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Acetylcholine

(Redirected fromACh)
Not to be confused withAcetyl chloride.

Acetylcholine(ACh) is anorganic compoundthat functions in the brain and body of many types of animals (including humans) as aneurotransmitter.[1]Its name is derived from its chemical structure: it is anesterofacetic acidandcholine.[2]Parts in the body that use or are affected by acetylcholine are referred to ascholinergic.

Acetylcholine
Clinical data
Other namesACh
License data
ATC code
Physiologicaldata
Sourcetissuesmotor neurons,parasympathetic nervous system,brain
Target tissuesskeletal muscles,brain, many other organs
Receptorsnicotinic,muscarinic
Agonistsnicotine,muscarine,cholinesterase inhibitors
Antagoniststubocurarine,atropine
Precursorcholine,acetyl-CoA
Biosynthesischoline acetyltransferase
Metabolismacetylcholinesterase
Identifiers
  • 2-Acetoxy-N,N,N-trimethylethanaminium
CAS Number
PubChemCID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
E numberE1001(i)(additional chemicals)Edit this at Wikidata
CompTox Dashboard(EPA)
ECHA InfoCard100.000.118Edit this at Wikidata
Chemical and physical data
FormulaC7H16NO2
Molar mass146.210g·mol−1

Acetylcholine is the neurotransmitter used at theneuromuscular junction—in other words, it is the chemical thatmotor neuronsof the nervous system release in order to activate muscles. This property means that drugs that affect cholinergic systems can have very dangerous effects ranging fromparalysistoconvulsions.Acetylcholine is also a neurotransmitter in theautonomic nervous system,both as an internal transmitter for both thesympatheticand theparasympathetic nervous system,and as the final product released by the parasympathetic nervous system.[1]Acetylcholine is the primary neurotransmitter of the parasympathetic nervous system.[2][3]

In the brain, acetylcholine functions as aneurotransmitterand as aneuromodulator.The brain contains a number of cholinergic areas, each with distinct functions; such as playing an important role inarousal,attention,memoryandmotivation.[4]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.[5]The protist pathogensAcanthamoebaspp. have shown evidence of the presence of ACh, which provides growth and proliferative signals via a membrane-located M1-muscarinic receptor homolog.[6]

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 andtoxinsproduced by plants, animals, and bacteria, as well as chemicalnerve agentssuch assarin,cause harm by inactivating or hyperactivating muscles through their influences on the neuromuscular junction. Drugs that act onmuscarinic acetylcholine receptors,such asatropine,can be poisonous in large quantities, but in smaller doses they are commonly used to treat certain heart conditions and eye problems.[7][8]Scopolamine,ordiphenhydramine,which also act mainly on muscarinic receptors in an inhibitory fashion in the brain (especially theM1receptor) can causedelirium,hallucinations,andamnesiathroughreceptor antagonismat these sites. So far as of 2016, only the M1receptor subtype has been implicated in anticholinergic delirium.[9]The addictive qualities ofnicotineare derived from its effects onnicotinic acetylcholine receptorsin the brain.

Chemistry

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Acetylcholine is acholinemolecule that has beenacetylatedat theoxygenatom. Because of the chargedammoniumgroup, 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

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Acetylcholine is synthesized in certainneuronsby theenzymecholine acetyltransferasefrom the compoundscholineandacetyl-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.[10][11] The enzymeacetylcholinesteraseconverts acetylcholine into the inactivemetabolitescholineandacetate.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. Certainneurotoxinswork by inhibiting acetylcholinesterase, thus leading to excess acetylcholine at theneuromuscular junction,causing paralysis of the muscles needed for breathing and stopping the beating of the heart.

Functions

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Acetylcholine pathway.

Acetylcholine functions in both thecentral nervous system(CNS) and theperipheral nervous system(PNS). In the CNS, cholinergic projections from thebasal forebrainto thecerebral cortexandhippocampussupport thecognitivefunctions of those target areas. In the PNS, acetylcholine activates muscles and is a major neurotransmitter in the autonomic nervous system.[12][2]

Cellular effects

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Main article:Acetylcholine receptor
Acetylcholine processing in a synapse. After release acetylcholine is broken down by the enzymeacetylcholinesterase.

Like many other biologically active substances, acetylcholine exerts its effects by binding to and activatingreceptorslocated on the surface of cells. There are two main classes of acetylcholine receptor,nicotinicandmuscarinic.They are named for chemicals that can selectively activate each type of receptor without activating the other:muscarineis a compound found in the mushroomAmanita muscaria;nicotineis found in tobacco.

Nicotinic acetylcholine receptorsareligand-gated ion channelspermeable tosodium,potassium,andcalciumions. 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 bycurare,the neuronal-type byhexamethonium.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 receptorshave 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 asG protein-coupled receptors,meaning that they exert their effects via asecond messenger system.The M1, M3, and M5 subtypes areGq-coupled; they increase intracellular levels ofIP3andcalciumby activatingphospholipase C.Their effect on target cells is usually excitatory. The M2 and M4 subtypes areGi/Go-coupled; they decrease intracellular levels ofcAMPby inhibitingadenylate 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

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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 thesynaptic 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 article:Neuromuscular junction

Acetylcholine is the substance the nervous system uses to activateskeletal muscles,a kind of striated muscle. These are the muscles used for all types of voluntary movement, in contrast tosmooth 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 bymotor neuronslocated in thespinal cordor, in a few cases, thebrainstem.These motor neurons send theiraxonsthroughmotor nerves,from which they emerge to connect to muscle fibers at a special type ofsynapsecalled theneuromuscular junction.

When a motor neuron generates anaction 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 producemuscle contraction.

Factors that decrease release of acetylcholine (and thereby affectingP-type calcium channels):[13]

  1. Antibiotics(clindamycin,polymyxin)
  2. Magnesium: antagonizes P-type calcium channels
  3. Hypocalcemia
  4. Anticonvulsants
  5. Diuretics(furosemide)
  6. Eaton-Lambert syndrome:inhibits P-type calcium channels
  7. Myasthenia gravis
  8. Botulinum toxin:inhibits SNARE proteins

Calcium channel blockers(nifedipine, diltiazem) do not affect P-channels. These drugs affectL-type calcium channels.

Autonomic nervous system

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Components and connections of theparasympathetic nervous system.

Theautonomic nervous systemcontrols a wide range of involuntary and unconscious body functions. Its main branches are thesympathetic nervous systemandparasympathetic 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 isfight-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 releasenoradrenaline,although acetylcholine is released at a few points, such as thesudomotorinnervation of the sweat glands.

Direct vascular effects

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Acetylcholine in theserumexerts a direct effect onvascular toneby binding tomuscarinic receptorspresent on vascularendothelium.These cells respond by increasing production ofnitric oxide,which signals the surrounding smooth muscle to relax, leading tovasodilation.[14]

Central nervous system

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Micrographof thenucleus 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 andreward.ACh has an important role in the enhancement of alertness when we wake up,[15]in sustaining attention[16]and in learning andmemory.[17]

Damage to the cholinergic (acetylcholine-producing) system in the brain has been shown to be associated with the memory deficits associated withAlzheimer's disease.[18]ACh has also been shown to promoteREMsleep.[19]

In the brainstem acetylcholine originates from thePedunculopontine nucleusandlaterodorsal tegmental nucleuscollectively known as the mesopontine tegmentumarea or pontomesencephalotegmental complex.[20][21]In the basal forebrain, it originates from thebasal nucleus of Meynertand medialseptal nucleus:

In addition, ACh acts as an important internal transmitter in thestriatum,which is part of thebasal ganglia.It is released by cholinergicinterneurons.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 thesubstantia nigra.[22][23]

Memory

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Acetylcholine has been implicated inlearningandmemoryin several ways. The anticholinergic drugscopolamineimpairs acquisition of new information in humans[24]and animals.[17]In animals, disruption of the supply of acetylcholine to theneocorteximpairs the learning of simple discrimination tasks, comparable to the acquisition of factual information[25]and disruption of the supply of acetylcholine to thehippocampusand adjacent cortical areas produces forgetfulness, comparable toanterograde amnesiain humans.[26]

Diseases and disorders

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Myasthenia gravis

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The diseasemyasthenia gravis,characterized by muscle weakness and fatigue, occurs when the body inappropriately producesantibodiesagainst acetylcholine nicotinic receptors, and thus inhibits proper acetylcholine signal transmission.[27]Over time, the motor end plate is destroyed. Drugs that competitively inhibit acetylcholinesterase (e.g.,neostigmine,physostigmine,or primarilypyridostigmine) are effective in treating the symptoms of this disorder.[28]They allow endogenously released acetylcholine more time to interact with its respective receptor before being inactivated by acetylcholinesterase in thesynaptic cleft(the space between nerve and muscle).

Pharmacology

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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 enzymeacetylcholinesterase,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

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Main article:Nicotinic receptor

Nicotine binds to and activatesnicotinic acetylcholine receptors,mimicking the effect of acetylcholine at these receptors. ACh opens aNa+channelupon binding so that Na+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.Curaresare arrow poisons, which act at nicotinic receptors and have been used to develop clinically useful therapies.

Muscarinic receptors

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Main article:Muscarinic receptor

Muscarinic receptors formG protein-coupled receptorcomplexes in thecell membranesofneuronsand other cells.Atropineis a non-selective competitive antagonist with Acetylcholine at muscarinic receptors.

Cholinesterase inhibitors

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Main article:Cholinesterase inhibitors

Many ACh receptor agonists work indirectly by inhibiting the enzymeacetylcholinesterase.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 ofenzyme inhibitors,and increase the action of acetylcholine by delaying its degradation; some have been used asnerve agents(SarinandVXnerve gas) orpesticides(organophosphatesand thecarbamates). Many toxins and venoms produced by plants and animals also contain cholinesterase inhibitors. In clinical use, they are administered in low doses[why?]to reverse the action ofmuscle relaxants,to treatmyasthenia gravis,and to treat symptoms ofAlzheimer's disease(rivastigmine,which increases cholinergic activity in the brain).

Synthesis inhibitors

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Organicmercurialcompounds, such asmethylmercury,have a high affinity forsulfhydryl 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

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Botulinum toxin(Botox) acts by suppressing the release of acetylcholine, whereas the venom from ablack widow spider(alpha-latrotoxin) has the reverse effect. ACh inhibition causesparalysis.When bitten by ablack widow spider,one experiences the wastage of ACh supplies and the muscles begin to contract. If and when the supply is depleted,paralysisoccurs.

Comparative biology and evolution

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Acetylcholine is used by organisms in all domains of life for a variety of purposes. It is believed thatcholine,a precursor to acetylcholine, was used by single celled organisms billions of years ago[citation needed]for synthesizing cell membrane phospholipids.[29]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 thenicotinic receptor familydates back longer than 2.5 billion years.[29]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 to5-HT3(serotonin),GABA,andGlycine receptors,both in sequence and structure, strongly suggesting that they have a common evolutionary origin.[30]

History

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In 1867,Adolf von Baeyerresolved the structures ofcholineand acetylcholine and synthesized them both, referring to the latter asacetylneurinin the study.[31][32]Choline is a precursor for acetylcholine. Acetylcholine was first noted to be biologically active in 1906, whenReid Hunt(1870–1948) and René de M. Taveau found that it decreasedblood pressurein exceptionally tiny doses.[33][32][34]This was afterFrederick Walker MottandWilliam Dobinson Halliburtonnoted in 1899 that choline injections decreased the blood pressure of animals.[35][32]

In 1914, Arthur J. Ewins was the first to extract acetylcholine from nature. He identified it as the blood pressure-decreasing contaminant from someClaviceps purpureaergotextracts, by the request ofHenry Hallett Dale.[32]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 viasubcutaneous injectionseven at doses of onenanogram.[36][32]

The concept ofneurotransmitterswas unknown until 1921, whenOtto Loewinoted that thevagus nervesecreted a substance that inhibited theheart musclewhilst working as a professor in theUniversity of Graz.He named itvagusstoff( "vagus substance" ), noted it to be astructural analogof choline and suspected it to be acetylcholine.[37][38]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 tissuelysatesthat contained acetylcholine-degrading enzymes (now known to becholinesterases).[39][40]This conclusion was accepted widely. Later studies confirmed the function of acetylcholine as aneurotransmitter.[38]

In 1936, H. H. Dale and O. Loewi shared theNobel Prize in Physiology or Medicinefor their studies of acetylcholine and nerve impulses.[32]

References

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