View source for Acetylcholine

{{Short description|Organic chemical and neurotransmitter}}
{{Distinguish|Acetyl chloride}}
{{More citations needed |date=August 2019}}
{{Use dmy dates|date=September 2024}}
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{{Infobox drug
| image = Acetylcholine-skeletal-formula.svg
| image_class = skin-invert-image
| alt =

<!-- Physiological data -->
| source_tissues = [[motor neuron]]s, [[parasympathetic nervous system]], [[brain]]
| target_tissues = [[smooth muscle]]s, brain, many other organs
| receptors = [[nicotinic acetylcholine receptor|nicotinic]], [[muscarinic acetylcholine receptor|muscarinic]]
| agonists = [[nicotine]], [[muscarine]], [[Acetylcholinesterase inhibitor|cholinesterase inhibitors]]
| antagonists = [[tubocurarine]], [[atropine]]
| precursor = [[choline]], [[acetyl-CoA]]
| biosynthesis= [[choline acetyltransferase]]
| metabolism =  [[acetylcholinesterase]]

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| pronounce         =
| tradename         =
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| MedlinePlus       =
| DailyMedID        = Acetylcholine
| pregnancy_AU      = <!-- A / B1 / B2 / B3 / C / D / X -->
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| class             =
| ATC_prefix        = S01
| ATC_suffix        = EB09
| ATC_supplemental  =

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<!-- Identifiers -->
| CAS_number = 51-84-3
| PubChem = 187
| IUPHAR_ligand = 294
| DrugBank = EXPT00412
| ChemSpiderID = 182
| UNII = N9YNS0M02X
| KEGG = C01996
| ChEBI = 15355
| ChEMBL = 667
| synonyms = ACh

| IUPAC_name = 2-Acetoxy-''N'',''N'',''N''-trimethylethanaminium
| C=7 | H=16 | N=1 | O=2
}}

'''Acetylcholine''' ('''ACh''')<ref>{{Cite encyclopedia |title=ACh |encyclopedia=Henderson's Dictionary of Biological Terms |last=Lawrence |first=Eleanor |page=1 |isbn=0-470-21446-5}}</ref> is an [[organic compound]] that functions in the brain and body of many types of animals (including humans) as a [[neurotransmitter]].<ref name="Tiwari 413–420">{{cite journal | vauthors = Tiwari P, Dwivedi S, Singh MP, Mishra R, Chandy A | title = Basic and modern concepts on cholinergic receptor: A review. | journal = Asian Pacific Journal of Tropical Disease | date = October 2012 | volume = 3 | issue = 5 | pages = 413–420 | pmc = 4027320 | doi = 10.1016/S2222-1808(13)60094-8 }}</ref> Its name is derived from its chemical structure: it is an [[ester]] of [[acetic acid]] and [[choline]].<ref name= "Sam_2023">{{cite book | vauthors = Sam C, Bordoni B | chapter = Physiology, Acetylcholine |date=2023 | chapter-url = https://www.ncbi.nlm.nih.gov/books/NBK557825/ | title = StatPearls |access-date=6 April 2023 |place=Treasure Island (FL) |publisher=StatPearls Publishing |pmid=32491757 }}</ref> 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 neuron]]s 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 [[convulsion]]s. Acetylcholine is also a neurotransmitter in the [[autonomic nervous system]], both as an internal transmitter for both the [[sympathetic nervous system|sympathetic]] and the [[parasympathetic nervous system]], and as the final product released by the parasympathetic nervous system.<ref name="Tiwari 413–420"/> Acetylcholine is the primary neurotransmitter of the parasympathetic nervous system.<ref name = "Sam_2023" /><ref>{{cite book | vauthors = Lott EL, Jones EB | chapter = Cholinergic Toxicity | chapter-url = https://www.ncbi.nlm.nih.gov/books/NBK539783/ | title = StatPearls | location = Treasure Island (FL) | publisher = StatPearls Publishing| date = June 2019 | pmid = 30969605 }}</ref>

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]].<ref name="Kapalka 2010 pp. 71–99">{{cite book | vauthors = Kapalka GM | title=Nutritional and Herbal Therapies for Children and Adolescents | url=https://archive.org/details/nutritionalherba00kapa | url-access=limited | chapter=Substances Involved in Neurotransmission | publisher=Elsevier | year=2010 | isbn=978-0-12-374927-7 | doi=10.1016/b978-0-12-374927-7.00004-2 | pages=[https://archive.org/details/nutritionalherba00kapa/page/n85 71]–99}}</ref> 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.<ref name="pmid29058403">{{cite journal | vauthors = Baig AM, Rana Z, Tariq S, Lalani S, Ahmad HR | title = Traced on the Timeline: Discovery of Acetylcholine and the Components of the Human Cholinergic System in a Primitive Unicellular Eukaryote ''Acanthamoeba'' spp.| journal = ACS Chem Neurosci | volume = 9 | issue = 3 | pages = 494–504 | date = March 2018 | pmid = 29058403 | doi = 10.1021/acschemneuro.7b00254 }}</ref> 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.<ref name="pmid27601178">{{cite journal | vauthors = Baig AM, Ahmad HR | title = Evidence of a M1-muscarinic GPCR homolog in unicellular eukaryotes: featuring ''Acanthamoeba'' spp bioinformatics 3D-modelling and experimentations | journal = J. Recept. Signal Transduct. Res. | volume = 37 | issue = 3 | pages = 267–275 | date = June 2017 | pmid = 27601178 | doi = 10.1080/10799893.2016.1217884 | s2cid = 5234123 | url = https://figshare.com/articles/journal_contribution/3807918 }}</ref>

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 [[toxin]]s produced by plants, animals, and bacteria, as well as chemical [[nerve agent]]s such as [[sarin]], cause harm by inactivating or hyperactivating muscles through their influences on the neuromuscular junction. Drugs that act on [[muscarinic acetylcholine receptor]]s, 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.<ref>{{cite journal | vauthors = Avetisov SE, Fisenko VP, Zhuravlev AS, Avetisov KS |trans-title =Atropine use for the prevention of myopia progression|title=Применение атропина для контроля прогрессирования миопии|lang=ru| journal = Vestnik Oftalmologii | volume = 134 | issue = 4 | pages = 84–90 | date = 2018 | pmid = 30166516 | doi = 10.17116/oftalma201813404184|doi-access=free}}</ref><ref>{{cite journal | vauthors = Smulyan H | title = The Beat Goes On: The Story of Five Ageless Cardiac Drugs | journal = The American Journal of the Medical Sciences | volume = 356 | issue = 5 | pages = 441–450 | date = November 2018 | pmid = 30055757 | doi = 10.1016/j.amjms.2018.04.011 }}</ref> [[Hyoscine hydrobromide|Scopolamine]], or [[diphenhydramine]], which also act mainly on muscarinic receptors in an inhibitory fashion in the brain (especially the [[Muscarinic acetylcholine receptor M1|M<sub>1</sub>]] receptor) can cause [[delirium]], [[hallucination]]s, 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.<ref>{{cite journal | vauthors = Dawson AH, Buckley NA | title = Pharmacological management of anticholinergic delirium - theory, evidence and practice | journal = British Journal of Clinical Pharmacology | volume = 81 | issue = 3 | pages = 516–524 | date = March 2016 | pmid = 26589572 | pmc = 4767198 | doi = 10.1111/bcp.12839 | quote = Delirium is only associated with the antagonism of post‐synaptic M1 receptors and to date other receptor subtypes have not been implicated }}</ref> The addictive qualities of [[nicotine]] are derived from its effects on [[nicotinic acetylcholine receptor]]s in the brain.
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==Chemistry==

Acetylcholine is a [[choline]] molecule that has been [[Acetylation|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 [[neuron]]s 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.<ref name="pmid19662940">{{cite journal | vauthors = Smythies J | title = Philosophy, perception, and neuroscience | journal = Perception | volume = 38 | issue = 5 | pages = 638–51 | date = 2009 | pmid = 19662940 | doi = 10.1068/p6025 | s2cid = 45579740 }}</ref><ref name="pmid27199688">{{cite journal | vauthors = Smythies J, d'Oreye de Lantremange M | title = The Nature and Function of Digital Information Compression Mechanisms in the Brain and in Digital Television Technology | journal = Front Syst Neurosci | volume = 10 | pages = 40 | date = 2016 | pmid = 27199688 | pmc = 4858531 | doi = 10.3389/fnsys.2016.00040  | doi-access = free }}</ref>
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==
[[File:Acetylcholine Pathway.png|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 [[Cognition|cognitive]] functions of those target areas. In the PNS, acetylcholine activates muscles and is a major neurotransmitter in the autonomic nervous system.<ref>{{cite book | vauthors = Waxenbaum JA, Reddy V, Varacallo M | chapter = Anatomy, Autonomic Nervous System |date=2023 | chapter-url=https://www.ncbi.nlm.nih.gov/books/NBK539845/ | title = StatPearls |access-date=6 April 2023 |place=Treasure Island (FL) |publisher=StatPearls Publishing |pmid=30969667 }}</ref><ref name= "Sam_2023" />

===Cellular effects===
{{Main|Acetylcholine receptor}}

[[File:Cholinergic synapse.svg|class=skin-invert-image|thumb|right|Acetylcholine processing in a synapse. After release acetylcholine is broken down by the enzyme [[acetylcholinesterase]].]]
Like many other biologically active substances, acetylcholine exerts its effects by binding to and activating [[receptor (biochemistry)|receptors]] located on the surface of cells. There are two main classes of acetylcholine receptor, [[nicotinic acetylcholine receptor|nicotinic]] and [[muscarinic acetylcholine receptor|muscarinic]]. They are named for chemicals that can selectively activate each type of receptor without activating the other: [[muscarine]] is a compound found in the mushroom ''[[Amanita muscaria]]''; [[nicotine]] is found in tobacco.

[[Nicotinic acetylcholine receptor]]s are [[ligand-gated ion channel]]s permeable to [[sodium]], [[potassium]], and [[calcium]] ions. In other words, they are ion channels embedded in cell membranes, capable of switching from a closed to an open state when acetylcholine binds to them; in the open state they allow ions to pass through. Nicotinic receptors come in two main types, known as muscle-type and neuronal-type. The muscle-type can be selectively blocked by [[curare]], the neuronal-type by [[hexamethonium]]. The main location of muscle-type receptors is on muscle cells, as described in more detail below. Neuronal-type receptors are located in autonomic ganglia (both sympathetic and parasympathetic), and in the central nervous system.

[[Muscarinic acetylcholine receptor]]s have a more complex mechanism, and affect target cells over a longer time frame. In mammals, five subtypes of muscarinic receptors have been identified, labeled M1 through M5. All of them function as [[G protein-coupled receptor]]s, meaning that they exert their effects via a [[second messenger system]]. The M1, M3, and M5 subtypes are [[Gq alpha subunit|G<sub>q</sub>]]-coupled; they increase intracellular levels of [[inositol trisphosphate|IP<sub>3</sub>]] and [[calcium]] by activating [[phospholipase C]]. Their effect on target cells is usually excitatory. The M2 and M4 subtypes are [[Gi alpha subunit|G<sub>i</sub>/G<sub>o</sub>]]-coupled; they decrease intracellular levels of [[cyclic adenosine monophosphate|cAMP]] by inhibiting [[adenylate cyclase]]. Their effect on target cells is usually inhibitory. Muscarinic acetylcholine receptors are found in both the central nervous system and the peripheral nervous system of the heart, lungs, upper gastrointestinal tract, and sweat glands.

===Neuromuscular junction===
[[File:The Muscle Contraction Process.png|thumb|400px|Muscles contract when they receive signals from motor neurons. The neuromuscular junction is the site of the signal exchange. The steps of this process in vertebrates occur as follows: (1) The action potential reaches the axon terminal. (2) Calcium ions flow into the axon terminal. (3) Acetylcholine is released into the [[synaptic cleft]]. (4) Acetylcholine binds to postsynaptic receptors. (5) This binding causes ion channels to open and allows sodium ions to flow into the muscle cell. (6) The flow of sodium ions across the membrane into the muscle cell generates an action potential which induces muscle contraction. Labels: A: Motor neuron axon B: Axon terminal C: Synaptic cleft D: Muscle cell E: Part of a Myofibril]]
{{main|Neuromuscular junction}}
Acetylcholine is the substance the nervous system uses to activate [[skeletal muscle]]s, a kind of striated muscle. These are the muscles used for all types of voluntary movement, in contrast to [[smooth muscle tissue]], which is involved in a range of involuntary activities such as movement of food through the gastrointestinal tract and constriction of blood vessels. Skeletal muscles are directly controlled by [[motor neuron]]s located in the [[spinal cord]] or, in a few cases, the [[brainstem]]. These motor neurons send their [[axons]] through [[motor nerve]]s, from which they emerge to connect to muscle fibers at a special type of [[chemical synapse|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 acetylcholine to be released into the space between the presynaptic terminal and the muscle fiber. The acetylcholine molecules then bind to nicotinic ion-channel receptors on the muscle cell membrane, causing the ion channels to open. Sodium ions then flow into the muscle cell, initiating a sequence of steps that finally produce [[muscle contraction]].

Factors that decrease release of acetylcholine (and thereby affecting [[P-type calcium channel]]s):<ref name="Miller">{{cite book|veditors = Miller RD, Eriksson LI, Fleisher LA, Wiener-Kronish JP, Young WL|title=Miller's Anesthesia| edition = 7th |date=1 January 2009|publisher=Elsevier Health Sciences|isbn=978-0-443-06959-8|pages=343–47}}</ref>

# [[Antibiotics]] ([[clindamycin]], [[polymyxin]])
# Magnesium:&nbsp;antagonizes P-type calcium channels
# [[Hypocalcemia]]
# [[Anticonvulsant]]s
# [[Diuretic]]s ([[furosemide]])
# [[Eaton-Lambert syndrome]]: inhibits P-type calcium channels
# [[Myasthenia gravis]]
# [[Botulinum toxin]]: inhibits SNARE proteins

[[Calcium channel blocker]]s (nifedipine, diltiazem) do not affect P-channels. These drugs affect [[L-type calcium channel]]s.

===Autonomic nervous system===

[[File:1503 Connections of the Parasympathetic Nervous System.jpg|thumb|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 response|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 (blood)|serum]] exerts a direct effect on [[vascular tone]] by binding to [[Muscarinic acetylcholine receptor|muscarinic receptor]]s present on vascular [[endothelium]]. These cells respond by increasing production of [[nitric oxide]], which signals the surrounding smooth muscle to relax, leading to [[vasodilation]].<ref name="pmid15649880">{{cite journal | vauthors = Kellogg DL, Zhao JL, Coey U, Green JV | title = Acetylcholine-induced vasodilation is mediated by nitric oxide and prostaglandins in human skin | journal = J. Appl. Physiol. | volume = 98 | issue = 2 | pages = 629–32 | date = February 2005 | pmid = 15649880 | doi = 10.1152/japplphysiol.00728.2004 | s2cid = 293055 }}</ref>

===Central nervous system===
[[File:Nucleus basalis of Meynert - intermed mag.jpg|thumb|right|[[Micrograph]] of the [[nucleus basalis]] (of Meynert), which produces acetylcholine in the CNS. [[LFB stain|LFB-HE stain]].]]
In the central nervous system, ACh has a variety of effects on plasticity, arousal and [[reward system|reward]]. ACh has an important role in the enhancement of alertness when we wake up,<ref name="pmid16183137">{{cite journal | vauthors = [[Barbara E. Jones|Jones BE]] | title = From waking to sleeping: neuronal and chemical substrates | journal = Trends Pharmacol. Sci. | volume = 26 | issue = 11 | pages = 578–86 | date = November 2005 | pmid = 16183137 | doi = 10.1016/j.tips.2005.09.009 }}</ref> in sustaining attention <ref name="pmid10808142">{{cite journal | vauthors = Himmelheber AM, Sarter M, Bruno JP | title = Increases in cortical acetylcholine release during sustained attention performance in rats | journal = Brain Res Cogn Brain Res | volume = 9 | issue = 3 | pages = 313–25 | date = June 2000 | pmid = 10808142 | doi = 10.1016/S0926-6410(00)00012-4 }}</ref> and in learning and [[memory]].<ref name="pmid6431311">{{cite journal | vauthors = Ridley RM, Bowes PM, Baker HF, Crow TJ | title = An involvement of acetylcholine in object discrimination learning and memory in the marmoset | journal = Neuropsychologia | volume = 22 | issue = 3 | pages = 253–63 | date = 1984 | pmid = 6431311 | doi = 10.1016/0028-3932(84)90073-3  | s2cid = 7110504 }}</ref>

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]].<ref name="pmid10071091">{{cite journal | vauthors = Francis PT, Palmer AM, Snape M, Wilcock GK | title = The cholinergic hypothesis of Alzheimer's disease: a review of progress | journal = J. Neurol. Neurosurg. Psychiatry | volume = 66 | issue = 2 | pages = 137–47 | date = February 1999 | pmid = 10071091 | pmc = 1736202 | doi = 10.1136/jnnp.66.2.137  }}</ref> ACh has also been shown to promote [[Rapid eye movement sleep|REM]] sleep.<ref name="pmid21238497">{{cite journal | vauthors = Platt B, Riedel G | title = The cholinergic system, EEG and sleep | journal = Behav. Brain Res. | volume = 221 | issue = 2 | pages = 499–504 | date = August 2011 | pmid = 21238497 | doi = 10.1016/j.bbr.2011.01.017  | s2cid = 25323695 }}</ref>

In the brainstem acetylcholine originates from the [[Pedunculopontine nucleus]] and [[laterodorsal tegmental nucleus]] collectively known as the meso[[pontine tegmentum]] area or pontomesencephalotegmental complex.<ref name="Woolf">{{cite journal | vauthors = Woolf NJ, Butcher LL | title = Cholinergic systems in the rat brain: III. Projections from the pontomesencephalic tegmentum to the thalamus, tectum, basal ganglia, and basal forebrain | journal = Brain Res. Bull. | volume = 16 | issue = 5 | pages = 603–37 | date = May 1986 | pmid = 3742247 | doi = 10.1016/0361-9230(86)90134-6 | s2cid = 39665815 }}</ref><ref name="Woolf89">{{cite journal | vauthors = Woolf NJ, Butcher LL | title = Cholinergic systems in the rat brain: IV. Descending projections of the pontomesencephalic tegmentum | journal = Brain Res. Bull. | volume = 23 | issue = 6 | pages = 519–40 | date = December 1989 | pmid = 2611694 | doi = 10.1016/0361-9230(89)90197-4 | s2cid = 4721282 }}</ref> In the basal forebrain, it originates from the [[basal optic nucleus of Meynert|basal nucleus of Meynert]] and medial [[septal nucleus]]:
* The ''pontomesencephalotegmental complex'' acts mainly on [[M1 receptor]]s in the [[brainstem]], deep [[cerebellar nuclei]], [[pontine nuclei]], [[locus coeruleus]], [[raphe nucleus]], [[lateral reticular nucleus]] and [[inferior olive]].<ref name="Woolf89"/> It also projects to the [[thalamus]], [[tectum]], [[basal ganglia]] and [[basal forebrain]].<ref name="Woolf"/>
* [[Basal optic nucleus of Meynert|Basal nucleus of Meynert]] acts mainly on [[M1 receptor]]s in the [[neocortex]].
* Medial [[septal nucleus]] acts mainly on [[M1 receptor]]s in the [[hippocampus]] and parts of the [[cerebral cortex]].

In addition, ACh acts as an important internal transmitter in the [[striatum]], which is part of the [[basal ganglia]]. It is released by cholinergic [[interneurons]]. In humans, non-human primates and rodents, these interneurons respond to salient environmental stimuli with responses that are temporally aligned with the responses of dopaminergic neurons of the [[substantia nigra]].<ref name="pmid21925242">{{cite journal | vauthors = Goldberg JA, Reynolds JN | title = Spontaneous firing and evoked pauses in the tonically active cholinergic interneurons of the striatum | journal = Neuroscience | volume = 198 | pages = 27–43 | date = December 2011 | pmid = 21925242 | doi = 10.1016/j.neuroscience.2011.08.067  | s2cid = 21908514 }}</ref><ref name="pmid15233923">{{cite journal | vauthors = Morris G, Arkadir D, Nevet A, Vaadia E, Bergman H | title = Coincident but distinct messages of midbrain dopamine and striatal tonically active neurons | journal = Neuron | volume = 43 | issue = 1 | pages = 133–43 | date = July 2004 | pmid = 15233923 | doi = 10.1016/j.neuron.2004.06.012 |doi-access=free }}</ref>

====Memory====
Acetylcholine has been implicated in [[learning]] and [[memory]] in several ways. The anticholinergic drug [[scopolamine]] impairs acquisition of new information in humans<ref name="pmid4793334">{{cite journal | vauthors = Crow TJ, Grove-White IG | title = An analysis of the learning deficit following hyoscine administration to man | journal = Br. J. Pharmacol. | volume = 49 | issue = 2 | pages = 322–7 | date = October 1973 | pmid = 4793334 | pmc = 1776392 | doi = 10.1111/j.1476-5381.1973.tb08379.x  }}</ref> and animals.<ref name="pmid6431311"/> In animals, disruption of the supply of acetylcholine to the [[neocortex]] impairs the learning of simple discrimination tasks, comparable to the acquisition of factual information<ref name="pmid3087582">{{cite journal | vauthors = Ridley RM, Murray TK, Johnson JA, Baker HF | title = Learning impairment following lesion of the basal nucleus of Meynert in the marmoset: modification by cholinergic drugs | journal = Brain Res. | volume = 376 | issue = 1 | pages = 108–16 | date = June 1986 | pmid = 3087582 | doi = 10.1016/0006-8993(86)90904-2  | s2cid = 29182517 }}</ref> and disruption of the supply of acetylcholine to the [[hippocampus]] and adjacent cortical areas produces forgetfulness, comparable to [[anterograde amnesia]] in humans.<ref name="pmid12050084">{{cite journal | vauthors = Easton A, Ridley RM, Baker HF, Gaffan D | title = Unilateral lesions of the cholinergic basal forebrain and fornix in one hemisphere and inferior temporal cortex in the opposite hemisphere produce severe learning impairments in rhesus monkeys | journal = Cereb. Cortex | volume = 12 | issue = 7 | pages = 729–36 | date = July 2002 | pmid = 12050084 | doi = 10.1093/cercor/12.7.729 | doi-access = free }}</ref>

==Diseases and disorders==

===Myasthenia gravis===

The disease [[myasthenia gravis]], characterized by muscle weakness and fatigue, occurs when the body inappropriately produces [[antibody|antibodies]] against acetylcholine nicotinic receptors, and thus inhibits proper acetylcholine signal transmission.<ref name="Pasnoor_2024">{{cite book | vauthors = Pasnoor M, Wolfe GI, Barohn RJ | title = Neurologic Channelopathies | chapter = Myasthenia gravis | series = Handbook of Clinical Neurology | volume = 203 | pages = 185–203 | date = 2024 | pmid = 39174248 | doi = 10.1016/B978-0-323-90820-7.00006-9 | isbn = 978-0-323-90820-7 }}</ref> 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.<ref name="Crisafulli_2024">{{cite journal | vauthors = Crisafulli S, Boccanegra B, Carollo M, Bottani E, Mantuano P, Trifirò G, De Luca A | title = Myasthenia Gravis Treatment: From Old Drugs to Innovative Therapies with a Glimpse into the Future | journal = CNS Drugs | volume = 38 | issue = 1 | pages = 15–32 | date = January 2024 | pmid = 38212553 | doi = 10.1007/s40263-023-01059-8 | hdl = 11586/461741 | hdl-access = free }}</ref> 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).

==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===
{{main|Nicotinic receptor}}
Nicotine binds to and activates [[nicotinic acetylcholine receptor]]s, 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. [[Curare]]s are arrow poisons, which act at nicotinic receptors and have been used to develop clinically useful therapies.

===Muscarinic receptors===
{{main|Muscarinic receptor}}
Muscarinic receptors form '''[[G protein-coupled receptor]]''' complexes in the [[cell membrane]]s of [[neuron]]s and other cells. [[Atropine]] is a non-selective competitive antagonist with Acetylcholine at muscarinic receptors.

===Cholinesterase inhibitors===
{{Main|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 agent]]s ([[Sarin]] and [[VX (nerve agent)|VX]] nerve gas) or [[pesticide]]s ([[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{{why?|date=July 2023}} to reverse the action of [[muscle relaxant]]s, to treat [[myasthenia gravis]], and to treat symptoms of [[Alzheimer's disease]] ([[rivastigmine]], which increases cholinergic activity in the brain).

===Synthesis inhibitors===
Organic [[Mercury (element)|mercurial]] compounds, such as [[methylmercury]], have a high affinity for [[thiol|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 [[latrodectus|black widow spider]] ([[alpha-latrotoxin]]) has the reverse effect. ACh inhibition causes [[paralysis]]. When bitten by a [[latrodectus|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.<ref>{{cite journal | vauthors = Colleoni A, Galli G, Dallanoce C, De Amici M, Gorostiza P, Matera C | title = Light-Activated Pharmacological Tools for Exploring the Cholinergic System | journal = Medicinal Research Reviews | volume = 45 | issue = 4 | pages = 1251–1274 | date = July 2025 | pmid = 40123150 | pmc = 12131668 | doi = 10.1002/med.22108 }}</ref>

== 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{{Citation needed|date=October 2019}} for synthesizing cell membrane phospholipids.<ref name="pmid20001397">{{cite journal | vauthors = Dean B | title = Evolution of the human CNS cholineric system: has this resulted in the emergence of psychiatric disease? | journal = Aust N Z J Psychiatry | volume = 43 | issue = 11 | pages = 1016–28 | date = November 2009 | pmid = 20001397 | doi = 10.3109/00048670903270431 | s2cid = 31059344 }}</ref> 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 acetylcholine receptor|nicotinic receptor family]] dates back longer than 2.5 billion years.<ref name="pmid20001397"/> Likewise, muscarinic receptors are thought to have diverged from other GPCRs at least 0.5 billion years ago. Both of these receptor groups have evolved numerous subtypes with unique ligand affinities and signaling mechanisms. The diversity of the receptor types enables acetylcholine to create varying responses depending on which receptor types are activated, and allow for acetylcholine to dynamically regulate physiological processes. ACh receptors are related to [[5-HT3 receptor|5-HT3]] ([[serotonin]]), [[Gamma-Aminobutyric acid|GABA]], and [[Glycine receptor]]s, both in sequence and structure, strongly suggesting that they have a common evolutionary origin.<ref>{{cite journal | vauthors = Ortells MO, Lunt GG | title = Evolutionary history of the ligand-gated ion-channel superfamily of receptors | journal = Trends in Neurosciences | volume = 18 | issue = 3 | pages = 121–127 | date = March 1995 | pmid = 7754520 | doi = 10.1016/0166-2236(95)93887-4 | s2cid = 18062185 }}</ref>

==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.<ref name=b>{{Cite journal|vauthors=Baeyer A|date=1867|title=I. Üeber das neurin|journal=Justus Liebigs Ann Chem|language=de|volume=142|issue=3|pages=322–326|doi=10.1002/jlac.18671420311|url=https://zenodo.org/record/2483316}}</ref><ref name=c>{{cite journal|vauthors=Kawashima K, Fujii T, Moriwaki Y, Misawa H, Horiguchi K|title=Non-neuronal cholinergic system in regulation of immune function with a focus on α7 nAChRs|journal=International Immunopharmacology|volume=29|issue=1|pages=127–34|date=2015|pmid=25907239|doi=10.1016/j.intimp.2015.04.015|doi-access=free}}</ref> 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.<ref>{{Cite journal|vauthors=Hunt R, Taveau M|date=1906|title=On the physiological action of certain choline derivatives and new methods for detecting choline|journal=BMJ|volume=2|pages=1788–1791}}</ref><ref name=c/><ref>{{cite journal|vauthors=Dorkins HR|title=Suxamethonium-the development of a modern drug from 1906 to the present day|journal=Medical History|volume=26|issue=2|pages=145–68|date=April 1982|pmid=7047939|pmc=1139149|doi=10.1017/s0025727300041132 }}</ref> This was after [[Frederick Walker Mott]] and [[William Dobinson Halliburton]] noted in 1899 that choline injections decreased the blood pressure of animals.<ref>{{Cite journal|vauthors=Mott FW, Halliburton WD|date=1899|title=VII. The physiological action of choline and neurine|journal=Philosophical Transactions of the Royal Society of London. Series B, Containing Papers of a Biological Character|volume=191|issue=2001|pages=211–267|doi=10.1098/rstb.1899.0007|pmid=20758460|pmc=2463419|doi-access=free}}</ref><ref name=c/>

In 1914, Arthur J. Ewins was the first to extract acetylcholine from nature. He identified it as the blood pressure-decreasing contaminant from some ''[[Claviceps purpurea]]'' [[ergot]] extracts, by the request of [[Henry Hallett Dale]].<ref name=c/> Later in 1914, Dale outlined the effects of acetylcholine at various types of peripheral synapses and also noted that it lowered the blood pressure of cats via [[subcutaneous injection]]s even at doses of one [[nanogram]].<ref name=a>{{Cite journal|vauthors=Dale HH|date=1914|title=The action of certain esters and ethers of choline, and their relation to muscarine|url=http://jpet.aspetjournals.org/content/6/2/147|journal=J Pharmacol Exp Ther|volume=6|issue=2|pages=147–190|doi=10.1016/S0022-3565(25)08268-0 |url-access=subscription}}</ref><ref name=c/>

The concept of [[neurotransmitter]]s was unknown until 1921, when [[Otto Loewi]] noted that the [[vagus nerve]] secreted a substance that inhibited the [[heart muscle]] whilst working as a professor in the [[University of Graz]]. He named it ''[[vagusstoff]]'' ("vagus substance"), noted it to be a [[structural analog]] of choline and suspected it to be acetylcholine.<ref>{{Cite journal|vauthors=Loewi O|date=1922|title=Über humorale übertragbarkeit der herznervenwirkung|journal=Pflug Arch Ges Phys|language=de|volume=193|issue=1|pages=201–213|doi=10.1007/BF02331588|s2cid=34861770}}</ref><ref name="his"/> In 1926, Loewi and E. Navratil deduced that the compound is probably acetylcholine, as vagusstoff and synthetic acetylcholine lost their activity in a similar manner when in contact with tissue [[lysate]]s that contained acetylcholine-degrading enzymes (now known to be [[cholinesterase]]s).<ref>{{Cite journal|vauthors=Loewi O, Navratil E|date=1926|title=Über humorale übertragbarkeit der herznervenwirkung|journal=Pflug Arch Ges Phys|language=de|volume=214|issue=1|pages=678–688|doi=10.1007/BF01741946|s2cid=43748121}}</ref><ref name="d">{{cite journal|vauthors=Zimmer HG|title=Otto Loewi and the chemical transmission of vagus stimulation in the heart|journal=Clinical Cardiology|volume=29|issue=3|pages=135–6|date=March 2006|pmid=16596840|pmc=6654523|doi=10.1002/clc.4960290313 }}</ref> This conclusion was accepted widely. Later studies confirmed the function of acetylcholine as a [[neurotransmitter]].<ref name="his">{{cite journal|vauthors=Zeisel SH|title=A brief history of choline|journal=Annals of Nutrition & Metabolism|volume=61|issue=3|pages=254–8|date=2012|pmid=23183298|pmc=4422379|doi=10.1159/000343120}}</ref>

In 1936, H. H. Dale and O. Loewi shared the [[Nobel Prize in Physiology or Medicine]] for their studies of acetylcholine and nerve impulses.<ref name=c/>

== References ==
{{Reflist}}

== Further reading ==
{{refbegin}}
* {{cite book | vauthors = Brenner GM, Stevens CW |title=Pharmacology |publisher=W. B. Saunders |location=Philadelphia PA |year=2006 |isbn=1-4160-2984-2 |edition=2nd |url-access=registration |url=https://archive.org/details/pharmacology0000bren }}
* {{cite book |author =Canadian Pharmacists Association |title=Compendium of Pharmaceuticals and Specialties |publisher=Webcom |location=Toronto ON |year=2000 |isbn=0-919115-76-4 |edition=25th}}
* {{cite book | vauthors = Carlson NR |title=Physiology of Behavior |publisher=Allyn and Bacon |location=Needham Heights MA |year=2001 |isbn=0-205-30840-6 |edition=7th}}
* {{cite book | vauthors = Gershon MD |title=The Second Brain |publisher=HarperCollins |location=New York NY |year=1998 |isbn=0-06-018252-0 |url-access=registration |url=https://archive.org/details/secondbrainscien00gers }}
* {{cite book | vauthors = Siegal A, Sapru HN |title=Essential Neuroscience | chapter-url = https://archive.org/details/essentialneurosc0000sieg | chapter-url-access = registration |publisher=Lippincott, Williams & Wilkins |location=Philadelphia |year=2006 |pages=[https://archive.org/details/essentialneurosc0000sieg/page/255 255–267] |edition=Revised 1st |chapter=Ch. 15}}
* {{cite journal | vauthors = Hasselmo ME |author-link=Michael Hasselmo |title=Neuromodulation and cortical function: modeling the physiological basis of behavior |journal=Behav. Brain Res. |volume=67 |issue=1 |pages=1–27 |date=February 1995 |pmid=7748496 |doi=10.1016/0166-4328(94)00113-T|s2cid=17594590 }} [http://people.bu.edu/hasselmo/HasselmoBBR1995.pdf as PDF]
* {{cite journal | vauthors = Yu AJ, Dayan P | title = Uncertainty, neuromodulation, and attention | journal = Neuron | volume = 46 | issue = 4 | pages = 681–92 | date = May 2005 | pmid = 15944135 | doi = 10.1016/j.neuron.2005.04.026 | s2cid = 15980355 | author-link2 = Peter Dayan | doi-access = free }} [http://www.gatsby.ucl.ac.uk/~dayan/papers/yud2005.pdf as PDF]
{{refend}}

==External links==
{{Wikiquote}}
* [https://www.bbc.co.uk/news/health-13880553 Warning over combining common medicines for elderly]

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