Acetylcholine: Functions, Associated Diseases, Pharmacology, History and Benefits

Known as Ach, it is an organic chemical that works in the brains and bodies of many types of animals.

Its name is derived from its chemical structure, it is an ester of acetic acid and choline. The parts of the body that use or are affected by acetylcholine are known as cholinergic. Substances that interfere with the activity of acetylcholine are called anticholinergics.

Acetylcholine is the neurotransmitter used at the neuromuscular junction, that is, it is the chemical released by motor neurons in the nervous system to activate muscles.

This property means that drugs that affect the cholinergic systems can have very dangerous effects ranging from paralysis to seizures.

Acetylcholine is also used as a neurotransmitter in the autonomic nervous system , as an internal transmitter in the sympathetic nervous system, and as an end product released by the parasympathetic nervous system.

In the brain, acetylcholine functions as a neurotransmitter and as a neuromodulator. The brain contains several cholinergic areas, each with different functions. They play an important role in arousal, attention, memory, and motivation.

Partly due to its activating function in muscles, but also due to its functions in the autonomic nervous system and in the brain, a large number of important drugs exert their effects by altering cholinergic transmission.

Numerous poisons and toxins produced by plants, animals, and bacteria, as well as chemical nerve agents such as sarin, cause damage by inactivating or hyperactivating muscles through their influences on the neuromuscular junction.

Drugs that target muscarinic acetylcholine receptors, such as atropine, can be toxic in large amounts, but in smaller doses they are commonly used to treat certain heart conditions and eye problems.

Scopolamine, which acts primarily on muscarinic receptors in the brain, can cause delirium and amnesia. The addictive qualities of nicotine stem from its effects on nicotinic acetylcholine receptors in the brain.

Chemistry

Acetylcholine is a choline molecule that has been acetylated at the oxygen atom. Due to the presence of a highly polar and charged ammonium group, acetylcholine does not penetrate lipid membranes.

Because of this, when the drug is introduced externally, it remains in the extracellular space and does not pass through the blood-brain barrier. A synonym for this drug is myocol.

Biochemistry

Acetylcholine is synthesized in certain neurons by the enzyme choline acetyl-transferase of the compounds choline and acetyl-CoA. Cholinergic neurons are capable of producing acetylcholine. An example of a central cholinergic area is the nucleus basalis of Meynert in the basal brain.

The enzyme acetylcholinesterase converts acetylcholine to the inactive metabolites choline and acetate. This enzyme is abundant in the synaptic cleft, and its role in the rapid removal of free acetylcholine from the synapse is essential for proper muscle function.

Certain neurotoxins work by inhibiting acetylcholinesterase, which leads to excess acetylcholine at the neuromuscular junction, causing paralysis of the muscles needed to breathe and stopping the heartbeat.

Features

Acetylcholine works in both the central nervous system (CNS) and the peripheral nervous system (PNS). In the central nervous system, cholinergic projections from the basal brain to the cerebral cortex and hippocampus support the cognitive functions of these target areas.

In the peripheral nervous system, acetylcholine activates muscles and is an important neurotransmitter in the autonomic nervous system.

Cell effects

Like many other biologically active substances, acetylcholine exerts its effects by binding and activating receptors located on the surface of cells. There are two main classes of acetylcholine receptors, nicotinic and muscarinic.

They are named for the chemicals that can selectively activate each type of receptor without activating the other: muscarine is a compound found in the Amanita muscaria mushroom; nicotine is found in tobacco.

Nicotinic acetylcholine receptors are bound ion channels permeable to sodium, potassium, and calcium ions.

In other words, they are ion channels embedded in cell membranes, capable of changing from a closed to an open state when acetylcholine binds to them; in the open state they allow the passage of ions.

Nicotinic receptors come in two main types, known as the muscle type and the neuronal type. The muscle type can be selectively blocked by curare, the neuronal type by hexamethonium.

The main location of muscle-type receptors is found in muscle cells, as described in more detail below. Neuronal-type receptors are found in the autonomic ganglia (both sympathetic and parasympathetic) and in the central nervous system.

Muscarinic acetylcholine receptors have a more complex mechanism and affect target cells for a longer period of time. In mammals, five muscarinic receptor subtypes have been identified, labeled M1 through M5.

They all function as G protein-coupled receptors, which means that they exert their effects through a second messaging system.

Subtypes M1, M3, and M5 are Gq-coupled; they increase intracellular levels of IP3 and calcium by activating phospholipase C. Its effect on target cells is usually excitatory.

The M2 and M4 subtypes are Gi / Go-coupled; intracellular levels of cyclic adenosine monophosphate decrease by inhibiting adenyl cyclase cyclase. Its effect on target cells is usually inhibitory.

Muscarinic acetylcholine receptors are found in both the central and peripheral nervous systems of the heart, lungs, upper gastrointestinal tract, and sweat glands.

Neuromuscular junction

Acetylcholine is the substance that the nervous system uses to activate skeletal muscles, a type of skeletal muscle.

These are the muscles used for all types of voluntary movement, in contrast to smooth muscle tissue, which is involved in a number of involuntary activities such as the movement of food through the gastrointestinal tract and the constriction of blood vessels.

Skeletal muscles are controlled directly by motor neurons located in the spinal cord or, in a few cases, in the brainstem.

These motor neurons send their axons through motor nerves, from which they emerge to connect to muscle fibers at a special type of synapse called the neuromuscular junction.

When a motor neuron generates an action potential, it travels rapidly along the nerve until it reaches the neuromuscular junction, where it initiates an electrochemical process that causes the release of acetylcholine into the space between the presynaptic terminal and the muscle fiber.

The acetylcholine molecules then bind to nicotinic ion receptors on the muscle cell membrane, causing the ion channels to open.

The calcium ions then flow into the muscle cell, initiating a sequence of steps that ultimately produce muscle contraction.

Autonomic nervous system

The autonomic nervous system controls a wide range of involuntary and unconscious bodily functions. Its main branches are the sympathetic nervous system and the parasympathetic nervous system.

Generally speaking, the function of the sympathetic nervous system is to mobilize the body for action: the slogan often used for this is “fight or flight.”

The function of the parasympathetic nervous system is to put the body in a state conducive to rest, regeneration, digestion and reproduction: it is sometimes described using the slogans “rest and digest” or “feed and reproduce.” Both branches use acetylcholine, but in different ways.

At the schematic level, the sympathetic and parasympathetic nervous systems are organized in essentially the same way:

The preganglionic neurons of the central nervous system send projections to the neurons located in the autonomic ganglia; These neurons then send out projections to virtually every tissue in the body.

In both branches, the internal connections (the projections from the central nervous system to the autonomic ganglia) use acetylcholine as a neurotransmitter, and the receptors it activates are of the nicotinic type.

In the parasympathetic nervous system, the outlet connections (the projections of ganglionic neurons to tissues outside the nervous system) also release acetylcholine, which acts on muscarinic receptors.

In the sympathetic nervous system, the outlets release primarily norepinephrine, although acetylcholine is released at some points, such as the sudomotor innervation of the sweat glands.

Direct vascular effects

Acetylcholine in serum exerts a direct effect on vascular tone by binding to muscarinic receptors present in the vascular endothelium. These cells respond by increasing nitric oxide production, which signals the surrounding smooth muscle to relax, leading to vasodilation.

Central Nervous System

In the central nervous system, acetylcholine has a variety of effects on plasticity, arousal, and reward.

Acetylcholine plays an important role in improving alertness when we wake up, in maintaining attention, and in learning and memory.

Damage to the cholinergic (acetylcholine-producing) system in the brain has been shown to be associated with memory deficits associated with Alzheimer’s disease. Acetylcholine has also been shown to promote REM sleep.

In the brainstem, acetylcholine originates from the pedunculopontine nucleus and the laterodorsal tegmental nucleus, collectively known as the mesopontine tegmentum area or pontomesencephalotegmental complex.

In the basal forebrain, it originates from the nucleus basalis of Meynert and the middle septal nucleus:

  • The pontomesencephalotegmental complex acts mainly on the brain stem M1 receptors, deep cerebellar nuclei, pontine nuclei, locus coeruleus, raphe nucleus, lateral reticular nucleus and inferior olive. It also projects to the thalamus, tectum, basal ganglia, and basal forearm.
  • The nucleus basalis of Meynert acts mainly on M1 receptors in the neocortex.
  • The nucleus of the median septum acts primarily on M1 receptors in the hippocampus and parts of the cerebral cortex.

In addition, cetylcholine acts as an important internal transmitter in the stratum, which is part of the basal ganglia. It is released by cholinergic interneurons.

In humans, primates, and nonhuman rodents, these interneurons respond to prominent environmental stimuli with responses that are temporally aligned with the responses of substantia nigra dopaminergic neurons.

Memory

Acetylcholine has been implicated in learning and memory in a number of ways. The anticholinergic drug, scopolamine, prevents the acquisition of new information in humans and animals.

In animals, the interruption of the supply of acetylcholine to the neocortex makes it difficult to learn simple discrimination tasks, comparable to the acquisition of objective information, and the interruption of the supply of acetylcholine to the hippocampus and adjacent cortical areas produces forgetfulness comparable to amnesia anterograde in humans.

Diseases and disorders

Myasthenia gravis

Myasthenia gravis disease, characterized by muscle weakness and fatigue, occurs when the body inappropriately produces antibodies against nicotinic acetylcholine receptors, thereby inhibiting the proper transmission of the acetylcholine signal.

Over time, the end plate of the motor is destroyed. Drugs that competitively inhibit acetylcholinesterase (eg, neostigmine, physostigmine, or primarily pyridostigmine) are effective in treating this disorder.

They allow endogenously released acetylcholine to interact longer with its respective receptor before being inactivated by acetylcholinesterase in the synaptic cleft (the space between the nerve and the muscle).

Pharmacology

Blocking, hindering, or mimicking the action of acetylcholine has many uses in medicine. Drugs that act on the acetylcholine system are receptor agonists, stimulating the system, or antagonists, inhibiting it.

Acetylcholine receptor agonists and antagonists can have a direct effect on the receptors or exert their effects indirectly, for example by affecting the enzyme acetylcholinesterase, which degrades the receptor ligand.

Agonists increase the level of receptor activation, antagonists reduce it. Acetylcholine itself has no therapeutic value as a drug for intravenous administration due to its multifaceted (non-selective) action and its rapid inactivation by cholinesterase.

However, it is used in the form of eye drops to cause constriction of the pupil during cataract surgery, facilitating rapid postoperative recovery.

Nicotine

Nicotine binds to and activates nicotinic acetylcholine receptors, mimicking the effect of acetylcholine on these receptors. When acetylcholine interacts with a nicotinic acetylcholine receptor, it opens a Na + channel and Na + ions flow into the membrane.

This causes depolarization, and results in an excitatory postsynaptic potential. Therefore, acetylcholine is exciting in skeletal muscle; electrical response is quick and short-lived.

Atropine

Atropine is a competitive non-selective antagonist with acetylcholine at muscarinic receptors.

Cholinesterase inhibitors

Many acetylcholine receptor agonists work indirectly by inhibiting the enzyme acetylcholinesterase.

The resulting accumulation of acetylcholine causes continuous stimulation of the muscles, glands, and the central nervous system, which can result in fatal seizures if the dose is high.

They are examples of enzyme inhibitors, and increase the action of acetylcholine by delaying its degradation; some have been used as nerve agents (Sarin and VX nerve gas) or pesticides (organophosphates and carbamates).

Many toxins and poisons produced by plants and animals also contain cholinesterase inhibitors.

In clinical use, they are given in low doses to reverse the action of muscle relaxants, to treat myasthenia gravis, and to treat the symptoms of Alzheimer’s disease (rivastigmine, which increases cholinergic activity in the brain).

Synthesis inhibitors

Organic mercury compounds, such as methylmercury, have a high affinity for sulfhydryl groups, causing dysfunction of the enzyme choline acetyltransferase. This inhibition can lead to acetylcholine deficiency and can have consequences on motor function.

Release inhibitors

Botulinum toxin (Botox) works by suppressing the release of acetylcholine, while black widow spider venom (alpha-latrotoxin) has the opposite effect. Acetylcholine inhibition causes paralysis.

When bitten by a black widow spider, one experiences wasted supplies of acetylcholine and the muscles begin to contract. When the supply runs out, paralysis occurs.

Comparative biology and evolution

Acetylcholine is used by animals in all domains of life for a variety of purposes. Choline, a precursor to acetylcholine, is believed to have been used by single-celled organisms billions of years ago to synthesize cell membrane phospholipids.

Following the evolution of choline transporters, the abundance of intracellular choline paved the way for choline to be incorporated into other synthetic pathways, including the production of acetylcholine. Interestingly, many of the uses for acetylcholine depend on its action on ion channels.

The two main types of acetylcholine receptors, muscarinic and nicotinic receptors, have convergently evolved to respond to acetylcholine.

This means that instead of having evolved from a common homolog, these receptors evolved from separate receptor families. The nicotinic receptor family is estimated to date back more than 2.5 billion years.

The nicotinic receptor family is estimated to date back more than 2.5 billion years. Also, muscarinic receptors are believed to have deviated from other G-protein-coupled or RAPG receptors at least 500 million years ago.

Both groups of receptors have evolved numerous subtypes with unique ligand affinities and signaling mechanisms.

The diversity of receptor types allows acetylcholine to create variable responses depending on which receptor types are activated, and it allows acetylcholine to dynamically regulate physiological processes.

History

Acetylcholine (Ach) was first identified in 1915 by Henry Hallett Dale from its actions on heart tissue. It was confirmed as a neurotransmitter by Otto Loewi , who initially gave it the name Vagusstoff because it was released from the vagus nerve.

They both received the Nobel Prize in Physiology or Medicine in 1936 for their work. Acetylcholine was also the first neurotransmitter to be identified.

Acetylcholine benefits

Acetylcholine prevents memory loss. Too little acetylcholine in the hippocampus has been associated with dementia and Alzheimer’s.

Since there is a relationship between acetylcholine and Alzheimer’s disease, it is estimated that there is a 90% loss of acetylcholine in the brains of people with Alzheimer’s.

Acetylcholine can improve memory by helping to encode new memories and increasing the modification of synapses. Acetylcholine improves attention. Acetylcholine helped improve attention and improve decision-making skills.

Acetylcholine helps you sleep better. Acetylcholine promotes REM sleep, which helps store memory and rest the brain. Acetylcholine release in the basal brain is greatest during REM sleep.

Acetylcholine regulates gastrointestinal activity. Presynaptic nicotinic acetylcholine receptors (nAChRs) help release acetylcholine in the intestine.

These receptors mediate positive feedback regarding ACh release from motor neurons, and therefore play an important role in the regulation of intestinal flow.

Acetylcholine protects against infection. Acetylcholine can modulate inflammatory responses. Acetylcholine was shown to have the ability to inhibit biofilm formation during a fungal infection (Candida albicans). In addition, it inhibited inflammation-induced damage to internal organs.

Acetylcholine affects hormone secretion. Acetylcholine affects the secretion of the pituitary hormone by acting on the hypothalamus. It causes prolactin and growth hormone to secrete from the pituitary.

Negative effects

Too much acetylcholine is associated with depression . Acetylcholine is also linked to myasthenia gravis.

In myasthenia gravis, antibodies block, alter, or destroy acetylcholine receptors at the neuromuscular junction, preventing muscle contractions.

It is a defect in the transmission of nerve impulses to the muscles. However, it is not clear whether antibodies against the receptors in the brain can directly cause the disease.

How to change your acetylcholine levels

There are supplements for acetylcholine deficiency and to increase acetylcholine levels in your body.

When it comes to the herbs listed, they increase acetylcholine by inhibiting the enzyme that breaks them down – acetylcholinesterase. Most common herbs have some inhibitory activity against the enzyme.