Acetylcholine (ACh) is an organic compound that functions in the brain and body of many types of animals (including humans) as a neurotransmitter. Its name is derived from its chemical structure: it is an ester of acetic acid and choline. Parts in the body that use or are affected by acetylcholine are referred to as cholinergic.
Acetylcholine is the neurotransmitter used at the neuromuscular junction. In other words, it is the chemical that motor neurons of the nervous system release in order to activate muscles. This property means that drugs that affect cholinergic systems can have very dangerous effects ranging from paralysis to convulsions. Acetylcholine is also a neurotransmitter in the autonomic nervous system, both as an internal transmitter for both the sympathetic and the parasympathetic nervous system, and as the final product released by the parasympathetic nervous system.
In the brain, acetylcholine functions as a neurotransmitter and as a neuromodulator. The brain contains a number of cholinergic areas, each with distinct functions; such as playing an important role in arousal, attention, memory and motivation. Acetylcholine has also been found in cells of non-neural origins as well as microbes. Recently, enzymes related to its synthesis, degradation and cellular uptake have been traced back to early origins of unicellular eukaryotes. The protist pathogens Acanthamoeba spp. have shown evidence of the presence of ACh, which provides growth and proliferative signals via a membrane-located M<sub>1</sub>-muscarinic receptor homolog.
Partly because of acetylcholine's muscle-activating function, but also because of its functions in the autonomic nervous system and brain, many important drugs exert their effects by altering cholinergic transmission. Numerous venoms and toxins produced by plants, animals, and bacteria, as well as chemical nerve agents such as sarin, cause harm by inactivating or hyperactivating muscles through their influences on the neuromuscular junction. Drugs that act on muscarinic acetylcholine receptors, such as atropine, can be poisonous in large quantities, but in smaller doses they are commonly used to treat certain heart conditions and eye problems. Scopolamine, or diphenhydramine, which also act mainly on muscarinic receptors in an inhibitory fashion in the brain (especially the M<sub>1</sub> receptor) can cause delirium, hallucinations, and amnesia through receptor antagonism at these sites. So far as of 2016, only the M<sub>1</sub> receptor subtype has been implicated in anticholinergic delirium. The addictive qualities of nicotine are derived from its effects on nicotinic acetylcholine receptors in the brain.
Chemistry
Acetylcholine is a choline molecule that has been acetylated at the oxygen atom. Because of the charged ammonium group, acetylcholine does not penetrate lipid membranes. Because of this, when the molecule is introduced externally, it remains in the extracellular space and at present it is considered that the molecule does not pass through the blood–brain barrier.
Biochemistry
Acetylcholine is synthesized in certain neurons by the enzyme choline acetyltransferase from the compounds choline and acetyl-CoA. Cholinergic neurons are capable of producing ACh. An example of a central cholinergic area is the nucleus basalis of Meynert in the basal forebrain.
The enzyme acetylcholinesterase converts acetylcholine into the inactive metabolites choline and acetate. This enzyme is abundant in the synaptic cleft, and its role in rapidly clearing free acetylcholine from the synapse is essential for proper muscle function. Certain neurotoxins work by inhibiting acetylcholinesterase, thus leading to excess acetylcholine at the neuromuscular junction, causing paralysis of the muscles needed for breathing and stopping the beating of the heart.
Functions
thumb|Acetylcholine pathway.
Acetylcholine functions in both the central nervous system (CNS) and the peripheral nervous system (PNS). In the CNS, cholinergic projections from the basal forebrain to the cerebral cortex and hippocampus support the cognitive functions of those target areas. In the PNS, acetylcholine activates muscles and is a major neurotransmitter in the autonomic nervous system.
- Antibiotics (clindamycin, polymyxin)
- Magnesium: antagonizes P-type calcium channels
- Hypocalcemia
- Anticonvulsants
- Diuretics (furosemide)
- Eaton-Lambert syndrome: inhibits P-type calcium channels
- Myasthenia gravis
- Botulinum toxin: inhibits SNARE proteins
Calcium channel blockers (nifedipine, diltiazem) do not affect P-channels. These drugs affect L-type calcium channels.
Autonomic nervous system
thumb|class=skin-invert-image|right|Components and connections of the [[parasympathetic nervous system.]]
The autonomic nervous system controls a wide range of involuntary and unconscious body functions. Its main branches are the sympathetic nervous system and parasympathetic nervous system. Broadly speaking, the function of the sympathetic nervous system is to mobilize the body for action; the phrase often invoked to describe it 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; the phrase often invoked to describe it is "rest and digest" or "feed and breed". Both of these aforementioned systems use acetylcholine, but in different ways.
At a schematic level, the sympathetic and parasympathetic nervous systems are both organized in essentially the same way: preganglionic neurons in the central nervous system send projections to neurons located in autonomic ganglia, which send output projections to virtually every tissue of the body. In both branches the internal connections, the projections from the central nervous system to the autonomic ganglia, use acetylcholine as a neurotransmitter to innervate (or excite) ganglia neurons. In the parasympathetic nervous system the output connections, the projections from ganglion neurons to tissues that do not belong to the nervous system, also release acetylcholine but act on muscarinic receptors. In the sympathetic nervous system the output connections mainly release noradrenaline, although acetylcholine is released at a few points, such as the sudomotor innervation of the sweat glands.
Direct vascular effects
Acetylcholine in the serum exerts a direct effect on vascular tone by binding to muscarinic receptors present on vascular endothelium. These cells respond by increasing production of nitric oxide, which signals the surrounding smooth muscle to relax, leading to vasodilation.
Central nervous system
thumb|right|[[Micrograph of the nucleus basalis (of Meynert), which produces acetylcholine in the CNS. LFB-HE stain.]]
In the central nervous system, ACh has a variety of effects on plasticity, arousal and reward. ACh has an important role in the enhancement of alertness when we wake up, in sustaining attention and in learning and memory.
Damage to the cholinergic (acetylcholine-producing) system in the brain has been shown to be associated with the memory deficits associated with Alzheimer's disease. ACh has also been shown to promote REM sleep.
In the brainstem acetylcholine originates from the Pedunculopontine nucleus and laterodorsal tegmental nucleus collectively known as the mesopontine tegmentum area or pontomesencephalotegmental complex. In the basal forebrain, it originates from the basal nucleus of Meynert and medial septal nucleus:
- The pontomesencephalotegmental complex acts mainly on M1 receptors in the brainstem, deep cerebellar nuclei, pontine nuclei, locus coeruleus, raphe nucleus, lateral reticular nucleus and inferior olive.
Memory
Acetylcholine has been implicated in learning and memory in several ways. The anticholinergic drug scopolamine impairs acquisition of new information in humans and animals. and disruption of the supply of acetylcholine to the hippocampus and adjacent cortical areas produces forgetfulness, comparable to anterograde amnesia in humans.
Acetylcholine (ACh) has traditionally been seen as vital for learning and memory, but recent studies question its purely positive role. Too much ACh can interfere with memory consolidation, particularly during sleep, and may worsen verbal memory in early Alzheimer’s disease (AD) and mild cognitive impairment (MCI). Excessive activation of ACh pathways can also overstimulate glutamate activity, contributing to AD progression. Researchers propose that ACh levels first increase and later decrease throughout AD and Parkinson’s disease dementia (PDD), due to initial overstimulation followed by neuron loss. They emphasize that cholinesterase inhibitors may not help all cognitive symptoms and could disrupt natural ACh balance, showing that ACh’s effects on memory are complex and require further investigation.
Diseases and disorders
Myasthenia gravis
The disease myasthenia gravis, characterized by muscle weakness and fatigue, occurs when the body inappropriately produces antibodies against acetylcholine nicotinic receptors, and thus inhibits proper acetylcholine signal transmission. Over time, the motor end plate is destroyed. Drugs that competitively inhibit acetylcholinesterase (e.g., neostigmine, physostigmine, or primarily pyridostigmine) are effective in treating the symptoms of this disorder. They allow endogenously released acetylcholine more time to interact with its respective receptor before being inactivated by acetylcholinesterase in the synaptic cleft (the space between nerve and muscle).
Nerves release ACh at the neuromuscular junction. ACh binds to ACh receptors on the muscle surface and causes muscle contraction. Then the immune system produces autoantibodies that attack or black the ACh receptors on the muscle. Therefore, the signal from the nerve to the muscle is weakened or lost. Juvenile MG is more frequently seen in people of Asian and African descent.
Pharmacology
Blocking, hindering or mimicking the action of acetylcholine has many uses in medicine. Drugs acting on the acetylcholine system are either agonists to the receptors, stimulating the system, or antagonists, inhibiting it. Acetylcholine receptor agonists and antagonists can either have an effect directly on the receptors or exert their effects indirectly, e.g., by affecting the enzyme acetylcholinesterase, which degrades the receptor ligand. Agonists increase the level of receptor activation; antagonists reduce it.
Acetylcholine itself does not have therapeutic value as a drug for intravenous administration because of its multi-faceted action (non-selective) and rapid inactivation by cholinesterase. However, it is used in the form of eye drops to cause constriction of the pupil during cataract surgery, which facilitates quick post-operational recovery.
Nicotinic receptors
Nicotine binds to and activates nicotinic acetylcholine receptors, mimicking the effect of acetylcholine at these receptors. ACh opens a Na<sup>+</sup> channel upon binding so that Na<sup>+</sup> flows into the cell. This causes a depolarization, and results in an excitatory post-synaptic potential. Thus, ACh is excitatory on skeletal muscle; the electrical response is fast and short-lived. Curares are arrow poisons, which act at nicotinic receptors and have been used to develop clinically useful therapies.
Muscarinic receptors
Muscarinic receptors form G protein-coupled receptor complexes in the cell membranes of neurons and other cells. Atropine is a non-selective competitive antagonist with Acetylcholine at muscarinic receptors.
Cholinesterase inhibitors
Many ACh receptor agonists work indirectly by inhibiting the enzyme acetylcholinesterase. The resulting accumulation of acetylcholine causes continuous stimulation of the muscles, glands, and central nervous system, which can result in fatal convulsions 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 the carbamates). Many toxins and venoms produced by plants and animals also contain cholinesterase inhibitors. In clinical use, they are administered in low doses to reverse the action of muscle relaxants, to treat myasthenia gravis, and to treat symptoms of Alzheimer's disease (rivastigmine, which increases cholinergic activity in the brain).
Synthesis inhibitors
Organic mercurial compounds, such as methylmercury, have a high affinity for sulfhydryl groups, which causes dysfunction of the enzyme choline acetyltransferase. This inhibition may lead to acetylcholine deficiency, and can have consequences on motor function.
Release inhibitors
Botulinum toxin (Botox) acts by suppressing the release of acetylcholine, whereas the venom from a black widow spider (alpha-latrotoxin) has the reverse effect. ACh inhibition causes paralysis. When bitten by a black widow spider, one experiences the wastage of ACh supplies and the muscles begin to contract. If and when the supply is depleted, paralysis occurs.
Photopharmacological agents
Photopharmacology is an emerging field that uses light to control the activity of biologically active compounds with high spatial and temporal precision. Recent advances have applied this approach to the cholinergic system, including photoactivatable agonists and antagonists of muscarinic and nicotinic acetylcholine receptors, as well as light-sensitive acetylcholinesterase inhibitors, that enable reversible and targeted modulation of cholinergic signaling upon irradiation. These light-regulated compounds, based on either photolabile protecting groups ("caged" ligands) or photoisomerizable scaffolds, offer unprecedented control over acetylcholine-mediated processes and represent promising tools for both basic research and potential therapeutic applications.
Comparative biology and evolution
Acetylcholine is used by organisms in all domains of life for a variety of purposes. It is believed that choline, a precursor to acetylcholine, was used by single celled organisms billions of years ago for synthesizing cell membrane phospholipids. Following the evolution of choline transporters, the abundance of intracellular choline paved the way for choline to become incorporated into other synthetic pathways, including acetylcholine production. Acetylcholine is used by bacteria, fungi, and a variety of other animals. Many of the uses of acetylcholine rely on its action on ion channels via GPCRs like membrane proteins.
The two major types of acetylcholine receptors, muscarinic and nicotinic receptors, have convergently evolved to be responsive to acetylcholine. This means that rather than having evolved from a common homolog, these receptors evolved from separate receptor families. It is estimated that the nicotinic receptor family dates back longer than 2.5 billion years.
History
In 1867, Adolf von Baeyer resolved the structures of choline and acetylcholine and synthesized them both, referring to the latter as acetylneurin in the study. Choline is a precursor for acetylcholine. Acetylcholine was first noted to be biologically active in 1906, when Reid Hunt (1870–1948) and René de M. Taveau found that it decreased blood pressure in exceptionally tiny doses. This was after Frederick Walker Mott and William Dobinson Halliburton noted in 1899 that choline injections decreased the blood pressure of animals. This conclusion was accepted widely. Later studies confirmed the function of acetylcholine as a neurotransmitter.
In 1936, H. H. Dale and O. Loewi shared the Nobel Prize in Physiology or Medicine for their studies of acetylcholine and nerve impulses.