Mediators of the nervous system (neurotransmitters)

Neurotransmitter (neurotransmitter, neurotransmitter) is a substance that is synthesized in a neuron, contained in presynaptic endings, released into the synaptic cleft in response to a nerve impulse and acts on special sites of the postsynaptic cell, causing changes in the membrane potential and cell metabolism.

Until the middle of the last century, only amines and amino acids belonged to mediators, but the discovery of neurotransmitter properties in purine nucleotides, lipid derivatives and neuropeptides significantly expanded the group of mediators. At the end of the last century it was shown that some of the ROS also have properties similar to mediators.

[1], [2], [3], [4], [5], [6], [7], [8], [9]

Chemical structure of mediators

According to the chemical structure, the mediators are a heterogeneous group. It includes the ether of choline (acetylcholine); a group of monoamines including catecholamines (dopamine, norepinephrine and epinephrine); indoles (serotonin) and imidazoles (histamine); acid (glutamate and aspartate) and basic (GABA and glycine) amino acids; purines (adenosine, ATP) and peptides (enkephalins, endorphins, substance P). To the same group there are substances that can not be classified as true neurotransmitters - steroids, eicosanoids and a number of ROS, primarily N0.

A number of criteria are used to address the issue of the neurotransmitter nature of a compound. The main ones are outlined below.

1. The substance must accumulate in the presynaptic endings, be released in response to the incoming impulse. The presynaptic region should contain a system for the synthesis of this substance, and the postsynaptic zone should detect a specific receptor for the compound.
2. When stimulating the presynaptic area, Ca-dependent excretion (by exocytosis) of this compound to the intersynaptic gap proportional to the stimulus strength should occur.
3. Mandatory identity of the effects of the endogenous neurotransmitter and the proposed mediator when it is applied to the target cell and the possibility of pharmacological blocking of the effects of the proposed mediator.
4. The presence of a re-capture system of the putative mediator in the presynaptic terminus and / or neighboring astroglial cells. There are cases when the mediator itself is not recaptured, but the product of its cleavage (for example, choline after cleavage of acetylcholine by enzyme acetylcholinesterase).

Influence of drugs on different stages of the mediator function in synaptic transmission

Stages	Modifying effect	Impact result
The mediator synthesis	Addition of precursor Blockade of re-uptake Blockade of enzymes of synthesis	↑ ↓ ↓
Accumulation	Inhibition of capture in vesicles inhibition of binding in vesicles	↑ ↓ ↑ ↓
Isolation (exocytosis)	Stimulation of inhibitory autoreceptors Blockade of autoreceptors Disorders of exocytosis mechanisms	↓ ↑ ↓
Act	Effects of agonists on receptors	↑
At the receptors	Blockade of postsynaptic receptors	↓
Destruction of the mediator	Blockade of reuptake by neurons and / or glia Deceleration inhibition in neurons	↑ ↑
	Deceleration inhibition in the synaptic cleft	↑

The use of various methods for testing the mediator function, including the most modern (immunohistochemical, recombinant DNA, etc.), is difficult due to the limited availability of most individual synapses, and also because of the limited set of targeted pharmacological agents.

An attempt to define the concept of "mediators" encounters a number of difficulties, since in recent decades the list of substances that perform the same signal function in the nervous system as the classical mediators has significantly expanded, but differ from them in chemical nature, synthesis routes, receptors. First of all, the above refers to a large group of neuropeptides, as well as to ROS, and primarily to nitrogen oxide (nitroxide, N0), for which the mediator properties are described rather well. Unlike "classical" mediators, neuropeptides tend to have a larger size, are synthesized at a low rate, accumulate in small concentrations and bind to receptors that have a low specific affinity, in addition, they do not have the mechanisms of re-capture by the presynaptic terminal. The duration of the effect of neuropeptides and mediators also differs significantly. As far as nitroxide is concerned, despite its participation in intercellular interaction, it can be attributed to a number of criteria rather than to mediators, but to secondary mediators.

Initially, it was believed that the nerve end can contain only one neurotransmitter. To date, it has been shown that several mediators released in the terminal can be released together in response to a pulse and act on a single target cell-concomitant (coexisting) mediators (comeditors, cotransmitters). In this case, there is accumulation of different mediators in one presynaptic region, but in different vesicles. An example of comedians can serve as classical mediators and neuropeptides, which differ in the place of synthesis and, as a rule, are localized in one end. The release of comedians occurs in response to a series of exciting potentials of a certain frequency.

In modern neurochemistry, in addition to neurotransmitters, substances that modulate their effects are isolated: neuromodulators. Their action is tonic and longer in time than the action of the mediators. These substances can have not only neuronal (synaptic), but also glial origin and not necessarily mediated by nervous impulses. Unlike the neurotransmitter, the modulator acts not only on the postsynaptic membrane, but also on other parts of the neuron, including intracellularly.

There are pre- and postsynaptic modulation. The concept of "neuromodulator" is broader than the concept of "neurotransmitter". In some cases, the mediator may also be a modulator. For example, norepinephrine released from the sympathetic nerve end acts as a neurotransmitter for a1 receptors, but as a neuromodulator it acts on a2-adrenoreceptors; in the latter case it mediates the inhibition of subsequent secretion of noradrenaline.

Substances that perform mediator functions differ not only in chemical structure, but also in the way in which compartments of the nerve cell their synthesis occurs. Classical low-molecular mediators are synthesized in the axon terminus and included in small synaptic vesicles (50 nm in diameter) for storage and release. N0 is also synthesized in terminology, but since it can not be packed into vesicles, it immediately diffuses from the nerve end and affects the target. Peptide neurotransmitters are synthesized in the central part of the neuron (pericarion), packaged in large vesicles with a dense center (100-200 nm in diameter) and transported by axonal current to the nerve endings.

Acetylcholine and catecholamines are synthesized from circulating progenitors, whereas amino acid mediators and peptides are ultimately formed from glucose. As is known, neurons (like other cells of the organism of higher animals and humans) can not synthesize tryptophan. Therefore, the first step leading to the onset of serotonin synthesis is the facilitated transport of tryptophan from blood to the brain. This amino acid, like other neutral amino acids (phenylalanine, leucine and methionine), is transported from blood to the brain by special vectors belonging to the family of monocarboxylic acid carriers. Thus, one of the important factors determining the level of serotonin in serotonergic neurons is the relative amount of tryptophan in food compared to other neutral amino acids. For example, volunteers who were fed low-protein food for one day and then gave a mixture of amino acids that did not contain tryptophan showed aggressive behavior and a change in the sleep-wake cycle, which was associated with a decrease in serotonin levels in the brain.

[10], [11], [12], [13], [14], [15]