8.2. Mechanism of nerve impulses conduction

Neurotransmitters are substances that are characterized by the following features:

• are accumulated in the presynaptic membrane in sufficient concentration;

• are released during the impulse transmission;

• after binding to the postsynaptic membrane cause the change of the velocity of metabolic processes and the emergence of an electrical impulse;

• have a system for inactivation or transport system for removing of the hydrolysis products from the synapse.

Neurotransmitters play an important role in the functioning of the nervous tissue for synaptic transmission of nerve impulses. Their synthesis occurs in the body of the neurons and the accumulation is in the specific vesicles that are slowly moving to the tips of axons with the help of the systems of neurofilament and neurotubules.

Neurotransmitters are amino acid derivatives: taurine, noradrenalin, dopamine, GABA, glycine, acetylcholine, homocysteine, and some others (adrenaline, serotonin, histamine), as well as neuropetidies.

Cholinergic synapses

Acetylcholine is synthesized from choline and acetyl-CoA. Amino acids, serine and methionine are required for the synthesis of choline. But as a rule, choline comes into the nervous tissue from the blood. Acetylcholine is involved in synaptic transmission of nerve impulses. It is accumulated in synaptic vesicles, forming complexes with negatively charged protein vesiculine. Transfer of excitation from one cell to another is done by means of a special mechanism of synaptic neurotransmission. Synapse is a functional contact of specialized sites of plasma membranes of two excitable cells. The synapse consists of a presynaptic membrane, synaptic gap and postsynaptic membrane. Membranes at the places of contact have thickenings in the form of plaques – the nerve endings. Nerve impulse, came the nerve ending, is unable to overcome the obstacle in front of it – the synaptic gap. Then electrical signal is converted to a chemical. Presynaptic membrane contains special channel proteins, such as proteins, forming the sodium channel in the membrane of the axon. They also respond to membrane potential, changing its conformation, and form a channel. As a result, the Ca ions pass through presynaptic membrane along the gradient of concentration in the nerve ending. Ca²⁺ concentration gradient is created by the work of the Ca²⁺-dependent ATPase. The increasing of concentrations of Ca²⁺ inside nerve endings causes fusion of vesicles available there, filled with acetylcholine. Then, acetylcholine is secreted into the synaptic gap by exocytosis and is joined to the receptor proteins, located on the surface of the postsynaptic membrane. Acetylcholine receptor is a transmembrane oligomeric glycoprotein complex composed of six subunits. The density of the location of protein receptors in the postsynaptic membrane is very high – about 20,000 molecules per 1 mcm². The spatial structure of the receptor is in strict correspondence with the mediator conformation. In the interaction with acetylcholine receptor protein changes its conformation so that the sodium channel is formed inside it. Cation selectivity of the channel is provided by the fact that the gates of the channel are formed by negatively charged amino acids. It increases the permeability of the postsynaptic membrane for sodium and the impulse (or contraction of muscle fibers) appears. Postsynaptic membrane depolarization causes dissociation of the complex "acetylcholine - receptor protein", and acetylcholine is released into the synaptic gap. Once acetylcholine is in the synaptic gap, it is rapidly (over 40 ms) hydrolyzed by the enzyme acetyl cholinesterase in choline and acetyl-CoA.

Irreversible inhibition of acetylcholine esterase causes death. Enzyme inhibitors are organophosphorus compounds. Death occurs as a result of respiratory standstill. Reversible acetylcholine esterase inhibitors are used as therapeutic drugs, such as the treatment of glaucoma and intestinal atony.

Adrenergic synapses occur in the postganglionic fibers, in the fibers of the sympathetic nervous system, in different parts of the brain. Their mediators are catecholamines: noradrenaline and dopamine. Catecholamines are synthesized in the nervous tissue by a common mechanism of tyrosine. The key enzyme in the synthesis is tyrosine hydroxylase, inhibited by end products.

Noradrenaline is a neurotransmitter in postganglionic fibers of sympathetic system and in different parts of the CNS.

Dopamine is a neurotransmitter of pathways, the neuron bodies of which are in a brain region. Dopamine is responsible for controlling voluntary movements. Therefore in violation of dopaminergic transmission Parkinson’s disease is observed.

Catecholamines, as well as acetylcholine, are accumulated in the synaptic vesicles and also released in the synaptic gap when entering the nerve impulse. But the regulation in adrenergic receptor is different. In the presynaptic membrane there is a special regulatory protein – ahromogranin; that in response to increasing concentrations of neurotransmitter in the synaptic gap binds already liberated mediator and stops its further exocytosis. There is no enzyme that destroys a mediator in adrenergic synapses. After the transfer of impulse, the molecules of mediator are pumped through a special transport system of active transport with the participation of ATP back into the presynaptic membrane and are included again in the vesicles. In the presynaptic nerve ending the surplus mediator can be inactivated by monoamine oxidase (MAO) and catecholamine-O-methyl-transferase (COMT) by the methylation of hydroxyl groups.

Signal transmission at adrenergic synapses proceeds with the participation of adenylate cyclase system. Binding of neurotransmitter to postsynaptic receptors almost instantly causes an increased concentration of cAMP, which leads to rapid phosphorylation of proteins of the postsynaptic membrane. As a result there is a changing of generation of nerve impulses of postsynaptic membrane (inhibited). In some cases, immediate reason is the increased permeability of the postsynaptic membrane to potassium, or decreased permeability for sodium (such condition leads to hyperpolarization).

Taurine is formed from the amino acid cysteine. First, we have the oxidation of sulfur in the SH-group of the residue of sulfuric acid (the process is of a few stages), then it is followed by decarboxylation. Taurine is not the usual acid; it has no carboxyl group but has a residue of sulfuric acid. Taurine is involved in conducting nerve impulses in the process of visual perception.

GABA is an inhibitory neurotransmitter (about 40% of neurons). GABA increases the permeability of the postsynaptic membrane to potassium ions. This leads to a change in membrane potential. GABA inhibits the ban on "unnecessary" information: attention, motor control.

Glycine is an auxiliary inhibitory transmitter (less than 1% of neurons). By the caused effects it is similar to GABA. Its function is the inhibition of motor neurons.

Glutamic acid is the main excitatory neurotransmitter (about 40% of neurons). Its primary function is holding the main information flows in the central nervous system (sensory signals, motor command, and memory).

The normal activity of the CNS is provided by the delicate balance of glutamate and GABA. Violation of this balance (usually in the direction of decreasing inhibition) negatively affects many neural processes. Without a proper balance there is developing attention deficit and hyperactivity disorder in children (ADHD), nervousness and anxiety of adults are increased, sleep disturbance, insomnia, epilepsy.

Neuropeptides are composed of from three to several tens of amino acid residues. They operate only in the higher parts of the nervous system. These peptides function not only as neurotransmitters, but also as hormones. They transmit information from cell to cell in the circulation system. These include:

• neurohypophyseal hormones (vasopressin, liberins, statins) – they are both hormones and transmitters;

• gastrointestinal peptides (gastrin, cholecystokinin). Gastrin causes the feeling of hunger, cholecystokinin is a feeling of fullness, but also stimulates the contraction of the gallbladder and pancreatic function;

• opiate peptides (peptides of anesthesia) are formed by partial proteolysis of precursor protein proopiocortin. It interacts with the same receptors as opiates (e.g. morphine), thereby simulates their action. The common name is endorphins. They are easily destroyed by proteases, so their pharmacological effect is negligible;

• sleep peptides. The molecular nature is not established. They cause sleep;

• memory peptides (skotofobin). They are accumulated during training on the avoidance of darkness;

• peptide which are components of the renin-angiotensin system. They stimulate the thirst center and the secretion of antidiuretic hormone.

The formation of peptides occurs as a result of limited proteolysis reactions, they are destroyed under the action of proteases.