Acetylcholine

FromWikipedia,thefreeencyclopedia

Acetylcholineisanorganicchemical
thatfunctionsinthebrainandbodyofmanytypesofanimals,includinghumans,as
aneurotransmitter
achemicalreleasedbynervecellstosendsignalstoothercells.Itsnameisderivedfromits
chemicalstructure:itisan
esterofaceticacidandcholine.Partsinthebodythatuseorareaf
fectedbyacetylcholineare
referredtoascholinergic.Substancesthatinterferewithacetylcholineactivityarecalled
anticholiner
gics.
Acetylcholineistheneurotransmitterusedatthe
neuromuscularjunction
inotherwords,itisthechemicalthat
motor
neuronsofthenervoussystemreleaseinordertoactivatemuscles.Thispropertymeansthatdrugsthataf
fectcholinergic
systemscanhaveverydangerousef
fectsrangingfromparalysistoconvulsions.Acetylcholineisalsousedasa
neurotransmitterinthe
autonomicnervoussystem
,bothasaninternaltransmitterforthe
sympatheticnervoussystem
and
asthefinalproductreleasedbythe
parasympatheticnervoussystem
.

Acetylcholine

IUPACname 2AcetoxyN,N,N
trimethylethanaminium
Abbreviation ACh

Insidethebrain,acetylcholinefunctionsasa
neuromodulatorachemicalthataltersthewayotherbrainstructures
Sources
processinformationratherthanachemicalusedtotransmitinformationfrompointtopoint.Thebraincontainsanumber
ofcholinergicareas,eachwithdistinctfunctions.Theyplayanimportantroleinarousal,attention,andmotivation.
Targets

Partlybecauseofitsmuscleactivatingfunction,butalsobecauseofitsfunctionsintheautonomicnervoussystemand
brain,alargenumberofimportantdrugsexerttheiref
fectsbyalteringcholiner
gictransmission.Numerousvenomsand
toxinsproducedbyplants,animals,andbacteria,aswellaschemical
nerveagentssuchasSarin,causeharmby
Receptors
inactivatingorhyperactivatingmusclesviatheirinfluencesontheneuromuscularjunction.Drugsthatacton
muscarinic
Agonists
acetylcholinereceptors
,suchasatropine,canbepoisonousinlar
gequantities,butinsmallerdosestheyarecommonly
usedtotreatcertainheartconditionsandeyeproblems.
Scopolamine,whichactsmainlyonmuscarinicreceptorsinthe
brain,cancausedeliriumandamnesia.Theaddictivequalitiesofnicotinederivefromitsef
fectsonnicotinicacetylcholine Antagonists
receptorsinthebrain.
Precursor

Contents
1 Functions
1.1 Cellulareffects
1.2 Neuromuscularjunction
1.3 Autonomicnervoussystem
1.3.1 DirectVascularEffects

motorneurons,parasympathetic
nervoussystem ,brain
skeletalmuscles,brain,manyother
organs
nicotinic,muscarinic
nicotine,muscarine,cholinesterase
inhibitors
tubocurarine,atropine
choline,acetylCoA

Synthesizing cholineacetyltransferase
enzyme
Metabolizing acetylcholinesterase
enzyme
Databaselinks
CASNumber 51843
PubChem

CID:187

IUPHAR/BPS 294(http://www .guidetopharmacolo

1.4 Centralnervoussystem

1.4 Centralnervoussystem
1.4.1 Decisionmaking
2 Diseasesanddisorders
2.1 Myastheniagravis
3 Pharmacology
3.1 Nicotine
3.2 Atropine
3.3 Cholinesteraseinhibitors
3.4 Curare
3.5 Synthesisinhibitors
3.6 Releaseinhibitors
4 Comparativebiologyandevolution
5 Biochemicalmechanisms
6 Chemistry
7 History
8 References
9 Bibliography
10 Externallinks

gy.org/GRAC/LigandDisplayForwar
d?ligandId=294)
DrugBank

EXPT00412

ChemSpider 182
KEGG

C01996

Functions
Acetylcholinehasfunctionsbothinthe
peripheralnervoussystem
(PNS)andinthecentralnervoussystem
(CNS)asa
neuromodulator.Intheperipheralnervoussystem,acetylcholineactivatesmuscles,andisamajorneurotransmitterintheautonomic
nervoussystem.

Cellulareffects
Likemanyotherbiologicallyactivesubstances,acetylcholineexertsitsef
fectsbybindingtoandactivating
receptorslocatedonthe
surfaceofcells.Therearetwomainclassesofacetylcholinereceptor
,nicotinicandmuscarinic.Theyarenamedforchemicalsthat
canselectivelyactivateeachtypeofreceptorwithoutactivatingtheother:
muscarineisacompoundfoundinthemushroom
Amanita
muscarianicotineisfoundintobacco.

Acetylcholinepathway.

Nicotinicacetylcholinereceptors
areligandgatedionchannels
permeabletosodium,potassium,andcalciumions.Inotherwords,
theyareionchannelsembeddedincellmembranes,capableofswitchingfromaclosedtoopenstatewhenacetylcholinebindstothemintheopenstatetheyallowionst
passthrough.Nicotinicreceptorscomeintwomaintypes,knownasmuscletypeandneuronaltype.Themuscletypecanbeselectivelyblockedby
curare,theneuronaltype
byhexamethonium
.Themainlocationofmuscletypereceptorsisonmusclecells,asdescribedinmoredetailbelow
.Neuronaltype

byhexamethonium
.Themainlocationofmuscletypereceptorsisonmusclecells,asdescribedinmoredetailbelow
.Neuronaltype
receptorsarelocatedinautonomicganglia(bothsympatheticandparasympathetic),andinthecentralnervoussystem.
Muscarinicacetylcholinereceptors
haveamorecomplexmechanism,andaf
fecttargetcellsoveralongertimeframe.Inmammals,
fivesubtypesofmuscarinicreceptorshavebeenidentified,labeledM1throughM5.Allofthemfunctionas
Gproteincoupled
receptors,meaningthattheyexerttheiref
fectsviaasecondmessengersystem
.TheM1,M3,andM5subtypesareGq coupled
theyincreaseintracellularlevelsof
IP3andcalciumbyactivating
phospholipaseC.Theireffectontargetcellsisusuallyexcitatory
.
TheM2andM4subtypesareGi/Go coupledtheydecreaseintracellularlevelsof
cAMPbyinhibiting
adenylatecyclase.Their
effectontargetcellsisusuallyinhibitory
.Muscarinicacetylcholinereceptorsarefoundinboththecentralnervoussystemandthe
peripheralnervoussystemoftheheart,lungs,uppergastrointestinaltract,andsweatglands.

Neuromuscularjunction
Acetylcholineprocessingina
synapse.Afterreleaseacetylcholineis
brokendownbytheenzyme
acetylcholinesterase.

Acetylcholineisthesubstancethenervoussystemusestoactivate
skeletalmuscles
,akindofstriatedmuscle.Thesearethemuscles
usedforalltypesofvoluntarymovement,incontrastto
smoothmuscletissue
,whichisinvolvedinarangeofinvoluntaryactivities
suchasmovementoffoodthroughthegastrointestinaltractandconstrictionofbloodvessels.Skeletalmusclesaredirectly
controlledbymotorneuronslocatedinthespinalcordor,inafewcases,thebrainstem.Thesemotorneuronssendtheiraxons
throughmotornerves,fromwhichtheyemer
getoconnecttomusclefibersataspecialtypeof
synapsecalledtheneuromuscularjunction
.

Whenamotorneurongeneratesan
actionpotential
,ittravelsrapidlyalongthenerveuntilitreachestheneuromuscularjunction,whereitinitiatesanelectrochemicalproces
thatcausesacetylcholinetobereleasedintothespacebetweenthepresynapticterminalandthemusclefiber
.Theacetylcholinemoleculesthenbindtonicotinicionchannel
receptorsonthemusclecellmembrane,causingtheionchannelstoopen.Sodiumionsthenflowintothemusclecell,initiatingasequenceofstepsthatfinallyproduce
muscle
contraction.

Autonomicnervoussystem

Theautonomicnervoussystem
controlsawiderangeofinvoluntaryandunconsciousbodyfunctions.Itsmainbranchesarethe
sympatheticnervoussystem
and
parasympatheticnervoussystem
.Broadlyspeaking,thefunctionofthesympatheticnervoussystemistomobilizethebodyforaction:thesloganoftenusedforitis
fightor
flight.Thefunctionoftheparasympatheticnervoussystemistoputthebodyinastateconducivetorest,regeneration,digestion,andreproduction:itissometimesdescrib
usingtheslogans"restanddigest"or"feedandbreed".Bothbranchesuseacetylcholine,butindif
ferentways.

Ataschematiclevel,thesympatheticandparasympatheticnervoussystemsarebothor
ganizedinessentiallythesameway:preganglionicneuronsinthecentralnervoussystem
sendprojectionstoneuronslocatedinautonomicgangliatheseneuronsthensendoutputprojectionstovirtuallyeverytissueofthebody
.Inbothbranchestheinternal
connectionstheprojectionsfromthecentralnervoussystemtotheautonomicgangliauseacetylcholineasneurotransmitter
,andthereceptorsitactivatesareofthe
nicotinictype.Intheparasympatheticnervoussystemtheoutputconnectionstheprojectionsfromganglionneuronstotissuesthatdon'tbelongtothenervoussystem
releaseacetylcholine,actingonmuscarinicreceptors.Inthesympatheticnervoussystemtheoutputconnectionsmainlyrelease
noradrenaline,althoughacetylcholineisreleased
atafewpoints,suchasthe
sudomotorinnervationofthesweatglands.

DirectVascularEffects
Acetylcholineintheserumexertsadirectef
fectonvasculartonebybindingto
muscarinicreceptors
presentonvascularendothelium.Thesecellsrespondbyincreasingproductionof
nitricoxide,which
[1]
signalsthesurroundingsmoothmuscletorelax,leadingtovasodilation.

Centralnervoussystem
Inthecentralnervoussystem,AChhasavarietyofef
fectsasaneuromodulatoruponplasticity
,
arousalandreward.AChhasanimportantroleintheenhancementofsensoryperceptionswhenwe
[3]
wakeup[2]andinsustainingattention.

Damagetothecholiner
gic(acetylcholineproducing)systeminthebrainhasbeenshowntobe
plausiblyassociatedwiththememorydeficitsassociatedwith
Alzheimer'sdisease
.[4]AChhasalso
beenshowntopromoteREMsleep.[5]
Inthebrainstemacetylcholineoriginatesfromthe
Pedunculopontinenucleus
andlaterodorsaltegmental
nucleuscollectivelyknownasthemeso
pontinetegmentum
areaorpontomesencephalotegmental
complex.[6][7]Inthebasalforebrain,itoriginatesfromthe
basalopticnucleusofMeynert
andmedial
septalnucleus:
Thepontomesencephalotegmentalcomplexactsmainlyon
M1receptorsinthebrainstem,
deepcerebellarnuclei
,pontinenuclei
,locuscaeruleus,raphenucleus,lateralreticularnucleus
andinferiorolive
.[7]Italsoprojectstothethalamus,tectum,basalgangliaandbasal
forebrain.[6]
BasalopticnucleusofMeynert
actsmainlyon
M1receptorsintheneocortex.
Medialseptalnucleusactsmainlyon
M1receptorsinthehippocampusandneocortex.

Musclescontractwhentheyreceivesignalsfrommotorneurons.The
neuromuscularjunctionisthesiteofthesignalexchange.Thesteps
ofthisprocessinvertebratesoccurasfollows:(1)Theaction
potentialreachestheaxonterminal.(2)Calciumionsflowintothe
axonterminal.(3)Acetylcholineisreleasedintothesynapticcleft.(4)
Acetylcholinebindstopostsynapticreceptors.(5)Thisbinding
causesionchannelstoopenandallowssodiumionstoflowintothe
musclecell.(6)Theflowofsodiumionsacrossthemembraneinto
themusclecellgeneratesanactionpotentialwhichinducesmuscle
contraction.Labels:A:MotorneuronaxonB:AxonterminalC:
SynapticcleftD:MusclecellE:PartofaMyofibril

Inaddition,AChactsasanimportantinternaltransmitterinthe
striatum,whichispartofthe
basalganglia.Itisreleasedbycholiner
gicinterneurons.Inhumans,nonhuman
primatesandrodents,theseinterneuronsrespondtosalientenvironmentalstimuliwithstereotypedresponsesthataretemporallyalignedwiththeresponsesofdopaminer
gic
neuronsofthesubstantianigra
.[8][9]
Decisionmaking

Onewellsupportedfunctionofacetylcholine(ACh)incortexisincreasedresponsivenesstosensorystimuli,aformof
attention.An
additionalsuggestedfunctionofAChincortexissuppressionofintracorticalinformationtransmission.Someformsoflearningand
plasticityincortexappeardependentonthepresenceofacetylcholine.AChhasbeenimplicatedinthereportingofexpected
[10]basedbothonthesuggestedfunctionslistedaboveandresultsrecordedwhilesubjectsperforma
uncertaintyintheenvironment
behavioralcuingtask.

Diseasesanddisorders
Myastheniagravis
Thediseasemyastheniagravis
,characterizedbymuscleweaknessandfatigue,occurswhenthebodyinappropriatelyproduces
antibodiesagainstacetylcholinenicotinicreceptors,andthusinhibitsproperacetylcholinesignaltransmission.Overtime,themotor
endplateisdestroyed.Drugsthatcompetitivelyinhibitacetylcholinesterase(e.g.,neostigmine,physostigmine,orprimarily
pyridostigmine)areef
fectiveintreatingthisdisorder
.Theyallowendogenouslyreleasedacetylcholinemoretimetointeractwithits
respectivereceptorbeforebeinginactivatedbyacetylcholinesteraseinthesynapticcleft(thespacebetweennerveandmuscle).

Pharmacology
Componentsandconnectionsofthe

Blocking,hinderingormimickingtheactionofacetylcholinehasmanyusesinmedicine.Drugsactingontheacetylcholinesystemare
parasympatheticnervoussystem.
eitheragoniststothereceptors,stimulatingthesystem,orantagonists,inhibitingit.Acetylcholinereceptoragonistsandantagonists
caneitherhaveanef
fectdirectlyonthereceptorsorexerttheiref
fectsindirectly
,e.g.,byaffectingtheenzyme
acetylcholinesterase
,
whichdegradesthereceptorligand.Agonistsincreasethelevelofreceptoractivation,antagonistsreduceit.
Acetylcholineitselfdoesnothavetherapeuticvalueasadrugforintravenousadministrationbecauseofitsmultifacetedactionand
rapidinactivationbycholinesterase.However
,itisusedintheformofeyedropstocauseconstrictionofthepupilduringcataract
surgery,whichfacilitatesquickpostoperationalrecovery
.

Nicotine
ImitatesACh,activatingAChreceptors

Atropine
AtropineisanonselectivecompetitiveantagonistwithAcetylcholineatmuscarinicreceptors.

Micrographofthenucleusbasalis(of
Meynert),whichproduces
acetylcholineintheCNS.LFBHE
stain.

Cholinesteraseinhibitors
ManyAChreceptoragonistsworkindirectlybyinhibitingtheenzyme
acetylcholinesterase
.Theresultingaccumulationofacetylcholinecausescontinuousstimulationofthe
muscles,glands,andcentralnervoussystem,whichcanresultinfatalconvulsionsifthedoseishigh.

Theyareexamplesof
enzymeinhibitors
,andincreasetheactionofacetylcholinebydelayingitsdegradationsomehavebeenusedas
nerveagents(SarinandVXnervegas)
orpesticides(organophosphatesandthecarbamates).Manytoxinsandvenomsproducedbyplantsandanimalsalsocontaincholinesteraseinhibitors.Inclinicaluse,theyar
administeredinlowdosestoreversetheactionof
musclerelaxants
,totreatmyastheniagravis
,andtotreatsymptomsof
Alzheimer'sdisease
(rivastigmine
,whichincreases
cholinergicactivityinthebrain).

Curare
Synthesisinhibitors
Organicmercurialcompounds,suchasmethylmercury
,haveahighaf
finityfor
sulfhydrylgroups
,whichcausesdysfunctionoftheenzymecholineacetyltransferase.This
inhibitionmayleadtoacetylcholinedeficiency
,andcanhaveconsequencesonmotorfunction.

Releaseinhibitors
Botulinumtoxin
(Botox)actsbysuppressingthereleaseofacetylcholine,whereasthevenomfroma
blackwidowspider(alphalatrotoxin
)hasthereverseeffect.ACh
inhibitioncauses
paralysis.Whenbittenbyablackwidowspider,oneexperiencesthewastageofAChsuppliesandthemusclesbegintocontract.Ifandwhenthesupplyis
depleted,paralysisoccurs.

Comparativebiologyandevolution
Biochemicalmechanisms
Acetylcholineissynthesizedincertain
neuronsbytheenzymecholineacetyltransferase
fromthecompounds
cholineandacetylCoA.Cholinergicneuronsarecapableof
producingACh.Anexampleofacentralcholiner
gicareaisthenucleusbasalisofMeynertinthebasalforebrain.
Theenzymeacetylcholinesterase
convertsacetylcholineintotheinactive
metabolitescholineandacetate.Thisenzymeisabundantinthesynapticcleft,anditsroleinrapidly
clearingfreeacetylcholinefromthesynapseisessentialforpropermusclefunction.Certain
neurotoxinsworkbyinhibitingacetylcholinesterase,thusleadingtoexcess
acetylcholineatthe
neuromuscularjunction
,causingparalysisofthemusclesneededforbreathingandstoppingthebeatingoftheheart.

Chemistry

Acetylcholineisacholinemoleculethathasbeenacetylatedattheoxygenatom.Becauseofthepresenceofahighlypolar
,chargedammoniumgroup,acetylcholinedoesnot
penetratelipidmembranes.Becauseofthis,whenthedrugisintroducedexternally
,itremainsintheextracellularspaceanddoesnotpassthroughthebloodbrainbarrier
.A
synonymofthisdrugis
miochol.

History
Acetylcholine(ACh)wasfirstidentifiedin1915by
HenryHallettDale
foritsactionsonhearttissue.Itwasconfirmedasaneurotransmitterby
OttoLoewi,whoinitiallygave
itthenameVagusstoffbecauseitwasreleasedfromthe
vagusnerve.Bothreceivedthe1936NobelPrizeinPhysiologyorMedicine
fortheirwork.Acetylcholinewasalsothe
firstneurotransmitter
tobeidentified.

References
1.Kellogg,D.L.Zhao,J.L.Coey,U.Green,J.V.(20050201)."Acetylcholine
inducedvasodilationismediatedbynitricoxideandprostaglandinsinhumanskin"
.
JournalofAppliedPhysiology.98(2):629632.
doi:10.1152/japplphysiol.00728.2004.ISSN87507587.PMID15649880.
2.Jones,BE(2005)."Fromwakingtosleeping:neuronalandchemicalsubstrates".
Trendsinpharmacologicalsciences.26(11):57886.
doi:10.1016/j.tips.2005.09.009.PMID16183137.
3.Himmelheber,AMSarter,MBruno,JP(2000)."Increasesincorticalacetylcholine
releaseduringsustainedattentionperformanceinrats".Brainresearch.Cognitive
brainresearch.9(3):31325.doi:10.1016/S09266410(00)000124.
PMID10808142.
4.FrancisPT,PalmerAM,SnapeM,WilcockGK(February1999)."Thecholinergic
hypothesisofAlzheimer'sdisease:areviewofprogress"
.J.Neurol.Neurosurg.
Psychiatr.66(2):13747.doi:10.1136/jnnp.66.2.137.PMC1736202 .
PMID10071091.

5.Platt,BettinaRiedel,Gernot(201
1)."Thecholinergicsystem,EEGandsleep".
BehaviouralBrainResearch.221(2):499504.doi:10.1016/j.bbr.2011.01.017.
PMID21238497.
6.Woolf,NJButcher,LL(1986)."Cholinergicsystemsintheratbrain:III.
Projectionsfromthepontomesencephalictegmentumtothethalamus,tectum,basal
ganglia,andbasalforebrain".BrainResearchBulletin.16(5):60337.
doi:10.1016/03619230(86)901346.PMID3742247.
7.Woolf,NJButcher,LL(1989)."Cholinergicsystemsintheratbrain:IV.
Descendingprojectionsofthepontomesencephalictegmentum".
BrainResearch
Bulletin.23(6):51940.doi:10.1016/03619230(89)901974.PMID2611694.
8.Goldberg,J.A.Reynolds,J.N.J.(201 1)."Spontaneousfiringandevokedpauses
inthetonicallyactivecholiner
gicinterneuronsofthestriatum".Neuroscience.198:
2743.doi:10.1016/j.neuroscience.2011.08.067.PMID21925242.
9.Morris,G.Arkadir,D.Nevet,A.Vaadia,E.Bergman,H.(2004)."Coincidentbut
DistinctMessagesofMidbrainDopamineandStriatalT
onicallyActiveNeurons".
Neuron.43(1):133143.doi:10.1016/j.neuron.2004.06.012.PMID15233923.
10.Yu&Dayan2005

5.Platt,BettinaRiedel,Gernot(201
1)."Thecholinergicsystem,EEGandsleep".

Bibliography
Brenner,G.M.Stevens,C.W.(2006).Pharmacology(2nded.).PhiladelphiaP
A:W.B.Saunders.ISBN1416029842 .
CanadianPharmacistsAssociation(2000).
CompendiumofPharmaceuticalsandSpecialties(25thed.).TorontoON:Webcom.ISBN0919115764.
Carlson,NR(2001).PhysiologyofBehavior(7thed.).NeedhamHeightsMA:AllynandBacon.
ISBN0205308406 .
Gershon,MichaelD.(1998).
TheSecondBrain.NewYorkNY:HarperCollins.
ISBN0060182520 .
Siegal,A.Sapru,H.N.(2006)."Ch.15".
EssentialNeuroscience(Revised1sted.).Philadelphia:Lippincott,W
illiams&W
ilkins.pp.255267.

HasselmoME(February1995)."Neuromodulationandcorticalfunction:modelingthephysiologicalbasisofbehavior"
.Behav.BrainRes.67(1):127.
doi:10.1016/01664328(94)00113T.PMID7748496.asPDF(http://people.bu.edu/hasselmo/HasselmoBBR1995.pdf)
Yu,AJDayan,P(May2005)."Uncertainty
,neuromodulation,andattention"
.Neuron.46(4):68192.doi:10.1016/j.neuron.2005.04.026.PMID15944135.as
PDF(http://www.gatsby.ucl.ac.uk/~dayan/papers/yud2005.pdf)

Externallinks
Warningovercombiningcommonmedicinesforelderly
(http://www.bbc.co.uk/news/health13880553)
Retrievedfrom"
https://en.wikipedia.or
g/w/index.php?title=Acetylcholine&oldid=747685003
"
Categories: Acetylcholine Cholineesters QuaternaryammoniumcompoundsAcetateesters
Thispagewaslastmodifiedon3November2016,at20:00.
Textisavailableunderthe
CreativeCommonsAttributionShareAlikeLicense
additionaltermsmayapply
.Byusingthissite,youagreetothe
TermsofUseand
PrivacyPolicy.Wikipediaisaregisteredtrademarkofthe
WikimediaFoundation,Inc.
,anonprofitorganization.