1NeurotransmitterSuBoInstituteofneurobiologbxs103@

2OutlineNeurotransmittercategoriesNeurotransmitterchemistrySomeimportantneurotransmittersDiscoveryofNeurotransmitter1904,RentonElliott,hypothesisneurotransmitter;1914,HenryDalediscoveredacetylcholine;stimulationoftheparasympatheticnervoussystem;1920,OttoLoewi(奧托

洛維);1929Dalepurifiedacetylcholinefrommammalianorgans31936Nobelprizewinner4BasicConceptsofNTNeurotransmitter遞質

Endogenoussignalingmoleculesthatalterthebehaviourofneuronsoreffectorcells.Neuromodulator調質

Endogenoussignalingmoleculesthatregulatethebehaviourofneuronsoreffectorcells.5CriteriaforneurotransmitterThemoleculemustbesynthesizedandstoredinthepresynapticneuron.Themoleculemustbereleasedbythepresynapticaxonterminaluponstimulation.Themolecule,whenexperimentallyapplied,mustproducearesponseinthepostsynapticcellthatmimicstheresponseproducedbythereleaseofneurotransmitterfromthepresynapticneuron.6ClassicalTransmitters(small-moleculetransmitters)Large-moleculeneurotransmittersothersCholinesAminesAminoacidsNeuropeptidesAcetylcholine(Ach)Dopamine(DA)GlutamateCCKNOEpinephrine（E）AspartateDynorphinCONorepinephrine(NE)GABAEnkephalinsATPSerotonin(5-HT)GlycineVIPHistamine(HIS)NeuropeptideYSubstancePCategoriesofneurotransmitters78Neuropeptides9OutlineNeurotransmittercategoriesNeurotransmitterchemistrySomeimportantneurotransmitters10ElementsofNeurotransmitterSystem11SynthesisSmall-moleculeneurotransmitterNeuropeptide12VesiculartransporterATP-dependentH+accumulationReversetransportVesicularAChtransporter(VAChT)Vesicularmonoaminetransporter(VMAT)VesicularGlutransporter(VGLUT)Vesicularinhibitoryaminoacidtransporter(VIAAT)13smallclear-corevesicles40-60nmStoragelargedense-corevesicles90-250nmAch,AminoacidsNeuropeptides,Amines囊泡儲存是遞質儲存的主要方式遞質合成后儲存在囊泡內，囊泡內可以有數千個遞質分子。待釋放的活動囊泡聚集在突觸前膜活動區，為遞質的胞裂外排作好準備小分子遞質如乙酰膽堿、氨基酸類遞質儲存在直徑40~60nm的小囊泡中，在電鏡下囊泡中央清亮，為小的清亮囊泡神經肽儲存在直徑約90~250nm的大囊泡中，電鏡下，囊泡中央電子密度較高，為大的致密核心囊泡單胺類遞質儲存的囊泡既有小的致密核心囊泡，也有大的（直徑60~120nm）不規則形狀的致密囊泡15NeurotransmitterCo-existenceDale’sprinciple:Aneuronhasonlyoneneurotransmitter.Bothaclassicalneurotransmitter(AChorcatecholamine)andapolypeptideneurotransmitterexistintheterminalofoneneurons.Theyarecontainedindifferentsynapticvesiclesthatcanbedistinguishedusingtheelectronmicroscope.Theneuroncanthusreleaseeithertheclassicalneurotransmitterorthepolypeptideneurotransmitterunderdifferentconditions.CotransmissionCotransmission

isthereleaseofseveraltypesofneurotransmittersfromasinglenerveterminal.Someneuronscanreleaseatleasttwoneurotransmittersatthesametime,theotherbeingacotransmitter,inordertoprovidethestabilizingnegativefeedbackrequiredformeaningfulencoding,intheabsenceofinhibitoryinterneurons.GABA–glycineco-release.Dopamine–glutamateco-release.Acetylcholine–glutamateco-release.Glutamate–dynorphinco-release1617fast300usslow50msRelease18Ca2+dependentRelease19Ca2+dependentreleaseFura-2staining20Tetanus21Lambert-Eatonmyasthenicsyndrome(LEMS)22TransmitterTerminationDiffusionReuptakeEnzymaticdegradation:neuropeptidesAutoreceptorCombinationofabove23TransporterexistinthepresynapticmembraneorthemembraneofgliasurroundingthesynapseNa+/K+-dependenttransporter：GlutamateNa+/Cl--dependenttransporter:GABA,AminesReuptakeTwoFamiliesofPostsynapticReceptorsTransmitter-gatedionchannelsdirectlycontrolschannelfastG-protein-coupledreceptorssecondmessengersystemsreceptorindirectlycontrolschannelslow2425Transmitter-gatedionchannels26Thegeneralarchitectureofligand-gatedreceptorsOneofthesubunitsofacompletereceptorAssemblyofeitherfourorfivesubunitsintoacompletereceptor2728Adiversityofsubunitscometogethertoformfunctionalionotropicreceptors29ThebasicstructureofGPCR30StructureofGPCRs31Thesereceptorproteinscontainseventransmembranedomains.PortionsofdomainsII,III,VI,andVIImakeuptheneurotransmitter-bindingregion.G-proteinsbindtoboththeloopbetweendomainsVandVIandtoportionsoftheC-terminalregion.StructureofGPCRs32G-protein-coupledreceptors33ThebasicmodeofoperationofG-proteins34ThebasicmodeofoperationofG-proteins3536Gs/Gi－AC－cAMP37GsACATPcAMP細胞膜核膜CCRRCCRR

2cAMP2cAMP+38ＣＣ結構基因ＣＲＥＢＣＲＥＢ細胞核PiPiＣＲＥＢPiＣＲＥＢPiＣＲＥDNA蛋白質生理效應QIAGEN40Gq-PLC-IP3/DAG41Varietiesofmetabotropicneurotransmitterreceptors4243AgonistandAntagonistEachneurotransmitterexertsitspostsynapticeffectsbybindingtospecificreceptors.Neuropharmacologicalanalysis:studyingdifferentreceptorsubtypesusingagonistandantagonist.44AgonistAsubstancethatmimicsaspecificneurotransmitter,isabletoattachtothatneurotransmitter'sreceptorandtherebyproducesthesameactionthattheneurotransmitterusuallyproduces.Drugsareoftendesignedasreceptoragoniststotreatavarietyofdiseasesanddisorderswhentheoriginalchemicalsubstanceismissingordepleted.45AntagonistDrugsthatbindtobutdonotactivateneuroreceptors,therebyblockingtheactionsofneurotransmittersortheneuroreceptoragonists.46NeuropharmacologyofReceptorSubtypesNeurotransmitterReceptorsubtypeAgonistAntagonistAcetylcholine(ACh)NicotinicreceptorNicotineCurareMuscarinicreceptorMuscarineAtropineNorepinephrine(NE)αreceptorPhenylephrinePhenixybenzamineβreceptorIsoproterenolPropranololGlutamate(Glu)AMPAAMPACNQXNMDANMDAAP5GABAGABAAMuscimolBicucullineGABABBaclofenPhaclofen47Neurotransmitterchemistry48OutlineNeurotransmittercategoriesNeurotransmitterchemistrySomeimportantneurotransmitters49Acetylcholine(ACh)50AChsystemArisingfromthebasalforebrain(基底前腦)andbrainstem(腦干)Themedialseptalnuclei(隔內側核)andbasalnucleusofMeynertprojectwidelyuponthecerebralcortex(hippocampus)Thepontomesencephalo-tegmentalcomplex(腦橋-中腦-被蓋復合體)projectstothethalamusandpartsoftheforebrain5152Cholineacetyltransferase(ChAT)BemanufacturedinthesomaandtransportedtotheaxonterminalOnlycholinergicneuronscontainChAT:amarkerofchonlinergicneuronsTransportofcholineintoneuronistherate-limitingstep53Acetylcholinesterase(AChE)CanbemanufacturedbycholinergicneuronsornoncholinergicneuronsSpecificforAChdegradationandhasfastcatalyticratesTargetofpharmacology

55AchReceptorsAChisbothanexcitatoryandinhibitoryNicotinicAChreceptors(Ligand-gatedionchannels)N1(nicotinicneruronal,NN)

:

allautonomicganglia

andhormoneproducingcellsofadrenalmedulla

N2(nicotinicmuscle,NM):neuromuscularjunction56NicotinicAChreceptorPermeableforNa+,K+andlittleCa2+

Depolarization:EPSP57MuscarinicAChreceptors(GPCR)MuscarinicAChreceptors(M1-M5)Foundintheplasmamembraneofsmoothandcardiacmusclecells,andincellsofparticularglands58MuscarinicAChreceptors(GPCR)M1-R:ganglionM2-R:heartM3-R:exocrineglands,smoothmuscle,endothelium(produceNO)59AgonistandAntagonist6061MonoamineCatecholamines(CAT)

Dopamine(DA)

Norepinephrine(NE)

EpinephrineSerotonin(5-HT)Histamine

62Thebiosyntheticpathwayforthecatecholamines

TyrosineTyrosinehydroxylase:Rate-limitingenzymeamarkerofcatecholaminergicneurons

63TerminationReuptake:Na+/Cl--dependenttransporterDopaminetransporter(DAT）Norepinepherinetransporter(NET)Targetofdifferentdrugs:amphetamineandcocaineEnzymatic

degradation:Monoamineoxidase(MAO):

MAOI:antidepressant–phenelzine(苯乙肼)andtranylcypromine(強內心百樂明)Catechol-O-methyltransferase(COMT)

Postsynapse,Synapticcleft64Stimulantdrugactiononthecatecholamineaxonterminal65Dopamine(DA)Arisingfromthesubstantianigraandtheventraltegmentalarea（腹側被蓋區）Projecttothestriatum(caudatenucleusandputamen),limbicandfrontalcorticalregionrespectively.66DAreceptorsD1-D5:allareGPCRsD1-likereceptors:D1andD5D2-likereceptors:D2:domperidone多潘立酮D3:autoreceptorD4:psychotropicdrugs(chlorpromazine氯丙嗪)67Norepinephrine(NE)asNTNEinbothPNSandCNSPNS:Smoothmuscles,cardiacmuscleandglands.Increaseinbloodpressure,constrictionofarteries

CNS:

Arisingfromthelocuscoeruleus（藍斑核）,projecttovastareaoftheCNS,includingthespinalcord,cerebellum,thalamusandcerebralcortex6870Adrenergicreceptorα1

:α1A

、α1B

、α1D

α2:α2A

、α2B、

α2Cβ:β1

、β2、

β371

locationfunctionatagonistα1bloodvesselsofskin,mucosa,abdominalviscera,kidneys,salivaryglandsvasoconstriction,sphincterconstriction

Phentolamine(酚妥拉明）Prazosin(哌唑嗪)

α2Membraneofadrenergicaxonterminals(pre-synapticreceptors),platelets

inhibitionofNErelease(autoreceptor);promotesbloodclotting,pancreasdecreasedinsulinsecretion

Phentolamine(酚妥拉明）Yohimbine(育亨賓)

β1Mainlyheartmusclecells

increasedheartrateandstrength

Propranolol(普萘洛爾)Atenolol(阿替洛爾)

β2Lungs,mostothersympatheticorgans,bloodvesselsservingtheheart(coronaryvessels);

dilationofbronchioles&bloodvessels(coronaryvessels),relaxationofsmoothmuscleinuterusPropranolol(普萘洛爾)Butoxamine

β3Adiposetissuestimulationoflipolysis

Adrenergicreceptor72Serotonin(5-HT)Arisingfromtheraphenuclei（中縫核群）,clusteredalongthemidlineofthebrainstemProjectextensivelytoalllevelsoftheCNS73TryptophanTPH:rate-limitingenzymeSSRI:serotoninreuptakeinhibitor--antidepressantFluoxetine氟西汀(百憂解)Serotonin(5-HT)74MedicationsAvailabletoTreatDepressionTricyclicantidepressants(TCA):amitriptyline（阿米替林）MAOinhibitors(MAOI):moclobemide（馬氯貝胺）NEreuptakeinhibitors(NRI):maprotiline（馬普替林）Serotonin

reuptakeinhibitors(SSRI):fluoxetine（氟西汀）Serotonin/NEreuptakeinhibitors(SNRI):venlafaxine（文拉法新）NaSSA:mirtazapine（米氮平）755-HTreceptors

GPCR:5-HT1－Gi:cerebrovascularconstriction(migraine)5-HT2－Gq:vasoconstriction(hypertension)Ligand-gatedionchannel5-HT3:permeableforNa+/K+

（ondansetron昂丹司瓊）76AminoacidsExcitatoryaminoacid,EAAInhibitoryaminoacid,IAA77GlutamateGlutaminecycle78GlutamatereceptorsLigand-gatedionchannelsNMDAreceptor:N-methyl-D-aspartate(N-甲基-D-天冬氨酸)AMPAreceptor:α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate(α-氨基-3-羥基-5-甲基-4-異噁唑-戊酸)KAreceptor:kainicacid(海人藻酸)GPCRsmGluRs:metabotropicglutamatereceptor1-779NMDAreceptorFoursubunits:NR1andNR2Glycinebindingsite(co-agonist)Mg2+bindingsite80NMDAandAMPAreceptorAMPAreceptorsarepermeabletoNa+andK+,notCa2+AMPAproducefastEPSCNMDAreceptorsproduceslowerEPSC

81NMDAreceptorTransmitter-gatedandvoltagedependentMK-801:open-channelblocker82CoexistenceofNMDAandAMPAreceptors83AgonistandAntagonistCNQX:6-氰基-7-硝基喹喔啉-2，3-二酮AP5:D-2-氨基-5-磷酸基戊酸84NMDAreceptorsarepermeabletoNa+/K+/Ca2+Ca2+isveryimportantforcellfunction.Itcantriggerneurotransmitterrelease,activemanyenzymes,regulatetheopeningofavarietyofchannels,andaffectgeneexpression;inexcessiveamounts,Ca2+caneventriggerthedeathofcell(Excitotoxicity).ActivationofNMDAreceptorscancausewidespreadandlastingchangesinthepostsynapticneuron,especiallylong-termmemory.NMDAandAMPAreceptor85GABA(γ-aminobutyricacid)GABAergicneuronsaredistributedwidelyintheNS.TheyarethemajorsourceofsynapticinhibitionintheNS.86GABA(γ-aminobutyricacid)GAD(glutamicaciddecarboxylase):agoodmarkerofGABAergicneuronsPyridoxalphosphate:VB6lackofB6---GABAcontent↓---lossofsynapticinhibition---seizuresGADGABAtansaminase87GABA

receptorsLigand-gatedionchannelsGABAAandGABAC:Cl-channel↑---IPSPInCNS,GABAAisthemajorreceptor.GABAAisthetargetofsedative-hypnoticsandantiepilepticdrugsGPCR:GABAB:Gi---AC↓/K+↑---IPSP88GABAAreceptorFivesubunits:αβγareabsolutelynecessary(2α2βγ)GABA:βsubunitAgonist:Muscimol（蠅蕈醇）Antagonist:Bicuculline（荷包牡丹堿）89GABAAreceptorBenzodiazepine:αsubunitSedative-hypnotics（鎮靜催眠藥）Agonist:diazepam（地西泮）安定Inverseagonist:β-carboline（卡波林）Antagonist:flumazenil（氟馬西尼）Barbiturate:antiepilepticdrugs（抗癲癇藥）andanaesthesia（麻醉）Neurosteroids:asbarbituratePicrotoxin:antagonist90Glycine91GlycineGlycineisthemajorNTininterneuronsatspinalcord(Renshawcell)Serinehydroxymethyltransferase:

Mutations---hyperglycinemia(adevastatingneonataldisease)---lethargy（嗜睡）seizures（抽搐）andmentalretardation（智力低下）Co-agonistforNMDAreceptorGlycinereceptor:Cl-channel3α2βAnta