ACETYLCHOLINE: FUNCTIONS, SYNTHESIS, MECHANISM OF ACTION - NEUROPSYCHOLOGY - 2024

The acetylcholine is the neurotransmitter in specific systems and the somatic nervous system ganglion synapse of the autonomic nervous system. It is a chemical substance that allows a large number of neurons to function and, at the same time, allows the performance of various brain activities.

Acetylcholine was the first neurotransmitter isolated, conceptualized and characterized by what many scientists say is the "oldest" substance in the brain. It was described pharmacologically by Henry Hallet Delt in 1914 and was later confirmed by Otto Loewi as a neurotransmitter.

Acetylcholine molecular structure

The main activity of acetylcholine falls on the cholinergic system, which is responsible for producing and synthesizing acetylcholine. Regarding its most important effects, it highlights muscle contraction, movement, digestive and neuroendocrine processes, and the activation of cognitive processes such as attention and arousal.

How does acetylcholine work?

In the mammalian brain, information between neurons is transmitted through a chemical called a neurotransmitter. This substance is released at the synapse in response to a specific stimulus and when released it transmits certain information to the next neuron.

The neurotransmitter that is secreted acts on specialized and highly selective receptor sites, thus, as there are different types of neurotransmitters, each of them acts in certain systems.

A cholinergic neuron can produce acetylcholine (but not other types of neurotransmitters), likewise, it can produce specific receptors for acetylcholine but not for other types of neurotransmitters.

The exchange of information carried out by acetylcholine is carried out in specific neurons and systems called cholinergic.

For acetylcholine to act, it requires a transmitter neuron to produce this substance and a receptor neuron to produce a cholinergic receptor that is capable of transporting acetylcholine when it is released from the first neuron. In the following image you can see how acetylcholine is released to muscle neurotransmitters:

Synthesis

Micrograph of the nucleus basalis of Meynert, which produces acetylcholine in the central nervous system. Source: Nephron

Acetylcholine is synthesized from choline, an essential nutrient generated by the body. Choline accumulates in cholinergic neurons through a reaction with actyl CoA and under the enzymatic influence of choline acetyltransferase.

These three elements are found in the specific regions of the brain where acetylcholine will be produced, which is why acetylcholine makes a neurotransmitter belonging to a specific system, the cholinergic system.

When we find these three substances in a neuron that we have just discussed, we know that it consists of a cholinergic neuron and that this neuron will produce acetylcholine through the interaction of choline and the corresponding enzymatic elements.

The synthesis of acetylcholine takes place within the neuron, specifically in the nucleus of the cell. Once synthesized, acetylcholine leaves the nucleus of the neuron and travels through the axon and dendrites, that is, the parts of the neuron that are responsible for communication and association with other neurons.

Release

Acetylcholine molecules. Source: Created with the data set and the free program Rasmol.

We already know that the function of this substance consists in associating and communicating specific neurons (cholinergic) with other specific neurons (cholinergic). To perform this process, the acetylcholine found within the neuron must be released to travel to the recipient neuron.

For acetylcholine to be released, it requires the presence of a stimulus that motivates its exit from the neuron. If an action potential carried out by another neuron is not present, acetylcholine will not be able to leave.

For acetylcholine to be released, an action potential must reach the nerve terminal where the neurotransmitter is located. When this happens, the same action potential generates a membrane potential, a fact that motivates the activation of calcium channels.

Due to the electrochemical gradient, an influx of calcium ions is generated that allows the membrane barriers to open and acetylcholine can be released.

As we can see, the release of acetylcholine responds to chemical mechanisms in the brain in which many substances and different molecular actions participate.

Receivers

Structure of the nicotinic receptor. Source: Opossum58

Once released, acetylcholine remains in no man's land, that is, it is outside neurons and is in the intersynaptic space. In order for the synapse to be realized and for acetylcholine to fulfill its mission of communicating with the consecutive neuron, the presence of substances known as receptors is required.

Receptors are chemical substances whose main function is to transduce the signals emitted by the neurotransmitter. This process is done selectively, so not all receptors respond to acetylcholine.

For example, the receptors of another neurotransmitter such as serotonin, will not pick up the signals of acetylcholine, so for it to work it must be coupled to a series of specific receptors.

In general, the receptors that respond to acetylcholine are called cholinergic receptors. We can find 4 main types of cholinergic receptors: muscarinic agonist receptors, nicotinic agonist receptors, muscarinic antagonist receptors and nicotinic antagonist receptors.

Acetylcholine functions

Acetylcholine processing at a synapse. Source: Smedlib, based on original work by Pancrat

Acetylcholine has many functions both on a physical level and on a psychological or brain level. This neurotransmitter is responsible for carrying out basic activities such as movement or digestion and, at the same time, it participates in more complex brain processes such as cognition or memory.

Below we review the main functions of this important neurotransmitter.

Motor functions

It is probably the most important activity of acetylcholine. This neurotransmitter is responsible for producing muscle contraction, controlling the resting potential of the intestinal muscle, increasing the production of spikes and modulating blood pressure.

It acts in a mild way as a vasodilator in the blood vessels and contains a certain relaxing factor.

Neuroendocrine functions

Another key role of acetylcholine is to increase vasopressin secretion by stimulating the posterior lobe of the pituitary.

Vasopressin is a peptide hormone that controls the reabsorption of water molecules, so its production is vital for neuroendocrine development and function.

Likewise, acetylcholine decreases prolactin secretion in the posterior pituitary.

Parasympathetic functions

Acetylcholine plays an important role in food intake and in the functioning of the digestive system.

This neurotransmitter is responsible for increasing blood flow in the gastrointestinal tract, increases gastrointestinal muscle tone, increases gastrointestinal endocrine secretions, and decreases heart rate.

Sensory functions

Cholinergic neurons are part of the great ascending system, so they also participate in sensory processes. This system begins in the brain stem and innervates large areas of the cerebral cortex where acetylcholine is found.

The main sensory functions that have been associated with this neurotransmitter lie in the maintenance of consciousness, the transmission of visual information and the perception of pain.

Cognitive functions

Acetylcholine has been shown to play a critical role in memory formation, the ability to concentrate, and the development of attention and logical reasoning.

This neurotransmitter provides protective benefits and could limit the occurrence of cognitive decline. In fact, acetylcholine has been shown to be the main affected substance in Alzheimer's disease.

Related diseases

Acetylcholine pathway in the central nervous system. Source: BruceBlaus

Acetylcholine participates in various brain functions, so the deficit of these substances can be reflected in the deterioration of some of the activities discussed above.

Clinically, acetylcholine has been associated with two main diseases, Alzheimer's disease and Parkinson's disease.

Alzheimer's

With regard to Alzheimer's, in 1976 it was found that in different regions of the brain of patients with this disease, there were levels of the enzyme choline acetyltransferase up to 90% lower than normal.

This enzyme is vital for the production of acetylcholine, which is why it was postulated that Alzheimer's disease could be caused by the deficiency of this brain substance.

At present, this factor constitutes the main clue that points to the cause of Alzheimer's and encompasses much of the scientific attention and research that is carried out both on the disease and on the development of possible treatments.

Parkinson's

With regard to Parkinson's, the association between the cause of the disease and acetylcholine is less clear. Parkinson's is a disease that mainly affects movement, which is why acetylcholine could play an important role in its genesis.

The cause of the disease is unknown today and, in addition, another neurotransmitter such as dopamine seems to play a more important role and most drugs for this pathology focus on the function of this neurotransmitter.

However, the close relationship between dopamine and acetylcholine suggests that the latter is also an important neurotransmitter in the disease.

References

1. Perry E, Walker M, Grace J, Perry R. Acetylcholine in mind: a neurotransmitter correlate of consciousness? TINS 1999; 22-6, 273-80.
2. McMahan UJ. The structure and regulation of agrin. In: Koelle GB. Symposium on the cholinergic synapse. Life Science, Vol. 50. New York: Pergamon Press; 1992, p. 93-4.
3. Changeux JP, Devillers-Thiéry A. Chemouilli P. The acetylcholine receptor: an "allosteric" protein engaged in intracellular communication. Science 1984; 225: 1335-45.
4. Duclert A, Chengeux JP. Acetylcholine receptor gene expression at the developing neuromuscular junction. Physiol Rev 1995; 75: 339-68.
5. Bosboom JL, Stoffers D, Wolters ECh. The role of acetylcholine and dopamine in dementia and psychosis in Parkinson's disease. J Neural Transm 2003; 65 (Suppl): 185-95.
6. Montgomery, SA and Corn, TH (Eds) Psychopharmacology of Depression Oxford University Press, British Association for Psychopharmacology, Monographs No. 13, 1994.