View source for Acetylcholine

{{Infobox neurotransmitter
|name = Acetylcholine
|abbrev = ACh
|img = ACh.png
|sources = many
|targets = many
|receptors = nicotinic; muscarinic
|agonists = [[nicotine]], [[physostigmine]]
|antagonists = [[curare]], [[atropine]]
|precursor = [[choline]]
|synth = [[Choline acetyltransferase]] (ChAT)
|breakdown = [[Acetylcholinesterase]] (AChE)
|footnotes = 
}}
The [[chemical compound]] '''acetylcholine''' (often abbreviated '''ACh''') is a [[neurotransmitter]] in both the [[peripheral nervous system]] (PNS) and [[central nervous system]] (CNS) in many organisms including [[homo sapiens|humans]]. Acetylcholine is one of many neurotransmitters in the [[autonomic nervous system]] (ANS) and the only neurotransmitter used in the [[somatic nervous system]]. It is also the neurotransmitter in all [[autonomic ganglia]].

==History==
Acetylcholine (ACh) was first identified in 1914 by [[Henry Hallett Dale]] for 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]]. Both received the 1936 [[Nobel Prize in Physiology or Medicine]] for their work. Acetylcholine was also the first [[neurotransmitter]] to be identified.

==Chemistry==
Acetylcholine is an [[ester]] of [[acetic acid]] and [[choline]] with [[chemical formula]] [[acetyl|CH<sub><small>3</small></sub>CO]][[oxygen|O]][[methylene|CH<sub><small>2</small></sub>]][[methylene|CH<sub><small>2</small></sub>]][[Nitrogen|N]]<sup><small>+</small></sup>([[methyl|CH<sub><small>3</small></sub>]])<sub><small>3</small></sub>. This structure is reflected in the systematic name, ''2-acetoxy-N,N,N-trimethylethanaminium''.

==Function==
Acetylcholine has functions both in the [[peripheral nervous system]] (PNS) and in the [[central nervous system]] (CNS) as a [[neuromodulator]].

In the PNS, acetylcholine activates muscles, and is a major neurotransmitter in the autonomic nervous system.

In the CNS, acetylcholine and the associated neurons form a [[neurotransmitter system]], the cholinergic system, which tends to cause excitatory actions. 

===In PNS===
In the [[peripheral nervous system]], acetylcholine activates muscles, and is a major neurotransmitter in the autonomic nervous system.
.
When acetylcholine binds to [[acetylcholine receptor]]s on [[skeletal muscle]] fibers, it opens [[ligand gated sodium channels]] in the [[cell membrane]]. Sodium ions then enter the muscle cell, stimulating muscle contraction. Acetylcholine, while inducing contraction of skeletal muscles, instead induces decreased contraction in [[cardiac muscle]] fibers. This distinction is attributed to differences in receptor structure between skeletal and cardiac fibers.

In the [[autonomic nervous system]], acetylcholine is released in the following sites:
*all pre- and post-ganglionic [[parasympathetic nervous system|parasympathetic]] neurons
*all preganglionic [[sympathetic nervous system|sympathetic]] neurons
**preganglionic sympathetic fibers to suprarenal medulla, the modified sympathetic ganglion; on stimulation by acetylcholine, the suprarenal medulla releases [[epinephrine]] and [[norepinephrine]]
*some postganglionic sympathetic fibers
**sudomotor neurons to [[sweat gland]]s.

===In CNS===
In the central nervous system, ACh has a variety of effects as a [[neuromodulator]], e.g., for plasticity and [[excitability]]. Other effects are arousal and [[reward system|reward]]. Damage to the cholinergic system in the brain has been suggested to play a role in the memory deficits associated with [[Alzheimer's Disease]].

====Structure====
Acetylcholine and the associated neurons form a [[neurotransmitter system]], the cholinergic system. It originates mainly in ''pontomesencephalotegmental complex'', [[basal optic nucleus of Meynert]] and medial [[septal nucleus]], and projects axons to vast areas of the brain:
* The ''pontomesencephalotegmental complex'' acts mainly on [[M1 receptor]]s in the [[brainstem]] .
*[[Basal optic 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 [[neocortex]].

====Plasticity====
ACh is involved with [[synaptic plasticity]], specifically in [[learning]] and [[Memory#Short-term|short-term memory]].

Acetylcholine has been shown to enhance the amplitude of synaptic potentials following [[long-term potentiation]] in many regions, including the [[dentate gyrus]], [[CA1]], [[piriform cortex]], and [[neocortex]]. This effect most likely occurs either through enhancing currents through [[NMDA]] receptors or indirectly by suppressing [[neural adaptation|adaptation]]. The suppression of adaptation has been shown in brain slices of regions CA1, [[cingulate cortex]], and piriform cortex, as well as [[in vivo]] in cat [[somatosensory cortex|somatosensory]] and [[motor cortex]] by decreasing the conductance of voltage-dependent [[M current]]s and [[calcium|Ca<sup>2+</sup>]]-dependent [[potassium|K<sup>+</sup>]] currents.  

====Excitability====
Acetylcholine also has other effects on excitability of neurons. Its presence causes a slow [[depolarization]]{{Fact|date=September 2008}} by blocking a tonically-active K<sup>+</sup> current, which increases neuronal excitability. It appears to be a paradox, however, that ACh increases spiking activity in [[inhibitory interneuron]]s{{Fact|date=September 2008}} while decreasing strength of synaptic transmission from those cells. This decrease in synaptic transmission also occurs selectively at some excitatory cells{{Fact|date=September 2008}}: For instance, it has an effect on intrinsic and associational fibers in layer Ib of piriform cortex, but has no effect on afferent fibers in layer Ia. Similar laminar selectivity has been shown{{fact}} in dentate gyrus and region CA1 of the hippocampus. One theory{{Fact|date=September 2008}} to explain this paradox interprets acetylcholine neuromodulation in the neocortex as modulating the estimate of expected uncertainty, acting counter to [[norepinephrine]] (NE) signals for unexpected uncertainty. Both would then decrease synaptic transition strength, but ACh would then be needed to counter the effects of NE in learning, a signal understood to be 'noisy'.

==Synthesis and Degradation==
Acetylcholine is synthesized in certain [[neuron]]s by the [[enzyme]] [[choline acetyltransferase]] from the compounds [[choline]] and [[acetyl-CoA]].

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]], thus causing paralysis of the muscles needed for breathing and stopping the beating of the heart.

==Receptors==
{{Main|Acetylcholine receptor}}
There are two main classes of acetylcholine receptor (AChR), [[nicotinic acetylcholine receptor]]s (nAChR) and [[muscarinic acetylcholine receptor]]s (mAChR).  They are named for the [[ligands]] used to activate the receptors. 

=====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. Over time, the motor end plate is destroyed. Drugs that competitively inhibit acetylcholinesterase (e.g., neostigmine, physostigmine, or primarily mestinon) are effective in treating this disorder. They allow endogenously-released acetylcholine more time to interact with its respective receptor before being inactivated by acetylcholinesterase in the gap junction.

===Nicotinic===
Nicotinic AChRs are [[Ligand-gated ion channel|ionotropic receptors]] permeable to [[sodium]], [[potassium]], and [[chloride]] ions. They are stimulated by [[nicotine]] and acetylcholine. They are of two main types, muscle type and neuronal type. The former can be selectively blocked by [[curare]] and the latter by [[hexamethonium]]. The main location of nicotinic AChRs is on [[muscle]] end plates, autonomic ganglia (both sympathetic and parasympathetic), and in the CNS.<ref> Katzung, B.G. (2003). ''Basic and Clinical Pharmacology (9th ed.).'' McGraw-Hill Medical. ISBN 0-07-141092-9</ref>

===Muscarinic===
Muscarinic receptors are [[metabotropic]], and affect neurons over a longer time frame. They are stimulated by [[muscarine]] and acetylcholine, and blocked by [[atropine]].  Muscarinic receptors are found in both the central nervous system and the peripheral nervous system, in heart, lungs, upper GI tract and sweat glands. Extracts from the plant [[Deadly nightshade]] included this compound (atropine), and the blocking of the muscarinic AChRs increases pupil size as used for attractiveness in many European cultures in the past. Now, ACh is sometimes used during [[cataract]] surgery to produce rapid constriction of the pupil. It must be administered intraocularly because [[cornea]]l [[cholinesterase]] metabolizes topically-administered ACh before it can diffuse into the eye. It is sold by the trade name Miochol-E (CIBA Vision). Similar drugs are used to induce [[mydriasis]] (dilation of the pupil) in [[cardiopulmonary resuscitation]] and many other situations.

==Drugs Acting on the ACh System== 
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.

=== ACh Receptor Agonists ===
Acetylcholine receptor agonists 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.

====Associated disorders====
ACh Receptor Agonists are used to treat [[myasthenia gravis]] and [[Alzheimer's disease]].

=====Alzheimer's disease=====
Since a shortage of acetylcholine in the [[brain]] has been associated with [[Alzheimer's disease]], some drugs that inhibit acetylcholinesterase are used in the treatment of that disease.

====Direct Acting====
* Acetylcholine
* [[Bethanechol]]
* [[Carbachol]]
* [[Cevimeline]]
* [[Pilocarpine]]
* [[Suberylcholine]]
* [[Nicotine]] (in small doses)

====Cholinesterase inhibitors====
{{main|Cholinesterase inhibitors}}
Most indirect acting ACh receptor agonists work by inhibiting the enzyme [[acetylcholinesterase]]. The resulting accumulation of acetylcholine causes continuous stimulation of the muscles, glands, and central nervous system.

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]]). In clinical use, they are administered 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).

=====Reversible=====
The following substances reversibly inhibit the enzyme [[acetylcholinesterase]] (which breaks down acetylcholine), thereby increasing acetylcholine levels.
* Many medications in [[Alzheimer's disease]]
** [[Donepezil]] 
** [[Galantamine]]
** [[Rivastigmine]]
** [[Tacrine]]
** [[THC]]
* [[Edrophonium]] (differs [[myasthenic crisis|myasthenic]] and [[cholinergic crisis]])
* [[Neostigmine]] (in [[myasthenia gravis]])
* [[Physostigmine]] (in [[glaucoma]] and [[anticholinergic]] drug overdoses)
* [[Pyridostigmine]] (in [[myasthenia gravis]]
* [[Carbamate]] [[insecticides]] (e.g., [[Aldicarb]])
* [[Huperzine A]]

=====Irreversible=====
Semi-permanently inhibit the enzyme acetylcholinesterase.
* [[Echothiophate]]
* [[Isofluorophate]]
* [[Organophosphate]] [[Insecticides]] ([[Malathion]], [[Parathion]], [[Azinphos methyl]], [[Chlorpyrifos]], among others)
* Organophosphate-containing [[nerve agents]] (e.g., [[Sarin]], [[VX (nerve agent)|VX]])

Victims of organophosphate-containing nerve agents commonly die of suffocation as they cannot relax their [[Thoracic diaphragm|diaphragm]].

====Reactivation of Acetylcholine Esterase====
* [[Pralidoxime]]

=== ACh Receptor Antagonists ===
====Antimuscarinic Agents====
* [[Atropine]]
* [[Ipratropium]]
* [[Scopolamine]]
* [[Tiotropium]]

====Ganglionic Blockers====
* [[Mecamylamine]]
* [[Hexamethonium]]
* [[Nicotine]] (in high doses)
* [[Trimethaphan]]

====Neuromuscular Blockers====
* [[Atracurium]]
* [[Cisatracurium]]
* [[Doxacurium]]
* [[Metocurine]]
* [[Mivacurium]]
* [[Pancuronium]]
* [[Rocuronium]]
* [[Succinylcholine]]
* [[Tubocurarine]]
* [[Vecuronium]]
* [[HemiCholine]]
dupogimine

====Synthesis inhibitors====
Organic [[Mercury (element)|mercurial]] compounds 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====
[[Botulism toxin|Botulin]] acts by suppressing the release of acetylcholine; where the venom from a [[black widow spider]] ([[alpha-latrotoxin]]) has the reverse effect.

====Other / Uncategorized / Unknown====
* [[surugatoxin]]
* [[suxamethonium]]

==References==
{{reflist}}

{{refbegin}}
*Brenner, G. M. and Stevens, C. W. (2006). ''Pharmacology (2nd ed.).'' Philadelphia, PA: W.B. Saunders Company (Elsevier). ISBN 1-4160-2984-2
*Canadian Pharmacists Association (2000). ''Compendium of Pharmaceuticals and Specialties (25th ed.)''. Toronto, ON: Webcom. ISBN 0-919115-76-4
*Carlson, NR (2001). ''Physiology of Behavior (7th ed.)''. Needham Heights, MA: Allyn and Bacon. ISBN 0-205-30840-6
*Gershon, Michael D. (1998). ''The Second Brain''.  New York, NY: HarperCollins. ISBN 0-06-018252-0
*Hasselmo, ME. [http://people.bu.edu/hasselmo/HasselmoBBR1995.pdf "Neuromodulation and cortical function: Modeling the physiological basis of behavior."] ''Behavioral Brain Research''. 1995 Feb; 67(1):1-27. PMID 7748496
*Yu, AJ & [[Peter Dayan|Dayan, P]]. [http://www.gatsby.ucl.ac.uk/~dayan/papers/yud2005.pdf "Uncertainty, neuromodulation, and attention."] ''Neuron''. 2005 May 19; 46(4):681-92. PMID 15944135
{{refend}}

==External links==
* [http://www.neuro.wustl.edu/neuromuscular/mother/acetylcholine.htm Washington University (St. Louis) writeup]

{{Neurotransmitter systems}}
{{Antiglaucoma preparations and miotics}}

[[Category:Choline esters]]
[[Category:Acetates]]
[[Category:Neurotransmitters]]
[[Category:Quaternary ammonium compounds]]

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