Biological Chemistry - Berezov, T. T., Korovkin, B. F. 1998

Nervous Tissue
Chemical Basis of the Generation and Conduction of Nerve Impulses
The Role of Neurotransmitters in the Transmission of Nerve Impulses

Billions of Neurons in the Brain communicate via Neurotransmitters. A chemical substance can be classified as a neurotransmitter only if it meets several criteria. Nerve fibers must contain the Enzymes required to synthesize this substance. Upon nerve stimulation, the substance must be released, bind to a specific receptor on the postsynaptic Cell, and trigger a biological response. Furthermore, mechanisms must exist to rapidly terminate the action of this substance.

Two substances fulfill all these criteria: acetylcholine and noradrenaline. The nerves containing them are referred to as cholinergic and adrenergic, respectively. Accordingly, all efferent systems are divided into cholinoreceptors and adrenoreceptors.

A number of other chemical substances meet many, but not all, of the listed criteria. Such neurotransmitters include dopamine, adrenaline, serotonin, octopamine, histamine, GABA, and others.

The extensive group of cholinoreceptors is highly heterogeneous both structurally and functionally. They are united by a common neurotransmitter, acetylcholine, and a General scheme of synapse Structure.

Acetylcholine* is an ester of acetic acid and Choline. It is synthesized within the nerve cell from choline and the active form of acetate—acetyl-coenzyme A—with the aid of a specific enzyme, choline acetyltransferase (choline acetylase):

Class="center">

A synapse can be visualized as a narrow space (cleft) bounded on one side by the presynaptic membrane and on the other by the postsynaptic membrane (Fig. 19.4). The presynaptic membrane consists of an inner layer belonging to the Cytoplasm of the nerve terminal and an outer layer formed by neuroglia. In some places, the membrane is thickened and dense, while in others it is thinned and contains pores that allow communication between the axon cytoplasm and the synaptic cleft. The postsynaptic membrane is less dense and lacks pores. Neuromuscular junctions are constructed in a similar manner, though they feature a more complex membrane complex structure.

In broad terms, The Role of acetylcholine in mediating the transmission of a Nerve Impulse of excitation can be described as follows. Synaptic nerve terminals contain vesicles with a diameter of 30–80 nm that store neurotransmitters. These vesicles are coated with a shell formed by the protein clathrin (molecular weight 180,000). In cholinergic synapses, each vesicle 80 nm in diameter contains ~ 40,000 molecules of acetylcholine. Upon excitation, neurotransmitter release occurs in "quanta," i.e., via the complete emptying of each individual vesicle. Under normal conditions, a strong impulse triggers the release of approximately 100–200 quanta of neurotransmitter—an amount sufficient to initiate an Action Potential in the postsynaptic neuron. This presumably occurs as follows: depolarization of the synaptic terminal membrane induces a rapid influx of Ca²⁺ ions into The Cell. The temporary increase in intracellular Ca²⁺ concentration stimulates the fusion of synaptic vesicle membranes with The Plasma Membrane, thereby triggering the release of their contents. The expulsion of the contents of a single vesicle requires approximately 4 Ca²⁺ ions. Acetylcholine released into the synaptic cleft interacts with a chemoreceptor protein embedded in the postsynaptic membrane. As a result, membrane permeability changes, with a sharp increase in its conductance for Na⁺ ions. The interaction between the receptor and the neurotransmitter triggers a cascade of reactions that prompt the postsynaptic or effector cell to perform its specific function. Following neurotransmitter release, a phase of rapid inactivation or removal must ensue to prepare the synapse for receiving a new impulse.

* Acetylcholine also acts as a neurotransmitter at motor end-plates (neuromuscular junctions, which are contact sites between nerves and striated Muscle).

Fig. 19.4. Schematic representation of a synapse (after Metzler).

1 - synaptic vesicles; 2 - lysosome; 3 - microfibrils (neurofibrils); 4 - axon; 5 - Mitochondria; 6 - presynaptic membrane thickening; 7 - postsynaptic membrane thickening; 8 - synaptic cleft (approx. 20 nm).

In cholinergic synapses, this occurs via two pathways. The first pathway involves the Enzymatic Hydrolysis of acetylcholine. The second pathway is the energy-dependent Active Transport of acetylcholine back into the neuron, where it is stored for subsequent reuse.

The hydrolytic breakdown of acetylcholine into acetic acid and choline is catalyzed by an enzyme named "acetylcholinesterase":

In most Regions of the brain, acetylcholine hydrolysis is carried out by acetylcholinesterase (true cholinesterase, which hydrolyzes acetylcholine faster than other choline esters). Nervous Tissue also contains other esterases capable of hydrolyzing acetylcholine, though significantly more slowly, such as butyrylcholine esterase. These esterases are referred to as cholinesterase (or pseudocholinesterase). Cholinergic systems include motor neurons forming neuromuscular junctions, all preganglionic neurons of the Autonomic Nervous system, and postganglionic neurons of the parasympathetic nervous system. A large number of cholinergic sympathetic regions have also been identified in the brain. Depending on their sensitivity to particular groups of chemical compounds, cholinergic neurons are divided into muscarinic (activated by muscarine) and nicotinic (activated by nicotine). Muscarinic acetylcholine receptors, found in many neurons of the autonomic nervous system, are specifically blocked by atropine. Nicotinic synapses are present in ganglia and skeletal Muscles, and are inhibited by curare and the active component of this poison, D-tubocurarine.

It must be emphasized that adrenoreceptors comprise Two Types of receptors for noradrenaline: α- and β-adrenergic receptors. These receptors can be distinguished from one another by the specific responses they elicit, as well as by the specific agents capable of blocking these responses.

β-Adrenergic receptors activate the effector cell via adenosine 3',5'-monophosphate, or cAMP—the universal "second messenger" mediating between Hormones and the various Functions of the Cells targeted by those hormones (see Chapter 8).

It has been established that as soon as a β-adrenergic receptor located on the outer surface of the effector cell membrane interacts with noradrenaline, the enzyme adenylate cyclase is activated on the inner surface of The cell membrane. Adenylate cyclase then converts ATP into cAMP within the cell; the latter, in turn, is capable of influencing cellular METABOLISM. This complex sequence of reactions can be blocked by propranolol, a substance that prevents the binding of noradrenaline to the β-adrenergic receptor.

The enzyme monoamine oxidase (MAO) is known to play a special role in the metabolism of catecholamine neurotransmitters. This enzyme removes the amino group (—NH₂) from noradrenaline, serotonin, dopamine, and adrenaline, thereby inactivating these neurotransmitters. In recent years, it has been demonstrated that In addition to enzymatic transformation, another mechanism exists for the rapid inactivation—more precisely, removal—of neurotransmitters. It turns out that noradrenaline rapidly disappears from the synaptic cleft as a result of reuptake by sympathetic nerves; once back inside the nerve fiber, the neurotransmitter naturally cannot exert any effect on postsynaptic cells. The exact mechanism of this phenomenon remains not yet fully understood.

The adrenergic and cholinergic systems of the brain interact closely with other brain systems, notably those utilizing serotonin as a neurotransmitter. Serotonin-containing neurons are concentrated primarily in the Brainstem nuclei. The neurotransmitter function of serotonin is carried out through its interaction with specific serotonergic receptors. Studies conducted with the serotonin synthesis inhibitor p-chlorophenylalanine, as well as other inhibitors, provide grounds to believe that serotonin influences Sleep processes. It has also been revealed that corticosteroid inhibition of pituitary secretory activity is less effective in animals with lower brain serotonin levels.

An important inhibitory neurotransmitter is γ-aminobutyric acid (GABA), the concentration of which in the brain is many times greater than that of other neurotransmitters. For instance, in the Hypothalamus, the combined content of acetylcholine, noradrenaline, dopamine, and serotonin does not exceed 10 μg/g, whereas GABA levels in this brain region exceed 600 μg/g. GABA increases the permeability of postsynaptic membranes to K⁺ ions, thereby shifting the Membrane Potential away from the threshold level required to trigger an action potential; thus, GABA acts as an inhibitory neurotransmitter. GABA is produced by the decarboxylation of glutamate in a reaction catalyzed by glutamate decarboxylase:

Medical practice employs a wide range of drugs that act via neurotransmitter systems. Many Pharmaceuticals successfully used in the Treatment of Hypertension affect the storage and release of adrenergic neurotransmitters. For example, reserpine, a Blood-pressure-lowering agent, specifically inhibits The transport of catecholamines into specialized neuronal granules, thereby making these amines accessible to the action of endogenous MAO.

Antihypertensive drugs such as α-methyldopa are converted by enzymes present within the nerve cell (axon) into substances structurally resembling noradrenaline. These "false" neurotransmitters accumulate and are released alongside natural neurotransmitters, "diluting" them and thereby diminishing their effect.

Many antidepressants (substances that relieve depression) increase the concentration of catecholamines in the synaptic cleft, meaning The amount of neurotransmitters available to stimulate the receptor increases. Such substances include imipramine (which blocks the reuptake of norepinephrine by nerve fibers), amphetamine (which both promotes the release of norepinephrine and blocks its reuptake), MAO inhibitors (which suppress Catecholamine Metabolism), and others. This gave rise to the catecholamine hypothesis of depression, which posits that clinical depression is linked to a deficiency of catecholamines in the brain.

In the early 1950s, pharmacologists discovered that the well-known hallucinogen lysergic acid diethylamide (LSD) is not only chemically similar to serotonin but also neutralizes some of its pharmacological effects by blocking serotonin receptors. Consequently, it was hypothesized that disruptions in serotonin metabolism might be the underlying cause of certain psychiatric disorders.

It is believed that antipsychotic drugs such as aminazine (chlorpromazine) and haloperidol, while enhancing catecholamine synthesis, are capable of blocking dopamine receptors in the brain.