Acetylcholine

Acetylcholine is a neurotransmitter, a substance produced by our body to transfer nerve impulses to multiple points of the central and peripheral nervous system. Neurons that secrete acetylcholine are defined as cholinergic; analogously for its receptors, which are divided into nicotinic receptors. The different concentration and chemical conformation of these receptors, and of the relative isoforms in the tissues, means that the various drugs that interfere with the action of acetylcholine can produce effects mainly limited to one sector rather than another. Despite this structural diversity, acetylcholine is able to bind to both receptors, since the part of the molecule that interacts with the muscarinic receptors is different from the nicotinic ones. This is one of the reasons why acetylcholine is not used directly for therapeutic purposes: since it acts on all the cholinergic receptors of the body (both muscarinic and nicotinic) its action is too widespread and not very specific.

Acetylcholine was the first neurotransmitter to be discovered, thanks to the studies of Otto Loewi crowned in 1924. From a chemical point of view, acetylcholine is formed by the union of a molecule of choline with one of acetyl-coenzyme A (acetyl -CoA); the first is a small molecule concentrated in the phospholipid membranes, while the Acetyl-CoA represents the metabolic intermediate between glycolysis and the Krebs cycle. The synthesis of acetylcholine starting from these two substances occurs along the axonal terminal; after being synthesized, it is then stored in vesicles, which upon the arrival of a nerve impulse bind to the presynaptic membrane, merging and releasing its contents by exocytosis. At this point the acetylcholine released in the synaptic cleft is free to reach the postsynaptic receptors and to interact with them, depolarizing the cell and triggering the formation of an action potential in the nerve fiber or in the muscle fiber lare that has stimulated; immediately after this interaction, much of the acetylcholine is immediately degraded by the acetylcholinesterase (ACHE). It is an enzyme located near the cholinergic receptors, where it acts by breaking the bond between acetate and choline; this last substance is readily reabsorbed by the presynaptic terminal and used for the synthesis of new acetylcholine (thanks to the choline-acetyltransferase enzyme). The action of this enzyme is very important, as it allows the transmission of the nerve impulse to be interrupted.

Acetylcholine is the transmitter of all the nerves that control the voluntary musculature (see neuromuscular plate); however, although at this level it produces an excitatory effect, within the parasympathetic system it carries out mainly inhibitory actions (most sympathetic neurons secrete epinephrine, while most parasympathetic neurons secrete acetylcholine). In fact, this molecule causes a slowing of the heart rate, while it stimulates the secretion of the bronchial, salivary, gastric and pancreatic glands, increasing intestinal peristalsis and in general all digestive functions. In addition to the motor plates of the skeletal muscles, and the post-ganglionic terminations of the parasympathetic nervous system, acetylcholine can be found at the level of the synapses between pre-ganglionic fibers and post-ganglionic neurons of the sympathetic and parasympathetic nervous system, and of the adrenal medulla, as well as in some synapses of the central nervous system.

The muscarinic actions correspond to those induced by the Acetylcholine released by the postganglionic parasympathetic nerve endings, with two significant exceptions:

Acetylcholine causes generalized vasodilation, although most of the vessels are not innervated by the parasympathetic system.

Acetylcholine causes secretion by the sweat glands, which are innervated by cholinergic fibers of the sympathetic nervous system.

The nicotinic actions they correspond to those of acetylcholine released at the level of the ganglionic synapses of the sympathetic and parasympathetic systems, of the neuromuscular plate of the voluntary muscles and of the nerve endings of the splanchnic nerves that surround the secretory cells of the adrenal medulla.

As anticipated, effects similar to those of acetylcholine can be produced by substances capable of stimulating cholinergic receptors (parasympathomimetics) or blocking the action of acetylcholinesterase (anticholinesterases). At the same time, the effects of acetylcholine can be blocked by substances capable of binding to cholinergic receptors, making them unavailable to pick up the signal transmitted by acetylcholine (anticholinergics). Let's see some examples.

Curare causes death from muscle paralysis, blocking the action of acetylcholine on muscle membranes (where nicotinic receptors are found); physostigmine, on the other hand, prolongs the action of acetylcholine by blocking cholinesterase, while the venom of the black widow stimulates an excess of release. Nerve gases also block this enzyme, causing acetylcholine to remain anchored to its receptors; the lethal effect of these gases is useful for investigating the effects of the interaction between acetylcholine and its muscarinic receptors: cough, chest tightness, bronchial hypersecretion up to pulmonary edema, nausea, vomiting, diarrhea, increased salivation, miosis and difficulty in vision, reduced heart rate up to stopping and urinary incontinence. Due to the accumulation of acetylcholine in nicotinic receptors, symptoms such as : skin pallor, tachycardia, arterial hypertension, hyperglycemia and alterations in the musculoskeletal system, in particular asthenia and easy muscle exhaustion, tremors and cramps. Due to the accumulation of acetylcholine the skeletal muscles can be paralyzed and death by muscle paralysis in contraction can occur. Finally, the effects on the central nervous system include tonic-clonic contractions of the epileptiform type, up to the depression of the respiratory centers and death. This usually occurs due to asphyxiation due to paralysis of the diaphragm and intercostal muscles. Even botulinum, a very poisonous toxin used in infinitesimal concentrations in aesthetic medicine, has to do with acetylcholine; with its action, in fact, it prevents their release from the vesicles. In this way, Botox causes flaccid paralysis of the muscles, becoming fatal when it heavily involves the respiratory ones; in this sense, it contrasts with the action of tetanus, characterized by spastic paralysis which is nevertheless independent of acetylcholine. Pilocarpine, a drug used mainly in ophthalmology to narrow the pupil and stimulate tearing of the eye (useful in the treatment of glaucoma) is a muscarinic agonist; in fact, it binds to the muscarinic receptors of acetylcholine. In this sense, pilocarpine counteracts the action of atropine, which is instead a muscarinic antagonist and as such inhibits the activity of the parasympathetic (parasympatholytic). The drug atropine blocks muscarinic receptors, while curare blocks nicotinic receptors.


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