supply information to the autonomic centers of the medulla oblongata, which regulate the work of the heart and blood pressure?

A. Heart; B. Aorta and carotid arteries; B. Large veins; D. Small arteries; D. Hypothalamus.

180. In a supine position, a person reflexively decreases the frequency of heart contractions and blood pressure. What receptors are activated that cause these changes?

A. Intrafusal muscle receptors; B. Tendon Golgi receptors; B. Vestibular receptors; D. Mechanoreceptors of the aortic arch and carotid arteries; D. Intracardiac mechanoreceptors.

181. What event is most likely to occur as a result of an increase in the voltage of carbon dioxide in the blood?

A. Decrease in respiratory rate; B. Decrease in the depth of breathing; B. Decrease in the frequency of contractions of the heart; D. Decrease in the force of contractions of the heart; D. Increased blood pressure.

182. What is the vital capacity of the lungs if the tidal volume is 400 ml, the inspiratory reserve volume is 1500 ml, and the expiratory reserve volume is 2 liters?

A. 1900 ml; B. 2400 ml; H. 3.5 l; G. 3900 ml; E. According to the available data, the vital capacity of the lungs cannot be determined.

183. What can happen as a result of a short voluntary hyperventilation of the lungs (rapid and deep breathing)?

A. Increasing the tone of the vagus nerves; B. Increased tone of sympathetic nerves; B. Increased impulse from vascular chemoreceptors; D. Increased impulse from vascular baroreceptors; D. Increase in systolic pressure.

184. What is meant by the tone of the autonomic nerves?

A. Their ability to be excited by the action of a stimulus; B. Ability to conduct arousal; B. Presence of spontaneous background activity; D. Increasing the frequency of conducted signals; E. Any change in the frequency of the transmitted signals.

The sympathetic nervous system, along with the parasympathetic, is an integral part of the autonomic (effector) nervous system, which regulates the involuntary activity of the internal organs of animals and humans.
The sympathetic nervous system, like the parasympathetic, consists of motor neurons that innervate the smooth muscles of the effector organs, and includes 2 types of neurons - preganglionic and postganglionic.
The bodies of preganglionic neurons of the autonomic nervous system lie in the brain or spinal cord, and their unmyelinated axons leave the central nervous system (CNS) as part of the anterior roots of the segmental nerve and form synapses with dendrites of postganglionic neurons. The bodies of postganglionic neurons are located in the ganglion, and the unmyelated axons are directed to the effector organ. General control of the activity of the autonomic nervous system is carried out by the centers located in the spinal cord and medulla oblongata, as well as the hypothalamus.
The sympathetic nervous system includes fibers (sympathetic nerve fibers) originating from neurons located in the sterno-lumbar spinal cord. Pre- and postganglionic sympathetic fibers are distinguished.
According to the mediators formed in the synapses of the autonomic nervous system, all efferent nerves of the autonomic nervous system can be divided into adrenergic (norepinephrine mediator) and cholinergic (acetylcholine mediator).
Of all the synapses of the autonomic nervous system located in the ganglia and in the area of ​​the endings of the postganglionic fibers, norepinephrine is a mediator only in the endings of the postganglionic fibers, which correspond to the preganglionic fibers extending from the thoracolumbar spinal cord.
The physiological data given are the basis for modern classification substances acting in the field of synaptic transmission of nerve impulses, both adrenergic and cholinergic.
In addition to the sympathetic nervous system, adrenergic regulation of internal organs is realized with the participation of structures that are anatomically unrelated to it, for example, extrasynaptic (non-nervous) adrenergic receptors, which react mainly to catecholamines circulating in the bloodstream.
If exogenous adrenergic substances activate adrenergic regulation of internal organs, they are called adrenomimetic agents (adrenomimetics)> if they inhibit it, then they are called antiadrenergic agents (substances) (the previously used term is adrenolytics).
Adrenomimetics reproduce, and antiadrenergic substances block in the body in whole or in part the effects of the main endogenous catecholamines of the body - adrenaline and norepinephrine.
The term "norepinephrine" comes from the conditional German abbreviation "NOR", which stands for Nohne Radikale, i.e. adrenaline without a radical (methyl) at the nitrogen atom.
In the literature, along with the term "adrenaline" and "norepinephrine" are used the terms "epinephrine" (from the Greek. Epine - on, over and pergov - kidney) and "norepinephrine", respectively.
By chemical structure catecholamines, adrenaline and norepinephrine are amines in which the MH 2 group is linked to pyrocatechol (catechol, orthoxybenzene) through an ethyl radical, i.e. epinephrine and norepinephrine are pyrocatechinethylamine derivatives (Fig. 4.1).
he
pyrocatechinethidamine (catecholamine)
In terms of chemical structure, adrenaline and norepinephrine are close to each other; both substances contain a hydroxyl group in the p-position and differ only in the presence of an additional methyl group on adrenaline at the amino nitrogen atom.
The main target of the action of adrenergic substances is adrenergic synapses.
A synapse (from the Greek synapsis - connection) is a structural formation at the site of contact of one neuron with another neuron or at the site of contact of the end of an efferent nerve with a cell of an effector organ.
The synapse consists of 3 main elements: the presynaptic membrane, the synaptic cleft and the postsynaptic membrane, which perform specific functions.
In the region of the presynaptic membrane, a mediator is synthesized and released (in the case of an adrenergic synapse, norepinephrine), which has an exciting effect on the postsynaptic membrane of an innervated cell.
In the case of an adrenergic synapse, the postsynaptic membrane is selectively sensitive to a chemical agent, norepinephrine, and is practically insensitive to electrical stimuli.
Selective sensitivity of the postsynaptic membrane to certain chemicals and mediators is associated with the presence of receptors on its surface - molecules that have the properties of specific interaction with mediator molecules. In addition to the postsynaptic membrane, receptors for a mediator can be located in areas distant from the synapse on the membrane surface.
Synapses in which norepinephrine is the mediator are called adrenergic (more precisely, noradrenergic) synapses, and the receptor structures that respond to norepinephrine and adrenaline are called adrenergic receptors.
Norepinephrine (NA) - the main mediator (neurotransmitter, neurotransmitter) of adrenergic synapses is synthesized in the region of the presynaptic membrane of the synapse in a multistep process (Fig.4.2) from the amino acid tyrosine obtained either from food or from essential amino acid phenylalanine, which is oxidized in the liver by hydroxylation to tyrosine. Tyrosine from the liver with the blood stream is brought to the nerve endings, captured by them, and a chain of transformations begins in the axoplasm, leading to the formation of HA from tyrosine. The synthesis of catecholamines is an enzymatic process. The enzymes involved in the synthesis of catecholamines are synthesized in the endoplasmic reticulum of the nerve cell body. With the natural flow of axoplasm, they are transported along the axon to the nerve endings, where all stages of the synthesis of catecholamines occur, up to the formation of NA.
At the stage of norepinephrine formation, the process of biosynthesis of catecholamines in sympathetic nerve endings ends. In the chromaffin cells of the adrenal medulla, it continues until adrenaline is formed. The conversion of norepinephrine to adrenaline is catalyzed by the cytosolic enzyme phenylethanolamine-M-methyltransferase, which, in addition to the adrenal medulla, may be present in small amounts in nerve endings.
HA is found in sympathetic nerve endings in 2 main forms - free and bound.
Free HA, not associated with any structures, consists of newly synthesized in the cytoplasm of nerve cells and recaptured from the synaptic cleft. Its amount is 10-20% of the total HA located in the nerve endings.
Bound HA includes tightly bound HA, localized in large synaptic vesicles (vesicles), and HA, labilely bound, localized in small synaptic vesicles.
Bound HA in synaptic vesicles, like free HA, consists of nerve cells newly synthesized and captured from axoplasm.
Synaptic vesicles play a central role in the formation, storage and release of a transmitter into the synaptic cleft.
The final stage of HA biosynthesis takes place in large synaptic vesicles. Small synaptic vesicles mainly accumulate HA and participate in its secretion into the synaptic cleft.
A significant difference in the concentration of HA in synaptic vesicles and the surrounding axoplasm indicates that there are special mechanisms for uptake of HA in synaptic vesicles. It is assumed that there are two mechanisms of the entry of ND into the small synaptic vesicle: passive, along the concentration gradient, and active, directed against the concentration gradient, capture of ND. The latter mechanism of HA uptake is realized in the presence of ATP with the participation of the H + -ATPase enzyme by a nonspecific protein carrier (carries HA, dopamine, adrenaline, serotonin).
The process of HA release from nerve endings through the presynaptic membrane into the synaptic cleft is carried out not by diffusion through the presynaptic membrane, but by exocytosis; without prior exit into the cytoplasm of the nerve cell.
It is believed that an increase in Ca 2+ content in adrenergic terminals under the influence of a nerve impulse induces the secretion of HA from synaptic vesicles through the presynaptic membrane. Ca 2+ enters the nerve cell from the extracellular fluid (its concentration outside is about 10,000 times greater) after the nerve impulse causes depolarization of the nerve ending. At the same time, the potential difference across its membrane decreases and calcium channels dependent on the potential difference open.
Ca 2+ delivered to the nerve ending during depolarization causes the release of HA from synaptic vesicles into the synaptic cleft by exocytosis.
After the fusion of synaptic vesicles with the presynaptic membrane and the release of their contents into the synaptic cleft, the parts of the presynaptic membrane that have been incorporated into it during exocytosis undergo “excision” and endocytosis, after which the presynaptic membrane restores its previous size.
In this case, the synaptic vesicles returned to the axoplasm are either reused, or undergo partial reconstruction in the Golgi apparatus, or are destroyed in phagolysosomes.
Released under the influence of a nerve impulse from the nerve endings of the NA:
interacts with pre- and postsynaptic adrenergic receptors in the synaptic region and extrasynaptic adrenergic receptors;
metabolized in the postsynaptic cell, in the synaptic cleft, as well as after diffusion into the bloodstream in the liver;
is captured back by nerve endings with subsequent reuse and partial enzymatic inactivation; reuptake is also inherent in various non-neuronal tissues.
The essence of reuptake is a decrease in the concentration released during a nerve impulse or exogenously introduced norepinephrine mediator in the synaptic cleft due to its absorption by neuronal or cell membranes of other tissues.
In this case, it is believed that approximately 80% of the NA that interacted with adrenergic receptors is removed (inactivated) from the synaptic cleft due to the reuptake mechanism. The need for rapid removal of NA from the synaptic cleft is dictated by purely regulatory reasons. The mediator must disappear from the receptor region quickly enough, otherwise its influence would be too long and precise regulation would be impossible.
Neuronal reuptake process is -dependent
and acts with the participation of several selective protein carriers not only in relation to HA, but also adrenaline, dopamine, serotonin, and a number of synthetic and natural analogs with similar chemical structure, for example, amphetamine.
Enzymatic inactivation of CA is mainly due to 2 enzymes - monoamine oxidase (MAO) and catechol-O-methyltransferase (COMT), localized in various organs, especially in the liver and kidneys (Fig. 4.3). MAO and COMT destroy about 10% of the released mediator. In the central nervous system, enzymatic destruction of norepinephrine and other CAs to a greater extent carried out by MAO than COMT; the opposite relationship exists in the peripheral nervous system.
MAO is a membrane-bound enzyme localized in the outer membranes of mitochondria, which are impermeable to amines. The MAO substrate of animal tissues is primary, secondary, and tertiary amines. MAO quaternary amines are not oxidized. There are isoenzymes of MAO type A (MAO A) and MAO type B (MAO B), which differ in sensitivity to substrates and inhibitors. MAO A deaminates mainly norepinephrine and serotonin and is sensitive to the inhibitor chlorgyline. MAO B deaminates phenylethylamines and benzylamines and is inhibited by biphenyl.
COMT is predominantly a soluble cytosolic enzyme, the cofactor of COMT is Mg 2+. No significant COMT activity was found in the fractions of synaptic vesicles, synaptic membranes, and mitochondria. COMT is an intracellular enzyme and is not localized on the outer side of the postsynaptic membrane, but can penetrate into the synaptic cleft. There are conflicting data on the presence of COMT in blood plasma. The functional role of COMT is to inactivate free catecholamines in effector cells, especially those innervated by the peripheral nervous system. Endogenous and exogenous catecholamines in the blood are mainly inactivated by liver COMT. COMT catalyzes the O-methylation of catecholamines. O-methylated derivatives of catecholamines have 100 times less biological activity than catecholamines. This pathway is more effective in reducing CA activity than deamination.
The result of the combined action of MAO and COMT is the formation of a deaminated and methylated product - 3-methoxy-4-hydroxy-mandelic acid.
The main object of the influence of HA released into the synaptic cleft are adrenergic receptors (adrenergic receptors) located on the postsynaptic membrane and, to a lesser extent, located outside the synapse (non-innervated); the latter react mainly to catecholamines circulating in the bloodstream (adrenaline).
The classification of adrenergic receptors is based on the following properties (Tepperman J., Tepperman H., 1989): 1) the intensity of the reaction to different agonists (activators of adrenergic receptors), the "preference" of some empirically discovered synthetic agonists;
2) the degree of their blockade by individual synthetic antagonists (blockers of adrenergic receptors); 3) the mechanism of transformation (stimulation or inhibition of adenylate cyclase, stimulation of the circulation of phosphatidylinositol polyphosphates, etc.).
With the help of these criteria, two main types of adrenergic receptors are currently distinguished - a and p and several of their subtypes - c ^, a 2, P 1? Р 2, Р 3, and also, according to the latest data, Р 4 (fig. 4.4).

Rice. 4.4. Types and subtypes of adrenergic receptors

A more detailed study, including with the help of molecular cloning methods, made it possible to identify several more varieties in each subtype of a-adrenergic receptors - a 1A, a 2A, etc.
Adrenergic receptors are members of a large family of cell plasma membrane receptors that respond to extracellular signaling molecules.
In addition to α- and β-adrenergic receptors, this family also includes M-cholinergic receptors, serotonin receptors, etc.
Structurally, the receptors of this family are very similar in structure and trigger a cellular reaction with the help of nucleotide-binding proteins (β-proteins) (see below).
Adrenergic receptors are widespread in the body. Localization distinguishes between central and peripheral adrenergic receptors.
Central adrenergic receptors are located in different areas brain and are involved in the regulation of the central nervous system.
Peripheral adrenergic receptors regulate the functions of internal organs and have been investigated in more detail (Table 4.1).
The main contribution to the response of an organ to catecholamines and adrenergic substances is made by post- and extra-synaptic adrenergic receptors.
In most cases, post- and extra-synaptic adrenergic receptors are localized on the surface of smooth muscle or secretory cells of organs and tissues, and their excitation leads either to an increase in contraction (or secretion), or to relaxation (a decrease in secretion).
c ^ - and p ^ Adrenoreceptors in peripheral organs usually have postsynaptic localization and therefore react mainly to the NA released from adrenergic nerve endings.
and 2 -, P 2 -adrenergic receptors are presynaptic, post- and extra-synaptic receptors. V the latter case they are often located on blood cells and vascular smooth muscle cells and react primarily to catecholamines in the bloodstream.
Adrenergic receptors and their subtypes are unevenly distributed in individual organs. In some organs and tissues there may be adrenergic receptors of several types and subtypes (heart, blood vessels, gastrointestinal tract, etc.), in others - receptors of only one type.
Of course, the presence in an organ or tissue of various subtypes of adrenergic receptors facilitates the fine regulation of the functions of organs and tissues. On the other hand, the presence of receptors of the same types and subtypes in different tissues does not allow obtaining a selective effect in relation to this or that organ.
The pharmacological response will always be the result of the interaction of the drug with receptors located in various organs and tissues. This situation in the field of pharmacotherapy will continue until a difference is established in the structure of adrenergic receptors of individual organs (if any) and substances that selectively interact with adrenergic receptors of individual organs and tissues of the body are synthesized.

			Table 4.1 Topography and main effects of peripheral α- and β-adrenergic receptors in the body Organ, tissue Adrenergic receptors (AR) a-adrenergic receptors | 3-adrenergic receptors Heart a 1 - an increase in the strength of heart contractions (^ (prevailing), P 2 (25% of the p-AR of the heart), P 4 - increase in strength and heart rate Lungs P 2 (prevails), P 1 (25% of the p-AR of the lungs) - relaxation of the smooth muscles of the trachea and bronchi Vessels: arterioles and systemic veins c ^, a 2 - vasoconstriction in various vascular areas Р 2 - vasodilation in various vascular areas Gastrointestinal tract a x - relaxation of intestinal smooth muscles, contraction of the sphincters of the gastrointestinal tract (stomach and intestines) and 2 (presynaptic AR at the endings of cholinergic nerves) - relaxation of intestinal smooth muscles Р1, Р 2 - relaxation of smooth muscles of the gastrointestinal tract Uterus: non-pregnant, pregnant a x - contraction of the pregnant uterus P 2 - relaxation of the non-pregnant and pregnant uterus Prostate gland 0 ^ (70% belongs to subtype a 1A) - contraction of smooth muscles of the prostate gland Pancreas gland a 2 - inhibition of insulin secretion Р 2 - increased insulin secretion Liver a 1 - increased glycogenolysis and gluconeogenesis Р 2 - increased glycogenolysis and gluconeogenesis Thyroid Р 2 - increased secretion of iodine-containing hormones

Organ, tissue	Adrenergic receptors (AR)
	a-adrenergic receptors	(3-adrenergic receptors
Skeletal muscle		Р 2 - increased contractile activity (tremor)
Gallbladder and extrahepatic bile ducts		Р 2 - relaxation
Bladder and ureters	a 1 - increased tone of the ureters and x - contraction of the sphincter of the bladder	Р 2 - relaxation of the walls of the bladder
Adipose tissue (lipocytes)	a 2 - inhibition of lipolysis	P1, P 2, P 3 - increased lipolysis
Spleen	a 1 - contraction of the spleen capsule	Р 2 - relaxation of the spleen capsule
Eyes	a 1 - contraction of the radial muscle of the iris (dilation of the pupil)
Skin, pilomotor muscles	c ^ - contraction of the muscles that raise the hair (piloerection)
Platelets	a 2 - stimulation of platelet aggregation
Mast cells		P 2 - suppression of histamine release

Note. Unless otherwise stated, we are talking about post- and extra-synaptic adrenergic receptors. When both types of adrenergic receptors (a and P) are stimulated, the final effect is determined by their relative density in tissues (for example, vasoconstriction or dilatation of blood vessels depends on the predominance of vasoconstrictor with β-AR or vasodilating β 2 -AR in individual vessels. Presynaptic receptors directly on the functions of organs and tissues are not affected.
Being localized in the region of the presynaptic membrane, they, according to the principle of feedback, regulate the release of a transmitter into the synaptic cleft.
Thus, the activation of presynaptic β-adrenergic receptors by noradrenaline reduces the release of NA from adrenergic nerve endings by inhibiting the activity of adenylate cyclase and inhibiting the entry of Ca 2+ ions into the nerve ending during the generation of the action potential, as well as increasing the potassium current.
Depending on the type (a 2 or P2), upon activation, they can either weaken or increase the release of HA into the synaptic cleft, thereby decreasing or increasing the concentration of the mediator acting on adrenergic receptors and, accordingly, exerting a depressing or stimulating effect on the function of effector cells.
a-adrenergic receptors are divided into 2 main subtypes: c ^ - and a-adrenergic receptors, which differ in their localization, function and mechanism of realization of the biological signal.
By location in the body, central and peripheral α-adrenergic receptors are distinguished. By localization in the synapse, pre-, post- and extrasynaptic a-adrenergic receptors.
V last years molecular cloning methods showed the presence of 3 subgroups of adrenergic receptors in each of the subtypes of a-adrenergic receptors (respectively a 1A, a 1B, a w and a 2A, a 2B and 2C). The study of their distribution in the body, structure and pharmacological properties continues. Selective activation or inhibition of some of them (a 2A in the neurons of the brain and a 1A in the smooth muscles of the prostate gland) finds practical use in the clinic for the treatment of diseases of the cardiovascular system and prostate gland.
The widespread prevalence of a-adrenergic receptors determines the variety of biological effects that occur when they are excited or pharmacological blockade.
a 1 -Adrenergic receptors are predominantly localized on the postsynaptic membrane of effector cells; only in recent years has evidence been obtained for the presence of presynaptic α 1 -adrenergic receptors.
The topography of postsynaptic α and α 2 -adrenoreceptors, their role in the body and the mechanism of functioning differ.
In the cardiovascular system found a-adrenergic receptors (a-AR) of both types. A significant number of postsynaptic c ^ -ARs were found in the heart tissue; when they are excited, there is an increase in strength and heart rate.
Located in the arteries and veins, c ^ - and a 2 -AP cause vasoconstriction.
In most cases, in arterial smooth muscle cells, postsynaptic sc-ARs are located on the postsynaptic membrane. and 2 -AP are located on smooth muscle cells extra-naphtha, i. e. in areas not directly adjacent to the adrenergic synapse.
It is believed that a2-AR reacts to HA released from adrenergic nerve endings, while extrasynaptically located a 2 -ARs interact with catecholamines circulating in the bloodstream.
It is believed that in hypertension, a long-term activation of a 2 -AP occurs, leading to an increase in vascular resistance.
In addition to the cardiovascular system, o ^ -ARs are also located in a number of other organs and tissues, where their excitation leads to an increase in smooth muscle contractions and an increase in secretion.
SC-AR cause contraction of the spleen capsule, bladder membrane, pilomotors, uterus, distal respiratory tract of the lungs, sphincters of the stomach, intestines, bladder. Excitation of a, -AR of the intestine causes its relaxation.
In the liver, under the influence of cs-AR, the enzyme glycogen phosphorylase is activated, and glycogenolysis is enhanced. Lipolysis is enhanced under the influence of c ^ -AR in brown adipose tissue.
Widespread in the body are a 2 -adrenergic receptors (a 2 -AR), which are of 2 types - pre- and postsynaptic. Presynaptic a 2 ARs located along the cholinergic nerves innervating the gastrointestinal tract cause a delay in the release of acetylcholine, which leads to its relaxation and suppression of the secretory function. a 2 -ARs located in fat cells inhibit lipolysis, in p-cells of the pancreas they reduce the release of insulin (the latter may serve as a basis for the use of a 2 -adrenergic blockers in antidiabetic therapy).
Activation of a 2 -AR of platelets circulating in the blood causes their aggregation.
In various areas of the central nervous system, c ^ - and a 2 -AP are present, the functions of which are being clarified.
Central a 2 -ARs are a target for antihypertensive drugs clonidine, guanfacine and a-methyldopa (acting through a-methylnor-adrenaline).
Central a 2 -ARs are localized in large numbers in the pontomedullary region, in which a high density of (nor) adrenergic synapses is observed. The main nuclei of this area: the vasomotor center, the nuclei of the solitary tract and the vagus nerve. and 2 -AP are present in all three nuclei.
When a 2 -adrenoreceptor agonists act on presynaptic a 2 -AR, the release of CNS mediators, in particular, such as serotonin, acetylcholine and dopamine, is delayed. The control of a 2 -AR over the release of several mediators explains the variety of changes in the central nervous system under the influence of a 2 -AR agonists.
Activation of a 2 -AR can be the cause of the development of sedation, analgesia, bradycardia, hypotension, and other phenomena.
p-adrenergic receptors (p-AR) are divided into two main subtypes - p ^ and p 2 -subtypes.
Currently, a significant number of agonists and antagonists, more or less selective in relation to r-AR, have been synthesized.
In contrast to other types of receptors, there are relatively few substances that are selective agonists of pNAP. The most famous of these is dobutamine. Compared with the blockers of P ^ AR, the number of compounds selectively blocking p 2 -AP is also small. The most famous of these is butoxamine.
Studies to determine the subtypes pg AP and P 2 -AP have not yet revealed the presence of heterogeneity within p ^ AP and p 2 -AP, although it is possible that it exists.
Currently, the presence of 3 subtypes of β-adrenergic receptors in the body is distinguished: p ^, p 2 - and P 3 -AP.
The subtypes of r-AR differ both in localization within synapses and in distribution in the body.
As for a-AR, there are central and peripheral r-ARs. Unlike a-AR, p-AR in relation to the synapse are mainly located postsynaptically (p ^ AR) or extrasynaptically (p 2 -AR). In the peripheral part of the nervous system, presynaptic p-ARs (apparently of the p 2 -AP subtype) are found. Their excitation according to the principle of positive feedback leads to the release of HA, and the blockade of presynaptic p 2 AR by the corresponding antagonists inhibits the release of HA into the synaptic cleft. Presynaptic r-ARs have not yet been identified in the central nervous system.
As well as for a-AR, the wide prevalence and heterogeneity of r-AR in the body determine the variety of biological effects arising from their excitation or blockade by pharmacological agents.
P * AR and their subtypes are found in almost all tissues and organs of the body. Moreover, cells of the same type may contain p-ARs of various subtypes.
In different parts of the heart, PgAR predominates. Their excitation leads to an increase in strength and heart rate, conduction, increased excitability and automatism, activation of glycogenolysis, and expansion of coronary vessels.
Activation of P, -AR located in the gastrointestinal tract causes its relaxation; in white and brown adipose tissue, they enhance lipolysis.
Compared to P ^ AP, P 2 -AP are more widespread in the body. Due to their extra-synaptic localization, they react primarily to catecholamines circulating in the bloodstream.
p 2 -AR are found in the lungs, blood vessels, uterus, as well as in the heart, adipose tissue, liver, skeletal muscles, pancreas, thyroid gland, testes, and lacrimal glands.
Their excitation leads to the expansion of the bronchi and blood vessels, relaxation of the uterus, increased secretion of renin, insulin and iodine-containing hormones, activation of glycogenolysis in skeletal muscles and liver, lipolysis in adipose tissue.
Presynaptic p 2 ARs are located at the endings of the peripheral sympathetic and cholinergic nerves. When activated, the release of norepinephrine and acetylcholine increases.
р 3 -ARs are involved in the regulation of lipolysis in adipose tissue, which leads to an increase in heat production. They have a much higher affinity for HA than for adrenaline; in contrast to p2-AR, p 2 -AR weakly respond to p-blockers such as propranolol and are not susceptible to desensitization. Currently, synthetic agonists of P 3 -AP are being developed, which, by increasing the intensity of metabolic processes in the body, could be used for obesity.
In terms of chemical structure, a- and p-AR are glycoproteins with a molecular weight of 70,000-90,000 daltons, containing several hundred amino acids (for example, human p, -AP, p 2 -AP and p 3 -AP contain 477,413 and 408 amino acids, respectively) ...
The receptor protein chain consists of 7 hydrophobic domains, each of which forms a transmembrane a-helix, with hydrophilic domains (loops) located between them, located alternately on both sides cell membrane.
The terminal region of the protein chain of the receptor containing the amino group (MH 2) is located extracellularly, and the one containing the carboxyl (COOH) group is located intracellularly.
Transmembrane hydrophobic domains are approximately the same in size and contain 20-25 amino acid residues; hydrophilic domains (loops) are more variable in length. Seven transmembrane domains are located in the membrane in the form of a "pocket" (pocket).
Transmembrane domains of various adrenergic receptors have similar regions of amino acid sequences. So, a- and p-AR are similar to each other by 40%. Individual subtypes of adrenergic receptors have greater similarity in structure (the subtypes ctj-AP and a 2 -AP are 75% similar to each other). The amino acid sequences of the transmembrane domains that bind endogenous catecholamines are 60% similar for all three subtypes of p-adrenergic receptors.
Different regions of the receptor are functionally heterogeneous: the zones responsible for the interaction of the receptor with adrenergic substances (hereinafter referred to as adrenergic ligands or simply ligands) and G-proteins are highlighted.
Comparative analysis of the chemical structure and activity of adrenergic ligands revealed their structural features necessary for interaction with receptors. In particular, for the manifestation of maximum activity against all types of adrenergic receptors, the presence of a catechol ring (a benzene ring containing 2 hydroxyl groups in the 3rd and 4th positions) is necessary, which forms hydrogen bonds and enters into hydrophobic interactions with amino acid side chains in the ligand-binding the receptor area.
Experiments with substitution of amino acids in the protein chain of the receptor have shown the important role of individual amino acids for ligand-receptor interaction.
Thus, replacement or even removal of individual sites in the hydrophilic loops of adrenergic receptors does not affect ligand-receptor binding.
At the same time, the replacement of individual amino acids in the transmembrane hydrophobic domains has a significant effect on it, for example, the replacement of aspartic amino acid 113 (Asp 113) in hydrophobic domain 3 leads to a sharp decrease in the binding capacity of the p 2 -adrenoceptor both in relation to agonists and antagonists. ...
Similar experiments with other amino acids of the transmembrane regions of the protein chain of the receptor made it possible to suggest the important role of individual amino acids in its interaction with catecholamines. One of the most studied in this regard is the structure of P2-AR, which has much in common with the structure of other types of adrenergic receptors (Fig. 4.5).
The formation of the ß-AP ligand-binding site involves the side chains of several amino acids from the transmembrane domains of the receptor lying in its hydrophobic part inside the phospholipid bilayer of the cell membrane.
Among them, aspartic amino acid 113 (Asp 113), located in the 3 transmembrane hydrophobic domain and containing a negatively charged carboxyl group, to which the positively charged protonated amino group of catecholamine binds due to electrostatic (ionic) interaction.
The hydroxyls of the catechol ring of the ligand molecule form hydrogen bonds with the hydroxyl groups of 2 serine molecules numbered 204 and 207 (Ser 204 and Ser 207) located in the 5 transmembrane domain.
In addition, the catechol ring of the ligand can enter into a hydrophobic interaction with the hydrophobic aromatic ring of the amino acid phenylalanine at number 290 (Phe 290) located in the 6th transmembrane domain.
The location of the ligand-binding site of the receptor inside the phospholipid bilayer of the cell membrane explains why hydrophobic β-blockers bind more tightly than endogenous hydrophilic catecholamines.
Another functionally significant center of ß-AP is the region of interaction with G-proteins that regulate the activity of effector systems of enzymes and ion channels (for all subtypes of ß-AP - adenylate cyclase). Binding of the adrenergic receptor to G-proteins occurs from the side of the inner surface of the plasma membrane at the location of the largest 3rd intracellular loop of the adrenergic receptor.
For binding to G-proteins and activation of adenylate cyclase, a loop region is absolutely necessary, consisting of 8 amino acids (residues 222-229) and forming a bond between the carboxyl end of the 5th transmembrane domain and the 3rd intracellular loop.
The β-adrenergic receptor model shown in Fig. 4.5, working, is based on pharmacological analysis of mutant receptors and analysis of the structure-activity relationship of adrenergic ligands.
The indicated interaction model was developed for ß 2 -AP, but it is universal for adrenergic receptors, since it was found that all receptors that bind catecholamines contain Asp in a position similar to Asp 113 in the 3 transmembrane domain of the ß-adrenergic receptor, two Ser in the 5 transmembrane domain and Phe - in the 6th, the differences relate mainly to the serial number of amino acids in the polypeptide chain of the receptor involved in the formation of its active center.
In addition to the amino acids required for the binding of catecholaminergic ligands, the polypeptide chain of adrenergic receptors also contains other amino acid residues (asparagine, tyrosine, threonine, tryptophan, cysteine, etc.), which determine the features of the interaction of the receptor with various adrenergic agonists and antagonists.
G-proteins play the most important role in changing functional and biochemical processes in cells under the action of catecholamines and related compounds (agonists) on adrenergic receptors.
It is the G-proteins that carry out the transduction (transmission) of the adrenergic signal from the adrenergic receptor to the effector (realizing the effect) enzymes and ion channels.
G-proteins are heterotrimers and consist of 3 subunits (a, b, y). The most important of them is played by the a-subunit, which provides binding to the receptor and attaches GTP (guanosine triphosphate).
Stimulating and inhibiting bleaches and & -proteins differ in the structure of the a-subunit (O d contains the a 8 -subunit, b contains the a-subunit). The p- and y-subunits are identical in both types of proteins.
Signal transmission from the receptor to effector structures occurs mainly with the help of the a-subunit. On the a-subunit there is a site that can bind either GTP or GDP (guanosine diphosphate).
The free a-subunit of the O-protein is an enzyme with GTPase activity; it converts GTP into GDP.
The interaction of the receptor activated by adrenergic ligands with O-proteins in the AP O-protein complex, the effector enzyme (or ion channel) activates the latter with further functional and biochemical changes in the cells. The sequence of events is as follows.
In an inactivated (unexcited) state in the membrane, the complex of the receptor and the O-protein is separate from the effector enzyme or ion channel.
In the unexcited state, the a-subunit of the O-protein is associated with the GDP molecule.
The interaction of the adrenergic ligand with the transmembrane domains responsible for binding leads to a change in the conformation of the third loop domain, to which the O-protein binds due to the carboxyl end, which is accompanied by a change in the properties of the a-subunit of the O-protein - the latter loses its affinity for GDP and binds to the GTP molecule.
Binding of GTP to the a-subunit of the O-protein leads to its cleavage from the receptor and dissociation into a- and tightly bound to each other (3y-subunits.
After dissociation, the activated GTP a-subunit and the complex of the Py-subunits of the O-protein act on various effector systems (enzymes and ion channels), which then changes intracellular processes through the system of secondary messengers (mediators).
If the object of regulation of O-proteins is adenylate cyclase (for example, for all subtypes of r-AR), then when it is activated in the cell, cAMP is synthesized from ATP, a secondary messenger that triggers the processes underlying cell activation.
There are several main types of O-proteins stimulating (O s) and inhibiting (O) adenylate cyclase, activating phospholipases (O h), affecting ion channels (O o). Each major adrenergic receptor subtype favors a specific class
O-proteins: a ^ AP - a 2 -AP - 0 / o, p-AP - O c.
In addition to adenylate cyclase, the object of regulation of O-proteins can also be other enzymatic proteins - guanylate cyclase, phospholipase C, phospholipase A2, ion channels (K + and Ca +), etc.
Since the a-subunit has internal GTP-ase activity, then hydrolysis of the GTP bound to the a-subunit with the formation of GDP and P. and reassociation of the a-subunit with the Py-subunits occurs. Ultimately, the a-subunit is cleaved from the effector enzyme and attached to the receptor. The system returns to its original state.
For each of the subtypes of adrenergic receptors, there is a certain mechanism for the transformation of a chemical signal into a biological response of a cell, which is realized when the corresponding adrenergic agonist binds to the receptor.
Thus, the main mechanism responsible for the work of a ^ AP is the activation of phospholipase C by O-proteins (O h -protein), which hydrolyzes the membrane phospholipid phosphatidylinositol-4,5-bisphosphate to inositol-1,4,5-triphosphate (1P 3 , ITP) and diacylglycerol (DAG). 1P 3, binding to specific Ca 2+ channels of the endoplasmic reticulum, causes the release of Ca 2+ from it, which leads to an increase in Ca 2+ content in the cytoplasm and activates calcium-dependent processes - smooth muscle contraction and glandular secretion. Under the influence of DAH in the presence of calcium, protein kinase C is activated. In the gastrointestinal tract, stimulation of α ^ AR and an increase in the content of Ca 2 ^ in cells, on the contrary, cause relaxation of smooth muscles due to hyperpolarization that develops upon opening of calcium-dependent potassium channels (Ca 2 + -dependent potassium channels).
Activation of each of the β-adrenergic receptor subtypes - p ^ p 2 and p 3 - leads to an increase in the activity of adenylate cyclase mediated through the O d-protein, to an increase in the level of cAMP, to the subsequent activation of cAMP-dependent protein kinase (protein kinase A), which, due to the phosphorylation of various proteins, in particular enzymatic, changes the functional and metabolic processes in the cell.
Other mechanisms associated with O-proteins can also participate in the development of the cellular response to the activation of adrenergic receptors.
As you know, with prolonged exposure to catecholamines (CA) and their analogs, there is a gradual decrease in tissue sensitivity to them. The mechanisms for reducing tissue response to CA are varied. One of them may be the so-called desensitization of receptors, well studied in the case of β-adrenoretdeptors. When adrenergic agonists bind to (3-AR, the latter is activated within a few seconds. Long-term interaction of an agonist with r-AR leads to a progressive decrease in the ability of r-AR to respond to the bound agonist. This phenomenon is called desensitization of adrenergic receptors and on molecular level consists in the cleavage of the adrenergic receptor from the O d-protein-adenylate cyclase complex. The process of desensitization of adrenergic receptors develops within a few minutes during the direct interaction of the receptor with the agonist and is caused by conformational changes in the region of the intracellular carboxyl (-COOH) end of the receptor, creating conditions for the phosphorylation of its individual amino acid residues. Receptors that bind O-proteins contain regions rich in serine and threonine (Eer / Thr) amino acid residues at the carboxyl end and in the 3rd intracellular loop, the hydroxyl groups (-OH) of which can be phosphorylated under the influence of protein kinases, including cAMP-dependent protein kinase (protein kinase A) and kinase (3-adrenergic receptors. Phosphorylated by kinase (3-adrenergic receptors) amino acid residues of the adrenergic receptor bind to a specific protein p-arrestin, which weakens the interaction between the receptor and 0 8 -protein and enhances desensitization. Thus, phosphorylated p- AR becomes functionally independent of O d-protein and adenylate cyclase, which reduces its stimulation.Desensitization, as a rule, is reversible.After removal of the adrenergic ligand under the influence of cellular phosphatases, phosphate groups are cleaved from the receptor (dephosphorylation), and it returns to its original state. difference from r-AR data on the possibility of a-A desensitization P are contradictory.
With prolonged stimulation of β-adrenergic receptors, the synthesis of new receptor molecules may also stop.
Theoretically, each process that occurs during the functioning of adrenergic structures can be an object of stimulating or depressing effects, but practically at the present time, the most studied and clinically significant process is the effect of medicinal substances on the following adrenergic processes and structures:
synaptic and extrasynaptic adrenergic receptors;
release of a neurotransmitter from a nerve ending;
neuronal or extra-neuronal seizure of CA;
deposition and release of CA from synaptic vesicles;
enzymatic decomposition of CA.