Mediators of the nervous system (neurotransmitters)

A 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 areas of the postsynaptic cell, causing changes in the membrane potential and metabolism of the cell.

Until the middle of the last century, only amines and amino acids were considered mediators, but the discovery of neuromediator 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 ROS also have properties similar to mediators.

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Chemical structure of mediators

In terms of chemical structure, mediators are a heterogeneous group. They include choline ester (acetylcholine); a group of monoamines, including catecholamines (dopamine, norepinephrine, and adrenaline); indoles (serotonin) and imidazoles (histamine); acidic (glutamate and aspartate) and basic (GABA and glycine) amino acids; purines (adenosine, ATP) and peptides (enkephalins, endorphins, substance P). This group also includes substances that cannot be classified as true neurotransmitters - steroids, eicosanoids, and a number of ROS, primarily NO.

To decide whether a compound is a neurotransmitter, a number of criteria are used. The main ones are outlined below.

1. The substance must accumulate in the presynaptic endings and be released in response to an incoming impulse. The presynaptic region must contain a system for synthesizing this substance, and the postsynaptic zone must detect a specific receptor for this compound.
2. When the presynaptic region is stimulated, there should be a Ca-dependent release (by exocytosis) of this compound into the intersynaptic cleft, proportional to the strength of the stimulus.
3. Mandatory identity of the effects of the endogenous neurotransmitter and the putative mediator upon its application to the target cell and the possibility of pharmacological blocking of the effects of the putative mediator.
4. The presence of a system for the reuptake of the putative mediator into presynaptic terminals and/or into neighboring astroglial cells. There may be cases when it is not the mediator itself that is reuptaken, but the product of its cleavage (for example, choline after the cleavage of acetylcholine by the enzyme acetylcholinesterase).

The influence of drugs on various stages of mediator function in synaptic transmission

Stages	Modifying influence	Result of the impact
Synthesis of mediator	Precursor supplementation Reuptake blockade Blockade of synthesis enzymes	↑ ↓ ↓
Accumulation	Inhibition of vesicle uptake Inhibition of vesicle binding	↑↓ ↑↓
Excretion (exocytosis)	Stimulation of inhibitory autoreceptors Blockade of autoreceptors Disruption of exocytosis mechanisms	↓ ↑ ↓
Action	Effects of agonists on receptors	↑
On the receptors	Blockade of postsynaptic receptors	↓
Destruction of the mediator	Blockade of reuptake by neurons and/or glia Inhibition of destruction in neurons	↑ ↑
	Inhibition of destruction in the synaptic cleft	↑

The use of various methods for testing mediator function, including the most modern ones (immunohistochemical, recombinant DNA, etc.), is complicated by the limited availability of most individual synapses, as well as by the limited range of means for targeted pharmacological action.

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 signaling function in the nervous system as classical mediators, but differ from them in chemical nature, synthesis pathways, and receptors, has significantly expanded. First of all, this applies to a large group of neuropeptides, as well as to ROS, and primarily to nitric oxide (nitroxide, NO), for which the mediator properties have been described quite well. Unlike "classical" mediators, neuropeptides, as a rule, are larger in size, are synthesized at a low rate, accumulate in small concentrations and bind to receptors with low specific affinity, in addition, they do not have mechanisms for reuptake by the presynaptic terminal. The duration of the effect of neuropeptides and mediators also varies significantly. As for nitroxide, despite its participation in intercellular interactions, according to a number of criteria it can be classified not as a mediator, but as a secondary messenger.

Initially, it was believed that a nerve ending could contain only one mediator. By now, the possibility of the presence of several mediators in the terminal, released together in response to an impulse and affecting one target cell - accompanying (coexisting) mediators (comediators, cotransmitters) - has been shown. In this case, accumulation of different mediators occurs in one presynaptic region, but in different vesicles. Examples of comediators are classical mediators and neuropeptides, which differ in the place of synthesis and, as a rule, are localized in one ending. The release of comediators occurs in response to a series of excitatory potentials of a certain frequency.

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

A distinction is made between pre- and postsynaptic modulation. The concept of "neuromodulator" is broader than the concept of "neuromediator". In some cases, a mediator can also be a modulator. For example, norepinephrine released from a sympathetic nerve ending acts as a neuromediator on a1-receptors, but as a neuromodulator on a2-adrenoreceptors; in the latter case, it mediates inhibition of subsequent secretion of norepinephrine.

Substances that perform mediator functions differ not only in chemical structure, but also in the compartments of the nerve cell in which they are synthesized. Classic low-molecular-weight mediators are synthesized in the axon terminal and included in small synaptic vesicles (50 nm in diameter) for storage and release. NO is also synthesized in the terminal, but since it cannot be packaged in vesicles, it immediately diffuses from the nerve ending and affects targets. Peptide neurotransmitters are synthesized in the central part of the neuron (pericaryon), packaged in large vesicles with a dense center (100-200 nm in diameter) and transported by axonal current to nerve endings.

Acetylcholine and catecholamines are synthesized from precursors circulating in the blood, while amino acid mediators and peptides are ultimately formed from glucose. As is known, neurons (like other cells of the body of higher animals and humans) cannot synthesize tryptophan. Therefore, the first step leading to the onset of serotonin synthesis is the facilitated transport of tryptophan from the blood to the brain. This amino acid, like other neutral amino acids (phenylalanine, leucine and methionine), is transported from the blood to the brain by special carriers 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 a low-protein diet for one day and then given an amino acid mixture that did not contain tryptophan showed aggressive behavior and an altered sleep-wake cycle associated with decreased serotonin levels in the brain.

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