The functioning of the brain is based on the interaction of nerve cells, and they talk to each other using substances called neurotransmitters. There are quite a lot of mediators, for example acetylcholine, norepinephrine. One of the most important mediators, and perhaps the most important one, is called glutamic acid, or glutamate. If you look at the structure of our brain and what substances are used by different nerve cells, then glutamate is secreted by about 40% of neurons, that is, this is a very large proportion of nerve cells. With the help of the release of glutamate in our brain, brain and spinal cord, the main information flows are transmitted: everything related to sensory (vision and hearing), memory, movement, until it reaches the muscles - all this is transmitted through the release of glutamic acid. Therefore, of course, this mediator deserves special attention and is being studied very actively.
In its own way chemical structure Glutamate is a fairly simple molecule. It is an amino acid, and a food amino acid, that is, we obtain similar molecules simply as part of the proteins that we eat. But it must be said that dietary glutamate (from milk, bread or meat) practically does not pass into the brain. Nerve cells synthesize this substance directly at the endings of axons, directly in those structures that are part of the synapses, “locally” and further secrete it in order to transmit information.
Making glutamate is very simple. The starting material is α-ketoglutaric acid. This is a very common molecule, it is produced during the oxidation of glucose; there is a lot of it in all cells, in all mitochondria. And then it is enough to transplant any amino group taken from any amino acid onto this α-ketoglutaric acid, and now you get glutamate, glutamic acid. Glutamic acid can also be synthesized from glutamine. This is also a food amino acid; glutamate and glutamine are very easily converted into each other. For example, when glutamate has fulfilled its function in a synapse and transmitted a signal, it is then destroyed to form glutamine.
Glutamate is an excitatory transmitter, that is, it is always in our nervous system, in synapses, causing nervous excitement and further signal transmission. This is how glutamate differs, for example, from acetylcholine or norepinephrine, because acetylcholine and norepinephrine can cause excitation in some synapses, and inhibition in others; they have a more complex operating algorithm. And glutamate in this sense is simpler and more understandable, although you will not find such simplicity at all, since there are about 10 types of receptors for glutamate, that is, sensitive proteins that this molecule acts on, and different receptors the glutamate signal is transmitted at different speeds and with different parameters.
The evolution of plants has found a number of toxins that act on glutamate receptors. In general, it is quite clear why plants need this. Plants, as a rule, are against being eaten by animals; accordingly, evolution comes up with some protective toxic structures that stop herbivores. The most powerful plant toxins are associated with algae, and it is algae toxins that can very powerfully influence glutamate receptors in the brain and cause total agitation and convulsions. It turns out that superactivation of glutamate synapses is a very powerful excitation of the brain, a convulsive state. Probably the most famous molecule in this series is called domoic acid, it is synthesized by unicellular algae - there are such algae, they live in the western part Pacific Ocean, on the coast, for example, Canada, California, Mexico. Poisoning with the toxin of these algae is very, very dangerous. And this poisoning sometimes happens because zooplankton, all sorts of small crustaceans or, for example, bivalves, feed on unicellular algae, when they filter water, they draw in these algal cells, and then in some mussel or oyster there is too high a concentration of domoic acid, and you can get seriously poisoned.
Even human deaths have been recorded. True, they are isolated, but nevertheless this speaks of the power of this toxin. And domoic acid poisoning is very typical in the case of birds. If some seabirds, which again eat small fish that feed on zooplankton, receive too much domoic acid, then a characteristic psychosis occurs: some seagulls or pelicans cease to be afraid of large objects and, on the contrary, attack them, that is, they become aggressive . There was an epidemic of such poisonings sometime in the early 1960s, and newspaper reports of this epidemic of "bird psychosis" inspired Daphne Du Maurier to write the novel The Birds, and then Alfred Hitchcock made the classic thriller The Birds. where you see thousands of very aggressive seagulls tormenting the main characters of the film. Naturally, in reality there were no such global poisonings, but nevertheless, domoic acid causes very characteristic effects, and it and molecules like it, of course, are very dangerous for brain function.
We eat glutamic acid and similar glutamate in large quantities simply with food proteins. Our proteins, which are included in various food products, contain 20 amino acids. Glutamate and glutamic acid are part of this twenty. Moreover, they are the most common amino acids if you look at the structure of proteins in total. As a result, we eat from 5 to 10 grams of glutamate and glutamine per day with regular food. At one time, it was very difficult to believe that glutamate functions as a neurotransmitter in the brain, because it turns out that the substance that we literally consume in huge doses performs such subtle functions in the brain. There was such a logical inconsistency. But then we realized that, in fact, dietary glutamate practically does not pass into the brain. For this we must thank a structure called the blood-brain barrier, that is, special cells surround all the capillaries, all the small vessels that penetrate the brain, and quite tightly control the movement of chemicals from the blood into the nervous system. If not for this, then some cutlet or bun we ate would cause us to have convulsions, and, naturally, no one wants this. Therefore, dietary glutamate almost does not pass into the brain and, indeed, is synthesized in order to perform mediator functions directly at the synapses. However, if you eat a lot of glutamate at once, a small amount still penetrates the brain. Then a slight excitement may arise, the effect of which is comparable to a cup of strong coffee. This effect of high doses of dietary glutamate is known, and it occurs quite often if a person uses glutamate in large quantities as a dietary supplement.
The fact is that our taste system is very sensitive to glutamate. Again, this is due to the fact that there is a lot of glutamate in proteins. It turns out that the evolution of the taste system, tuning into the chemical analysis of food, isolated glutamate as a sign of protein food, that is, we must eat protein, because protein is the main construction material our body. In the same way, our taste system has learned to detect glucose very well, because glucose and similar monosaccharides are the main source of energy, and protein is the main building material. Therefore, the taste system is tuned to identify glutamate specifically as a signal about protein food, and along with sour, sweet, salty, bitter tastes, we have sensitive cells on the tongue that react specifically to glutamate. And glutamate is also a well-known so-called flavoring additive. Calling it a taste enhancer is not entirely correct, because glutamate has its own taste, which is as important as bitter, sour, sweet and salty.
It must be said that the existence of glutamate taste has been known for more than a hundred years. Japanese physiologists discovered this effect due to the fact that glutamate (in the form of soy sauce or sauce made from seaweed) has been used in Japanese and Chinese cuisine for a very long time. Accordingly, the question arose: why are they so tasty and why is this taste so different from standard tastes? Then glutamate receptors were discovered, and then glutamate began to be used almost in its pure form (E620, E621 - monosodium glutamate) in order to be added to a wide variety of foods. Sometimes it happens that glutamate is blamed for all mortal sins and is called “another white death”: salt, sugar and glutamate are white death. This, of course, is greatly exaggerated, because I repeat once again: during the day, with regular food, we eat from 5 to 10 grams of glutamate and glutamic acid. Therefore, if you add a little glutamate to your food to create this meaty taste, there is nothing wrong with that, although, of course, excess is not healthy.
There are indeed many receptors for glutamate (about 10 types of receptors), which conduct glutamate signals at different speeds. And these receptors are studied primarily from the point of view of analyzing memory mechanisms. When memory arises in our brain and in the cerebral cortex, this actually means that synapses begin to work more actively between nerve cells transmitting some kind of information flow. The main mechanism for activating synapses is to increase the efficiency of glutamate receptors. By analyzing different glutamate receptors, we see that different receptors change their effectiveness in different ways. Probably the most studied are the so-called NMDA receptors. This is an acronym that stands for N-methyl-D-aspartate. This receptor responds to glutamate and NMDA. The NMDA receptor is characterized by the fact that it can be blocked by magnesium ion, and if a magnesium ion is attached to the receptor, then this receptor does not function. That is, you get a synapse that has receptors, but these receptors are turned off. If some strong, significant signal passes through the neural network, then magnesium ions (they are also called magnesium plugs) break away from the NMDA receptor, and the synapse literally instantly begins to work many times more efficiently. At the level of information transfer, this precisely means recording a certain memory trace. In our brain there is a structure called the hippocampus, there are just a lot of such synapses with NMDA receptors, and the hippocampus is perhaps the most studied structure from the point of view of memory mechanisms.
But NMDA receptors, the appearance and departure of the magnesium plug is a mechanism of short-term memory, because the plug can go away and then return - then we will forget something. If long-term memory is formed, everything is much more complicated, and other types of glutamate receptors work there, which are capable of transmitting a signal from the membrane of a nerve cell directly to nuclear DNA. And having received this signal, nuclear DNA triggers the synthesis of additional receptors in glutamic acid, and these receptors are integrated into synaptic membranes, and the synapse begins to work more efficiently. But this no longer happens instantly, as in the case of knocking out a magnesium plug, but requires several hours and requires repetitions. But if it happened, it happened seriously and for a long time, and this is the basis of our long-term memory.
Of course, pharmacologists use glutamate receptors to influence various functions brain, mainly to reduce arousal nervous system. A very well known drug is called ketamine. It works as an anesthetic substance. Ketamine, in addition, is known as a molecule with a narcotic effect, because hallucinations quite often occur when recovering from anesthesia, so ketamine is also classified as a drug with a hallucinogenic, psychedelic effect, and it is very difficult to use. But in pharmacology this often happens: a substance, which is an essential drug, has some side effects, which ultimately lead to the need to strictly control the distribution and use of this substance.
Another molecule very well known in connection with glutamate is memantine, a substance that can quite mildly block NMDA receptors and ultimately reduce the activity of the cerebral cortex in a variety of areas. Memantine is used in a fairly wide range of situations. Its pharmacy name is “Akatinol”. It is used to lower the overall level of arousal to reduce the likelihood of epileptic seizures, and perhaps the most active use of memantine is in situations of neurodegeneration and Alzheimer's disease.
What are neurotransmitters?
Whatever our brain is doing, be it working on a scientific problem, trying to remember a phone number, or looking at a pastry shop window while choosing a cake, the process is based on the timely release of neurotransmitters at the synapses of neurons and binding them to the corresponding receptors of other neurons. We cannot hug someone without one biomolecule in our brain connecting to another, perfectly matching in shape, like puzzle pieces.
"Neurotransmitter" means "intermediary between neurons." It is biologically active Chemical substance, through which an electrochemical impulse is transmitted from one nerve cell to another, therefore it is also called a “neurotransmitter”.
Every millisecond, a remarkable chain of events unfolds in the human brain: billions of neurons send messages to each other at trillions of connections called synapses.
Each synapse consists of the endings of two neurons separated by a microscopic synaptic cleft, measured in nanometers, that is, billionths of a meter.
When a neuron receives new information, it generates an electrical impulse that causes the neurotransmitter to be released from a special sac called a vesicle. Next, the neurotransmitter molecule passes through the synaptic cleft and connects with a special receptor molecule at the end of the second neuron.
Each specific neurotransmitter has its own receptor, perfectly matching its shape, as if it were a keyhole into which a key fits. The signal is transmitted through a network of neurons in the brain, and also from neurons to muscle tissue or glandular cells, initiating the movement of body parts or some stage in the functioning of an organ.
These processes occur with tremendous speed and accuracy, providing all the functions of the brain, and any failure in this finely tuned system leads to neurological and mental disorders, including autism, schizophrenia, Alzheimer's disease, and epilepsy.
Even a disease such as botulism (severe food poisoning) is associated with a problem in signal transmission in the synapse. Botulinum toxin is known to attack proteins that play an important role in the release of neurotransmitters, and this leads to muscle paralysis. Doctors, however, have learned to use this property of botulinum toxin to paralyze muscles to relieve pain from spasms in a neurological disease such as muscular dystonia.
Synaptic function and neurotransmitter balance are extremely important for neurological and mental health and are areas of intense research by microbiologists, biochemists and pharmacologists.
A number of medications are aimed at correcting the imbalance of neurotransmitters in the brain in mental disorders. For example, in depression, serotonin reuptake inhibitors are often used, which block the uptake of this neurotransmitter by the emitting neuron, thereby increasing its content in the synaptic cleft and making it available to the receiving neuron.
But let's take a closer look at some of the most studied neurotransmitters. There are about fifty of them today.
Let's start with serotonin, which we already know.
Serotonin
This neurotransmitter helps control mood, appetite, pain and sleep. Research shows that serotonin levels are low in depression, which is why pharmacists are developing drugs to boost them.
Amazing fact: 90% of serotonin is found in the gastrointestinal tract, and only 10% is in the brain. Serotonin is involved in physiological processes such as digestion and the formation of blood clots. It belongs to the inhibitory, that is, calming neurotransmitters, so its deficiency can lead to increased excitability and anxiety.
Gamma-amino-butyric acid (GABA)
Another inhibitory neurotransmitter is GABA. The release of GABA leads to calmness. Caffeine is a stimulant precisely because it inhibits the release of GABA, and many sedatives, hypnotics, and tranquilizers act by promoting the release of this neurotransmitter.
GABA plays an important role in vision and motor control. There are medications that work to increase GABA levels in the brain, helping with seizures (epilepsy) and tremors (Huntingtog's disease).
GABA also controls other neurotransmitters such as norepinephrine, dopamine and serotonin.
Decline normal level GABA can lead to anxiety, impulsivity, inability to cope with stress, restlessness and irritability.
Dopamine (dopamine)
This neurotransmitter has a number of important roles in the brain depending on its location. In the frontal cortex, dopamine controls the flow of information to other areas of the brain. It is also involved in functions such as attention, memory, problem solving, and movement.
However, its most famous role is as a mediator of pleasure. When you eat a piece of chocolate, dopamine is released in a certain area of your brain, motivating you to eat another piece. Dopamine plays an important role in the development of addictions (alcohol, drugs, gambling). Addictions most often occur when dopamine levels are low.
Decreased dopamine levels are common and manifest in decreased motivation, ability to concentrate on tasks and remember information.
Impaired dopamine production can also lead to Parkinson's disease, which manifests itself in a decrease in the ability to voluntarily move, tremors, muscle numbness and other symptoms.
And here high level of this neurotransmitter, the so-called “dopamine storm” can lead to hallucinations, agitation, mania and psychosis. Such cases require immediate medical intervention.
Acetylcholine (AcCh)
This neurotransmitter plays a leading role in the formation of memories, verbal and logical thinking and concentration. ACh is also involved in synaptogenesis, that is, the production of new healthy synapses in the brain. Acetylcholine itself is formed from a substance called choline, which is found in eggs, seafood and nuts.
ACh plays a vital role in movement. When it is released into the synaptic cleft between the muscle fiber and the nerve cell, a series of mechanical and chemical reactions leading to muscle contraction. When the ACh level decreases, the reaction stops and the muscle relaxes.
Norepinephrine (norepinephrine)
It is another excitatory neurotransmitter that helps activate the sympathetic nervous system, which is responsible for the fight-or-flight response to external stressors. Norepinephrine is important for concentration, emotions, sleep and dreams, and learning. When norepinephrine is released into the bloodstream, it speeds up the heart rate, releases glucose, and increases blood flow to the muscles.
A decrease in the normal level of this neurotransmitter leads to chronic fatigue, inattention, and weight problems. The increase results in sleep problems, anxiety and ADHD.
Glutamate
It is one of the main excitatory neurotransmitters. Its release increases the flow of electricity between neurons, which is necessary for the normal functioning of neural networks. Glutamate plays a critical role in early brain development, memory and learning.
Lack of glutamate production leads to chronic fatigue and low brain activity. Increased level leads to the death of nerve cells. Glutamate imbalances have been linked to many neurodegenerative diseases such as Alzheimer's, Parkinson's, Huntington's and Tourette's syndrome.
Scientists believe that there are several hundred neurotransmitters that have yet to be discovered and studied. This is one of the most important ways to find effective therapies for neurodegenerative and mental diseases, so any discovery in this area is a big step forward on the path of medical progress.
The most common excitatory transmitter in the brain and spinal cord is the amino acid L-glutamate. Significant example excitatory neurons using glutamate as a transmitter - all neurons going from the cerebral cortex to the white matter of the brain, regardless of their direction in other parts of the cerebral cortex, brainstem or spinal cord. Glutamate is synthesized from α-ketoglutarate, which also serves as a substrate for the formation of GABA.
GABA is the most common inhibitory transmitter in the spinal cord and brain, participating in the functioning of approximately a third of all synapses in the nervous system. Millions of GABAergic neurons form the bulk of the substance of the caudate and lenticular nuclei, and they are also found in large numbers in the periaqueductal gray matter, hypothalamus and hippocampus. In addition, GABA functions as a transmitter in large Purkinje cells, which are the only cells emerging from the cerebellar cortex. Axons of Purkinje cells descend to the dentate and other cerebellar nuclei. GABA is synthesized from glutamate under the action of the enzyme glutamate decarboxylase.
The third amino acid neurotransmitter is glycine. Glycine is involved in the synthesis of proteins in all tissues of the body and is the simplest amino acid synthesized from serine during the catabolism of glucose. This neurotransmitter has an inhibitory effect primarily at the synapses of associative neurons in the brain stem and spinal cord.
Three amino acid mediators.Glutamate is synthesized from α-ketoglutarate by the enzyme GABA transaminase (GABA-T);
γ-Aminobutyric acid (GABA) is synthesized from glutamate by the action of glutamic acid decarboxylase (DHA).
Glycine is the simplest amino acid.
A) Glutamate. Glutamate functions as a neurotransmitter at both ionotropic and metabotropic receptors. Ionotropic receptors include AMPA, kainate and NMDA receptors, which got their names due to the synthetic agonists that activate them: amino-methyl-isoxazole-propionic acid, kainate and N-methyl-D-aspartate, respectively. Kainate receptors are rarely found in isolation; most often they are combined with AMPA receptors and are part of the AMPA-kainate (AMPA-K) receptors.
Ionotropic glutamate receptors. When AMPA-K receptors are activated on the postsynaptic membrane, immediate large quantity Na + ions into the cell and the release of a small amount of K + ions from the cell, which leads to the formation of an early component of the EPSP of the target neuron, depolarizing the target cell membrane from -65 mV to -50 mV. This process leads to the electrostatic “pushing out” of magnesium cations (Mg 2+), which, in a resting state, “close” the NMDA receptor ion channel. Na+ ions pass through the ion channel and an action potential is formed.
It is important to note that Ca 2+ ions also penetrate into the cell and, due to a long period of depolarization, the duration of which reaches 500 ms from the occurrence of a single action potential, activate Ca 2+ -dependent enzymes that can change the structure of the target cell and even the number of its synaptic contacts . The phenomenon of synaptic plasticity in response to receptor activation can be clearly seen in experimental studies on cultured rat hippocampal slices. This phenomenon is considered the main mechanism for the development of short-term memory. For example, the analgesic ketamine, which blocks NMDA channels, in addition to its main effect, interferes with memory formation.
A characteristic feature of repeatedly repeated activation of NMDA receptors is long-term potentiation, manifested by the appearance of EPSPs with values exceeding normal indicators even a few days later (see below - long-term depression).
The role of NMDA receptors in the development of the phenomenon of glutamate excitotoxicity is confirmed by the development of ischemic strokes in experimental animals. It is believed that the cause of the death of a large number of neurons was the excessive entry of Ca 2+ ions into the cell during the following events: ischemia > excess entry of Ca 2+ ions into the cell > activation of Ca 2+ -dependent proteases and lipases > destruction of proteins and lipids > cell death . Administration of an NMDA receptor antagonist immediately after an initial stroke can reduce the severity of ischemic brain damage.
Metabotropic glutamate receptors There are more than 100 different metabotropic glutamate receptors. All metabotropic receptors are internal membrane proteins, most of which are located on postsynaptic membranes and have an excitatory effect. Some metabotropic receptors are localized on the presynaptic membrane and are inhibitory autoreceptors.
Ionotropic glutamate receptors. (1) When an action potential occurs in the area of the nerve ending, (2) calcium channels (Ca 2+) open.
(3) Under the influence of Ca 2+ ions, synaptic vesicles approach the plasma membrane.
(4) Glutamate molecules are released into the synaptic cleft by exocytosis.
(5) The transmitter binds to AMPA-K receptors, which causes the opening of ion channels and the entry of a large number of Na + ions into the cell, as well as the exit of a small amount of K + ions from the cell, resulting in (6) an excitatory postsynaptic potential (EPSP) , causing depolarization with a value of 20 mV, which makes it possible (7) activation of the NMDA receptor by glutamate due to the “pushing out” of the Mq24 ion from the ion channel of the receptor. Na + and Ca 2+ ions penetrate through the NMDA receptor channel, which leads to depolarization of the cell.
(8) The EPSP generated by the NMDA receptor is sufficient to (9) enhance action potentials with a long period of repolarization due to an increase in the intracellular concentration of Ca 2+ ions.
Drugs and the ionotropic GABA A receptor. Green color indicates the action of agonists, red color indicates the action of antagonist. Barbiturates, benzodiazepines and ethanol cause cell hyperpolarization due to their effect on the receptor.
Bicuculline receptor antagonist. Picrotoxin has a direct effect by closing the opening of the ion channel.
Glutamatergic and GABAergic synapses of a multipolar neuron with spiny dendrites. The spatial summation of excitations for each pair of synapses is demonstrated.
b) GABA. GABA receptors can be either ionotropic or metabotropic.
1. Ionotropic GABA receptors. Receptors called GABA A are located in large numbers in the limbic lobe of the brain. Each receptor is associated with a chloride channel. When GABA A receptors are activated, chloride channels open, and Cl- ions flow along a concentration gradient from the synaptic cleft into the cytosol. The cause of hyperpolarization, at which values of -70 mV and below are reached, is the summation of successive IPSPs.
The action of sedative hypnotic drugs barbituric acid and benzodiazepine (for example, diazepam) is realized through the activation of GABA A receptors. Similar effect of ethanol (loss of control social behavior under the influence of ethanol occurs due to the disinhibition of excitatory target neurons, which in the normal state are “restrained” under the influence of GABAergic influences). The mechanism of action of some volatile anesthetics also involves receptor binding, causing ion channels to remain open for a longer time.
The main antagonist occupying the active site of the receptor is the convulsant bicuculline. Another convulsant, picrotoxin, binds to protein subunits that, in the active state, close the ion channel.
2. Metabotropic GABA receptors. Metabotropic receptors, called GABA B, are evenly distributed in all brain structures; they are also found in the peripheral autonomic nerve plexuses. Despite the fact that a large number of G-proteins of these receptors act as second messengers, a significant part of the G-proteins influence a special type of postsynaptic potassium channels - GIRK channels (G-protein coupled inwardly rectifying potassium channels). When a mediator attaches, the β-subunit is separated, which “pushes out” K+ ions through the GIRK channel, which leads to the formation of IPSP.
The response of this type of receptor to the target neuron is slower and weaker compared to GABA A iontophoresis, and stimulation of a higher frequency is required to activate them. In this regard, it is believed that GABA A receptors are located not in the outer layer of the synaptic cleft, but extrasynaptically. This assumption can be confirmed by the presence of another type of extrasynaptically located G-directed channels. These calcium channels are also voltage-dependent and are involved in providing the cell with the amount of Ca 2+ ions necessary for the movement of synaptic vesicles across the presynaptic membrane. When the G-Ca 2+ ligand binding site is activated, calcium channels close, which leads to a decrease in the influence of the action potential, as well as to inhibition of the source neuron (source of excitation) and other adjacent glutamatergic neurons.
In some cases, to treat diseases associated with excessive reflex muscle tone (muscle spasticity), injections of the muscle relaxant baclofen (GABA B agonist) into the subarachnoid space surrounding the spinal cord are used. Baclofen penetrates the spinal cord and inhibits the release of glutamate from sensory nerve endings mainly by reducing the entry of large amounts of Ca 2+ ions into the cell, which occurs under the influence of action potentials of excessive frequency.
Scheme of opening of the GIRK channel located on the postsynaptic membrane by G protein. (A) Resting state. (B) GABA activates the receptor and the G protein βγ subunit moves toward the GIRK channel.
(B) The βγ subunit causes the release of K + ions, which leads to hyperpolarization of the membrane.
Release of the transmitter and further processes occurring in the GABAergic neuron. (1) By binding to GABA A receptors, the transmitter causes hyperpolarization of the membrane of the target neuron due to the opening of chloride (Cl -) channels.
(2) GIRK-binding GABA B receptors have a similar effect by opening G-protein coupled inward rectifying potassium channels (GIRK S).
(3) When GABA B autoreceptors bind, neurotransmitter release from the source neuron is reduced by closing ligand-G protein-dependent calcium (Ca 2+) channels.
(4) The binding of GABA B receptors to neighboring glutamatergic receptors has a similar effect, mediated by the action of Ca 2+ ions.
3. Reuptake of glutamate and GABA. Reuptake of glutamate and GABA occurs in two ways. The left side of each figure shows that some transmitter molecules are taken up from the synaptic cleft by membrane transport proteins and placed back into the synaptic vesicles. The right parts of the figures depict the capture of mediator molecules by adjacent astrocytes. While in the astrocyte, glutamate is converted into glutamine by the action of glutamine synthetase. In the process of subsequent transport to the synaptic seal, glutamate is completed under the action of glutaminase and placed in the synaptic vesicle. GABA is converted to glutamate by the action of GABA transaminase. During transport, glutamate is transformed into glutamine by the action of glutamine synthetase.
Returning to the area of synaptic compaction, glutamine, under the action of glutaminase, is converted into glutamate, from which, under the action of glutamate decarboxylase, GABA is synthesized, the molecules of which are placed in synaptic vesicles.
Blocking the enzyme glutamate decarboxylase underlies the well-known autoimmune disease - “stiff person” syndrome.
Scheme of glutamate reuptake and resynthesis. On the left side of the figure, the glutamate molecule is reuptaken unchanged.
On the right side of the figure (1) glutamate is taken up by astrocytes, then (2) under the action of glutamine synthetase it is converted into glutamine.
(3) Glutamine enters the nerve ending, (4) where, under the action of glutaminase, it is converted into glutamate, which (5) is returned to the synaptic vesicles.
Scheme of GABA reuptake and re-synthesis. On the left side of the figure, the GABA molecule is reuptaken unchanged. On the right side of the figure, GABA is taken up by astrocytes, then (1) by GABA transaminase is converted to glutamate, which (2) by glutamine synthetase is converted to glutamine.
(3) Glutamine enters the nerve ending and, under the action of glutaminase, forms glutamate.
(4) Glutamate is converted by glutamate decarboxylase to GABA, which (5) is returned to synaptic vesicles.
G) Glycine. Glycine is synthesized from serine during glucose catabolism. The main function of this neurotransmitter is to provide negative feedback to motor neurons in the brain stem and spinal cord. When glycine is inactivated (for example, during strychnine poisoning), painful convulsions occur.
Recapture. In the area of synaptic compaction, with the help of axonal transporter proteins, glycine is rapidly reuptaken and subsequently placed into synaptic vesicles.
Negative feedback circuit: Renshaw cells inhibit overexcitation of motor neurons. ACh-acetylcholine. (1) The descending motor tract neuron has an excitatory effect on the spinal cord motor neuron.
(2) The motor neuron causes muscle contraction.
(3) The recurrent branch stimulates the Renshaw cell.
(4) The Renshaw cell exerts an inhibitory effect sufficient to prevent excessive activation of the motor neuron.
18.07.2015 |
Glutamate and gamma-aminobutyric acid (GABA) are the two most abundant neurotransmitters in the brain. Ninety percent of cortical neurons use glutamate – main excitatory transmitter, increasing the likelihood of an axonal action potential developing on the postsynaptic neuron when released into the synaptic cleft.
IN human brain glutamate is most often used by large pyramidal neurons in the cortex and deeper brain structures. Also, this transmitter is often used in modified synapses, causing learning.
Gamma-aminobutyric acid (GABA), in contrast to glutamate, is the main inhibitory neurotransmitter of the cerebral cortex. Inhibitory synapses reduce the likelihood of an action potential traveling along the axon of the postsynaptic neuron.
GABA is abundant in interneurons surrounding pyramidal cells. It is believed that in this case it serves to regulate the continuous excitatory activity of the cortex.
The brain does not require the constant activity of all excitatory synapses to function. In this case, positive feedback loops would form in the brain, intensifying with each cycle. The cortex will be overloaded, as in the case of epileptic seizures.
Excess glutamate is toxic and leads to a phenomenon called excitotoxicity. Much of the damage from seizures does not come directly from them, but from the excess release of glutamate.
This is similar to a fuel tank exploding in a burning car: the explosion causes much more damage than the flame that caused it. Neurotransmitters are useful only in strictly defined quantities.
Glutamate (Glu) is also great for looking at how neurotransmitters are formed from pre-existing molecules. Glutamine is one of the amino acids that animals receive from food.. The brain, in turn, uses glutamine to transmit excitatory signals.
We can taste glutamate in food, as was discovered by Japanese scientists in 1907 when studying soy sauce. The taste of glutamate is the fifth basic taste, in addition to the four main ones, for which we have separate receptors; it is called umami. The taste of glutamate helps determine the edibility and freshness of food, a feature vital to the hunter-gatherers of the primitive world.
We can consider the three-cell system shown in the figure below as a line for producing certain quantities of the neurotransmitter glutamate, transporting them to the synapse using vesicular transport, and releasing them into the synaptic cleft. The small oval organelle at the top of the cell is the mitochondrion, which produces most cellular ATP.
This entire system is fed by glucose and oxygen diffusing through the membranes from the capillary on the right. Glucose is used for energy and also for the synthesis of the neurotransmitter glutamate.
Glutamatergic signaling requires the participation of three cells. The three cells work together to mediate glutamatergic signaling. Note the blood capillary providing the astrocyte and neurons with glucose and oxygen.
Glucose is also one of the intermediate metabolites in the synthesis of glutamate. Vm – membrane potential upper neuron, which shows several spikes that cause the release of the transmitter into the synaptic cleft, PGK - phosphoglycerate kinase.
Note that the postsynaptic cell has two types of glutamate receptors. Metabotropic receptors are used to respond to cell metabolic pathways. Ionotropic receptors activate ion channels: sodium, potassium and calcium.
Astrocyte in the middle of the circuit is also important for the operation of the entire system. It takes up glucose, breaks it down and converts ADP to ATP in its mitochondria, sends glutamine into the presynaptic cell where it is synthesized into glutamate, and captures excess glutamate diffusing from the synaptic cleft.
The latter is very important, since glutamate, if left outside the cell for a long time, is toxic. Glutamate toxicity is believed to cause severe brain vomiting. (This disorder is also called excitotoxicity because glutamate is the brain's primary excitatory neurotransmitter.)
Glutamatergic signaling is extremely precise in timing, its neurotransmitter can be quickly removed from the extracellular space; it also does not leave toxic compounds in the extracellular environment. At the same time, almost all biochemical processes, especially oxidative ones, produce some amount of toxic substances and can be very harmful over long-term operation.
Historically, the first neurotransmitters discovered were acetylcholine and monoamines. This is due to their wide distribution in the peripheral nervous system (at least in the case of acetylcholine and norepinephrine). However, they are far from being the most common CNS mediators. More than 80% of nerve cells in the brain and spinal cord use amino acid substances as mediators, which carry the bulk of sensory, motor and other signals through neural networks (excitatory amino acids), and also control such transfer (inhibitory amino acids). We can say that amino acids implement the rapid transfer of information, and monoamines and acetylcholine create a general motivational-emotional background and “monitor” the level of wakefulness. There are even “slower” levels of regulation of brain activity - these are neuropeptide systems and hormonal influences on the central nervous system.
Compared to the formation of monoamines, the synthesis of amino acid mediators is a simpler process for the cell, and all of them are simple in chemical composition. Mediators of this group are characterized by greater specificity of synaptic effects - either a particular compound has excitatory properties (glutamic and aspartic acids) or inhibitory properties (glycine and gamma-aminobutyric acid - GABA). Amino acid agonists and antagonists produce more predictable effects in the central nervous system than acetylcholine and monoamine agonists and antagonists. On the other hand, effects on glutamate or GABAergic systems often lead to too “broad” changes in the entire central nervous system, which creates its own difficulties.
The main excitatory transmitter of the central nervous system is glutamic acid. In nervous tissue, the mutual transformations of glutamic acid and its precursor glutamine are as follows:
Being a non-essential dietary amino acid, it is widely distributed in a wide variety of proteins, and its daily intake is at least 5-10 g. However, dietary glutamic acid normally penetrates the blood-brain barrier very poorly, which protects us from serious disruptions in brain activity. Almost all the glutamate needed by the central nervous system is synthesized directly in the nervous tissue, but the situation is complicated by the fact that this substance is also an intermediate stage in the processes of intracellular amino acid metabolism. Therefore, nerve cells contain a lot of glutamic acid, only a small part of which performs mediator functions. The synthesis of such glutamate occurs in presynaptic terminals; the main precursor source is the amino acid glutamine.
Released into the synaptic cleft, the mediator acts on the corresponding receptors. The variety of receptors for glutamic acid is extremely large. Currently, there are three types of ionotropic and up to eight types of metabotropic receptors. The latter are less common and less studied. Their effects can be realized both by suppressing the activity of acenylate cyclase and by enhancing the formation of diacylglycerol and inositol triphosphate.
Ionotropic receptors for glutamic acid are named after specific agonists: NMDA receptors (agonist N-methyl-D-aspartate), AMPA receptors (agonist alpha-amiacid) and kainate receptors (agonist kainic acid). Today, most attention is paid to the first of them. NMDA receptors are widely distributed in the central nervous system from the spinal cord to the cerebral cortex, most of them in the hippocampus. The receptor (Fig. 3.36) consists of four subunit proteins that have two active sites for binding glutamic acid 1 and two active sites for glycine binding 2. These same proteins form an ion channel that can be blocked by magnesium ion 3 and channel blockers 4.