The most important neurotransmitter
Glutamate
Physiologist Vyacheslav Dubynin on sensory transmission, NMDA receptors and properties of glutamic acid.
The brain is based on the interaction of nerve cells, and they talk to each other with the help of substances called mediators. There are quite a lot of mediators, for example acetylcholine, norepinephrine. One of the most important mediators, and perhaps the most important, is called glutamic acid, or glutamate. If you look at the structure of our brain and what substances different nerve cells use, then glutamate excrete about 40% of neurons, that is, it is a very large proportion of nerve cells.
With 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 with the release of glutamic acid. Therefore, of course, this mediator deserves special attention and is being studied very actively.
According to its chemical structure, glutamate is a fairly simple molecule. It is an amino acid, and a food amino acid, that is, we get similar molecules simply as part of those proteins that we eat. But I must say that dietary glutamate (from milk, bread or meat) practically does not pass into the brain. Nerve cells synthesize this substance directly at the ends of axons, directly in those structures that are part of synapses, "in place" and then 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 obtained during the oxidation of glucose, in all cells, in all mitochondria there is a lot of it. And then it is enough to transplant any amino group taken from any amino acid to this α-ketoglutaric acid, and now glutamate, glutamic acid is obtained. Glutamic acid can still 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 the synapse and transmitted a signal, then it is destroyed to form glutamine.
Glutamate is an excitatory mediator, 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 in some synapses can cause excitation, in others – inhibition, they have a more complex algorithm of operation. 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 on which this molecule acts, and different receptors conduct a glutamate signal at different speeds and with different parameters.
The evolution of plants has found a number of toxins acting on glutamate receptors. Why this is for plants, in general, is quite clear. Plants, as a rule, are against being eaten by animals, respectively, 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 affect the glutamate receptors of the brain and cause total excitement and seizures. It turns out that the superactivation of glutamate synapses is a very powerful brain excitement, 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 Pacific Ocean, on the coast, for example, Canada, California, Mexico. Toxin poisoning of these algae is very, very dangerous. And this poisoning sometimes happens because zooplankton, all kinds of small crustaceans or, for example, bivalves feed on unicellular algae, when they filter the water, they draw these algae cells into themselves, and then in some mussel or oyster there is too high a concentration of domoic acid, and you can seriously get poisoned.
Even deaths among people have been recorded. They are, however, isolated, but nevertheless it speaks about the power of this toxin. And domoic acid poisoning is very characteristic in the case of birds. If some seabirds, who eat small fish feeding on zooplankton, get too much domoic acid, then a characteristic psychosis occurs: some seagulls or pelicans stop being afraid of large objects and, conversely, attack them, that is, they become aggressive. There was a whole epidemic of such poisoning somewhere in the early 1960s, and newspaper reports about this epidemic of "bird psychoses" inspired Daphne Du Maurier to write the novel "Birds", and then Alfred Hitchcock shot the classic thriller "Birds", where you see thousands of very aggressive seagulls that torment the main characters of the film. Naturally, in reality there were no such global poisoning, but nevertheless domoic acid causes very characteristic effects, and it and similar molecules are, of course, very dangerous for the brain.
We eat glutamic acid and similar glutamate in large quantities simply with dietary proteins. Our proteins, which are part of various foods, 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 totally. As a result, we eat 5 to 10 grams of glutamate and glutamine per day with regular food. At one time, it was very difficult to believe that glutamate performs the functions of a mediator in the brain, because it turns out that the substance that we literally consume in horse doses performs such subtle functions in the brain. There was such a logical discrepancy. But then they realized that, in fact, the food glutamate practically does not pass into the brain. For this, you need to thank the structure called the blood-brain barrier, that is, special cells surround all capillaries, all small vessels that permeate the brain, and quite tightly control the movement of chemicals from the blood into the nervous system. If it weren't for this, then some kind of eaten cutlet or bun would cause us cramps, and, of course, no one needs this. Therefore, dietary glutamate almost does not pass into the brain and, indeed, is synthesized in order to perform mediator functions directly in synapses. Nevertheless, if you eat a lot of glutamate at the same time, then a small amount still penetrates the brain. Then there may be a slight excitement, 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 in to the chemical analysis of food, it was glutamate that singled out as a sign of protein food, that is, we should eat protein, because protein is the main building material of our body. Similarly, 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 precisely 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 flavor additive. It is not quite right to call it a flavor enhancer, because glutamate has its own taste, which is as important as bitter, sour, sweet and salty.
I must say 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 delicious and why is this taste so different from standard tastes? Then glutamate receptors were discovered, and then glutamate was already used almost in its pure form (E620, E621 – monosodium glutamate), in order to add to a variety of foods. Sometimes it happens that glutamate is blamed for all mortal sins, called "another white death": salt, sugar and glutamate are white death. This is, of course, greatly exaggerated, because I repeat once again: during the day, we eat from 5 to 10 grams of glutamate and glutamic acid with regular food. Therefore, if you add a little glutamate to the food for the appearance of this meat taste, there is nothing to worry about, although, of course, the excess is not useful.
There are indeed many receptors for glutamate (about 10 types of receptors) that conduct glutamate signals at different speeds. And these receptors are studied primarily from the point of view of analyzing the mechanisms of memory. When memory arises in our brain and in the cerebral cortex, it really means that synapses begin to work more actively between nerve cells transmitting some kind of information flow. The main mechanism of activation of synapses is an increase in the effectiveness of glutamate receptors. 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 abbreviation, it stands for N-methyl-D-aspartate. This receptor reacts to glutamate and NMDA. The NMDA receptor is characterized by the fact that it is able to be blocked by a magnesium ion, and if a magnesium ion is attached to the receptor, then this receptor does not function. That is, you get a synapse in which there are receptors, but these receptors are turned off. If some strong, significant signal has passed through the neural network, then magnesium ions (they are also called magnesium plugs) break away from the NMDA receptor, and the synapse begins to work literally instantly many times more efficiently. At the level of information transfer, this means recording a certain memory trace. There is a structure in our brain 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 a magnesium plug is a mechanism of short-term memory, because the plug can go away and then come back – then we will forget something. If long-term memory is formed, everything is much more complicated there, and other types of glutamate receptors work there, which are capable of transmitting a signal directly to nuclear DNA from the membrane of a nerve cell. And having received this signal, nuclear DNA triggers the synthesis of additional receptors in glutamic acid, and these receptors are embedded in synaptic membranes, and the synapse begins to work more efficiently. But this does not happen instantly, as in the case of knocking out a magnesium plug, but requires several hours, requires repetitions. But if it happened, then 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 brain functions, mainly to reduce the excitation of the nervous system. A very well-known drug called ketamine. It works as a substance for anesthesia. Ketamine, in addition, is known as a molecule with a narcotic effect, because hallucinations often occur when coming out of anesthesia, so ketamine is also attributed to drugs of hallucinogenic, psychedelic action, it is very difficult with it. But in pharmacology, this often happens: a substance that is the most necessary drug has some side effects, which eventually lead to the fact that it is necessary to control the distribution and use of this substance very strictly.
Another molecule very well known in connection with glutamate is memantine, a substance capable of blocking NMDA receptors quite gently and eventually reducing the activity of the cerebral cortex in a variety of zones. Memantine is used in a fairly wide range of situations. Its pharmacy name is "Acatinol". It is used to lower the total level of arousal in order to reduce the likelihood of epileptic seizures, and perhaps the most active use of memantine is in situations of neurodegeneration and Alzheimer's disease.
About the author:
Vyacheslav Dubynin – Doctor of Biological Sciences, Professor of the Department of Human and Animal Physiology, Faculty of Biology, Moscow State University, specialist in the field of brain physiology.
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07.10.2016