神经生物学课件：乙酰胆碱和其他神经递质

乙酰胆碱和其他神经递质1Chapter6:Acetylcholine

乙酰胆碱2GeneralknowledgeHistoryofAChasaneurotransmitter:1867:Chemicallysynthesized.乙酰胆碱3Dale(1914):theeffectofAChontheheartissimilarwiththatofvagalstimulation

Loewi(1921)、Dale（1924):infusionexperimentoffrogheart.1936:NobelPrize.Conceptofcholinergicneurons:Neuronsthatuseacetylcholineastheneurotransmitter.GeneralknowledgeChemicalpropertyofacetylcholine：a.Easilyhydrolyzed:stableatpH3.8-4.5；completehydrolysisatpH10and100°C.b.Easilycatalyticallyhydrolyzedbycholinesterase.生物学作用的即时性生物样品的保存和检测4Indirectmethods：a.Measureofcholinesteraseactivity：Acetylthiocholine(乙酰硫代胆碱法,AChE法）.b.ChAT:1970’s,ChATmultiplecolonialantibody;Eckenstein(1981)ChATmonoclonalantibody.Houser(1983):ConsistenceofAchEmethodandChATmethod.DirectmethodsRIA;ELISAChromatogram;HPLCetal.Imunohistology+fluorescenttracing.MeasureofacetylcholineGeneralknowledge56SectionI:DistributionandprojectionofcholinergicneuronsintheCNS分布与投射Classificationofcentralcholinergicneurons：ProjectionneuronLocalcircuitneuronACh神经元分布在哪里？(I)基底前脑胆碱能系统(basalforebraincholinergicsystem)Mesulam和Perry分群：ch1-ch6。Ch1、Ch2、Ch3分别相当于隔内侧核（medialseptalnucleus）、斜角带垂直部（verticalnucleusofthediagonalband）、斜角带水平部（horizontallimbofthediagonalband）；Ch4则包含了视前大细胞区、苍白球底板的无名质及其向前延伸的苍白球腹侧区（纹状体下灰质）、Meynert基底核（nucleusbasalisofMeynert）、豆状攀核等界限并不很清楚的区域。I.胆碱能投射神经元(Projectionneuron)7基底前脑胆碱能系统(basalforebraincholinergicsystem)的主要投射通路：它们的投射纤维主要形成以下通路：①隔内侧核、斜角带-海马通路；②斜角带-杏仁复合体通路；③隔区-僵内侧核（medialhabenula）、中脑脚间核通路；④斜角带、Meynert基底核-大脑皮层通路。其中由Meynert基底核向皮质额叶、颞叶、顶叶和视皮层的胆碱能投射，与学习和记忆功能密切相关。①②③④8④(II)脑干胆碱能系统(brainstemcholinergicsystem)

由脑桥被盖胆碱能系统（pontinetegmentalcholinergicsystem）和延髓的胆碱能神经元组成。纤维：背侧被盖束和腹侧被盖束，向头端投射至丘脑、丘脑下部、苍白球、尾壳核等，并与其它上行纤维一起组成网状上行激活系统，引起觉醒和警觉。脑桥被盖胆碱能系统主要包括脚间脑桥被盖区（pedunculopontinetegmentalregion,ppt）和背外侧或外侧被盖核（dorsolateralorlaterodorsaltegmentalnucleus,ldt）中的胆碱能神经元，相当于Mesulam和Perry分群中的Ch5、Ch6。I.胆碱能投射神经元(Projectionneuron)910中脑和脑桥动眼神经（III）、滑车神经（IV）、外展神经（VI）的胆碱能运动神经元胞体。延髓胆碱能神经元主要分布：舌下神经核（XII）、迷走神经背核与疑核（X）、面神经核（VII）、三叉神经脊束核（V）11I.胆碱能投射神经元(Projectionneuron)(III)Cholinergicneuronsinthespinalcord脊髓前脚运动神经元侧角交感和副交感节前神经元12局部环路神经元这类神经元在核团内局部组成环路，不向核外发出投射，属中间神经元。纹状体（尾-壳核复合体，Caudate-putamencomplex）、伏隔核(nucleusaccumben)、嗅结节（olfactorytubercle）、海马和大脑皮质内Ⅱ-Ⅴ层。纹状体内胆碱能神经元主要为大、中型无棘突多极神经元，参与黑质-纹状体多巴胺系统对运动的调节，其异常与帕金森氏病（Parkinson’sDisease,PD）的病理过程密切相关。孤束核、前庭外侧核、外侧网状核、巨细胞网状核、中缝大核等。脊髓背角的胆碱能神经元投射到脊髓RexedⅡ-III层、小脑内第Ⅱ层颗粒细胞投射到Ⅴ层细胞也形成局部环路。II.Localcircuitneuron13基底前脑乙酰胆碱能系统(basalforebraincholinergicsystem)的主要投射通路有哪些？皮层和海马是否有乙酰胆碱能神经元？Question

114-S-(I)BiosynthesisCholineAcetylcoenzymeACholineacetyltransfease胆碱乙酰转移酶Cholineacetylase胆碱乙酰化酶Substrates:胆碱乙酰辅酶ASectionII:biosynthesis,storageandrelease15ChAT,globulin,MW68000.Synthesizedincellbody,takeseffectinterminals.Essentialchemicalgroups:imidazole,-SH.Enzymedynamics(Km)：choline7.5×10-4mol/L;AcetylCoA1.0×10-5mol/L.Siteofsynthesis合成部位：CholinergicterminalsEnzyme:(I)Biosynthesis16ChAT咪唑基乙酰化转乙酰作用活性中心：咪唑基巯基AcetylcoenzymeACholine(I)BiosynthesisCholineacetyltransfease胆碱乙酰转移酶ChATCholineacetylase胆碱乙酰化酶171.AcetylCoA.Source:(1)glucose-pyruvicacid-AcetylCoA.

（2）Fattyacidb-oxidation.

（3）synthesizedfromcitricacid.(4)acetate(non-neuraltissues)Substrate:(I)Biosynthesis182.CholineSource:

a.uptakeandhydrolyzelecithinfromcirculation.b.hydrolysisoflecithinofneuronaltissues.c.hydrolysisofAchandreuptakeofcholine.1/3-1/2.卵磷脂(I)BiosynthesisSubstrate:19

Lowaffinitycarrier:distributedinallneuronsandgliacells.Km:40-100micromol/L.facilitateddiffusionTransportationofcholine:Highaffinitycarrierspecificallydistributedincholinergicterminals.Km:0.4-4micromol/LNa+,ATP-dependentactivetransportation.Satureduptake.Themosteffectivelimitfactorofacetylcholinesynthesis(!).Cholineisthelimitsubstrate.(I)Biosynthesis20Hemicholium-3(HC-3)密胆碱Mechanism：competehighaffinitycarrierwithcholine.Antagonizedbycholine.

神经末梢characteristics：unabletopassthoughblood-brainbarrier;centraladministrationneeded.Strong,slow,lastingeffect.Triethylcholine三乙基胆碱(CH3CH2)3N+-(CH2)2-OHMechanism：synthesisoffakeneurotransmitter，inadditiontocompetingwithcholineforuptake4-(1-naphthylvinyl)pyridine]

4-(1-萘乙烯基)吡啶Mechanism：：specificChATinhibitorinvitro.AgentsaffectingthebiosynthesisofACh(I)Biosynthesis21试述乙酰胆碱生物合成的主要底物、以及影响乙酰胆碱生物合成的主要因素。如何调节乙酰胆碱的合成?Question

222ATP--vesicleprotein---Ach+VesicleAcetylcholineTransporter(VAChT)(II)StorageandreleaseStorage:胆碱能神经元标志高浓度质子泵23Release:PhosphorylationanddephosphorylationofsynapsinIinregulationofreleasableandreservepoolsofvesicles.(II)StorageandreleaseCa++synapsinIactinActivezoneofsynapse.24稳定池不稳定池盈余池Electrophysiologicalobservations:-restingneuromuscularjunctionsoftenhadspontaneousminiatureendplatepotentials(mepps)oflessthan1mVinamplitude.微小（最小）终板电位amplitudeofstimulatedeppweremultiplesofthemepps.Conclusion:-transmitterisreleasedindiscreteunits(quanta).-smallestmepprepresentsthereleaseof1quanta.(II)StorageandreleaseEvidenceofquatarelease:252.ElectronmicroscopyEvidenceofquatarelease:Freeze-fractureelectronmicrograph263.NeurochemistryNa+K+Ca2+VSCCreleaseeffluxLactatedehydrogenase*Evidenceofquatarelease:4.CloningofVAChTandfindingitsblockervesamicolQuestion3什么是量子释放？依你所知，有哪些证据证明神经递质是以量子方式释放的？检测-释放量27SNAP-25SYNTAXINSynaptobrevin(VAMP)Botulinumtoxin肉毒杆菌毒素Tetanus

toxin破伤风毒素-bungarotoxin-bungarotoxinH+vesamicol银环蛇毒素α-BGT与运动终板乙酰胆碱受体结合，抑制乙酰胆碱对横纹肌细胞膜的去极化作用，横纹肌松弛。β-BGT作用于运动神经突触前膜产生一种三相变化，1）递质释放减少，2）释放增加，3）随后是进一步抑制，使骨骼肌不能兴奋收缩而转入持续性麻痹，其毒性比突触后毒素高得多。运动终板Blackwidowspidervenom1）阻断SNARE蛋白分离2）形成离子通道28TransmitterisGLYCINETransmitterisACETYLCHOLINEBotulinumToxin29Specificcholinesterase(AchE)：mainlyinneuraltissues。Non-Specificcholinesterase(butyrylcholinesterase):gliacells,non-neuraltissues.I.Enzymaticdecompositionandinactivation乙酰胆碱酯酶-水解速度106Ach/S丁酰胆碱酯酶SectionIII:Enzymaticdecompositionandinactivation30StructureofAchE1)Anionsite:imidazolegroupofhistidine(组氨酸）.2)SiteofEnzymaticdecomposition:-OHofserine,nucleophilic（I）reversiblePhysostigmine,毒扁豆碱neostigmine:新斯的明

为含季铵基团的氨基甲酸酯类。Edrophonium:Edrophoniumchloride依酚氯铵：

含季铵基团，但无氨基甲酰基。起效快，作用短。（II）irreversible:organicphosphoruspesticide,chemicalwarfareagent（VX,沙林）II.Cholinesteraseinhibitors31有机磷农药32生化武器33antidotestoanticholineesterasessymptomatic“antidote”-atropinepralidoxime(2-PAM)解磷定BACD解毒剂A氯磷定(2-PAM·Cl)

B双复磷(LüH-6)

C甲磺磷定(P2S)

D双磷定(TMB-4)1.2.直接与有机磷结合34解毒：Alzheimer’sdisease四氢氨基吖啶（tetrohydroaminoacridine）

TacrineHydrochloride35抑制胆碱酯酶的药用价值SectionIV:CholinergicReceptorsAch某些效应可被毒蕈碱（muscarine）模拟而被阿托品阻断另一些效应可被烟碱（nicotine）模拟而被箭毒（curare）阻断36I.Muscarinicreceptor1.G蛋白偶联2.7次跨膜3.差异--大环4.两类M1,3,5;M2,437Meffects:

1)Inhibitingheart(M2)todecreaseheartrate,conductionandcontractility.

2)Vasodilationofartery(M1血管内皮--

NO）

3)Contractionofbronchial,gastrointestinalandgenitourinarysmoothmuscles,butrelaxationofsphincters

4)Increasing

secretion(M3)ofsalivary,respiratoryandgastrointestinaltractglands

5)Eye(M3):miosis.nearvision.泌尿生殖器括约肌瞳孔缩小38外周效应M1，3，4receptors----cortex,hippocampus—learningandmemoryM1,4receptors----striatum–extrapyramidalmotorcircuitsM2–basalforebrain—autoreceptorstocontrolAChsynthesisandreleaseM5istheleastabundant—Substantianigra.Mreceptorantagonists(trihexyhenidylandbenztropine)areprescribedtoPDpatients苯海索苯托品Tricyclicantidepressantsandlow-potencyantipsychoticdrug(chlorpromazine氯丙嗪)antagonizeMreceptors中枢的M受体分布东莨菪硷M1andM2MuscarinicReceptorSubtypesRegulateAntidepressant-LikeEffectsoftheRapidlyActingAntidepressantScopolamineJPharmacolExpTher351:448–456,39II.Nicotinicreceptor40Purificationofcholinergicreceptors

金环蛇Bungarusfasciatus银环蛇Bungarusmulticinctus41应用金银环蛇毒素PurificationofreceptorsCarb-nAchRTorpedoelectricorgannAchRnAchRnAchRsolubilizationHomogenizationCarbamylcholineSequenceanalysisofsegmentsSynthesisofprobeRNAa-BTXReconstructioninlipidbilayer(functional?)电鳐42氨基甲酰胆碱洗脱cDNAlibraryscreeningLowdensityreceptorsintissueIsolatetotalRNAsIsolatemRNAsprobeRNAcDNAlibraryInvitrotranscriptionofthecDNAlibraryInjectionofcRNAsintoXenopusoocytesElectrophysiologicalmeasurementofligand-inducedcurrent SequencingInjectionofcRNAsintoXenopusoocytesPCR43HomologyscreeningTorpedoelectricorganSubunitsofAchRare4TMHydropathyindexanalysis44thesuperfamilyofcys-loopreceptors亲水面形成离子通道内壁45TM2segmentisthepore-liningdomainofAchR46Structureandfunctions：Membrane-bindingglucoprotein.Fivehomologoussubunits(1,,1,1,)makeupthechannel.Eachsubunitshasfour-helicalmembranespinningdomains(M1-M4),andM2domainofeachsubunitmakeupthelinenofthechannel.ThetwosubunitsarethebindingsitesforACh

(-BGTX)Bothareceptorandachannel,mediatesfastsignaling.(I)Peripheralnicotinicreceptors47Ach功能？48解剖位置属于外周受体分型属于中枢NolossofAPinnervecellsAristotleOnassislossofmuscletoneMG-myastheniagravisAutoimmunedestructionofacetylcholinereceptorsnAChRHinderACh-receptorinteractionIncreasereceptorturnoveranddegradationTreatment:AChEinhibitors,glucocorticoidsorotheragentstosuppressimmunefunction重症肌无力机制49试述外周尼古丁型乙酰胆碱受体的结构和功能特点Question450（II）Centralnicotinicreceptors(includingganglion)Subunitcompositionofcentralnicotinicreceptors:2-10(theperipheralsubunitas1)2-4(theperipheralsubunitas1)About2-6,2-4:Donotformhomomericreceptors,noreceptorswithonlyoronlysubunitsexist.51Commonreceptortypes52Theheteromeric

4223

subtype:facilitateGABAergicandglycinergicneurotransmission.Insensitiveto-BGTX，sensitivetoKappaorFtoxin.GABAglycine4223422353Thehomomeric75subtype:facilitateglutamatergicneurotransmission.sensitiveto-BGTX.glutamate757具有-BGTX高亲和力结合部位7-10只形成同聚体（成熟神经元细胞表面）54GarduñoJetal.J.Neurosci.2012;32:15148-15157©2012bySocietyforNeuroscience例外Presynapticα4β2nicotinicacetylcholinereceptorsincreaseglutamatereleaseandserotoninneuronexcitabilityinthedorsalraphenucleus.JNeurosci.2012Oct24;32(43):15148-5755Fig.1(A)PhotomicrographshowingbasalocorticalPHA-L-labeledfibersintheretrosplenialgranularcortex(RSG)followingaseriesofinjectionsofPHA-Lintothemedialpartofthehorizontallimbofthediagonalban(HDBm).PHA-Llabeledfibersarecon...Localizationofα7nicotinicacetylcholinereceptorimmunoreactivityonGABAergicinterneuronsinlayersI–IIIoftheratretrosplenialgranularcortexNeuroscience,Volume252,2013,443-459N受体在细胞体的分布563,5,72,4makeupthechannel.homomericreceptorscontaining3inmostcondition.Heteromericreceptorscontaining7(胚胎期)(III)Nicotinicreceptorsinautonomicganglions解剖分类属于外周型亚单位组成属于中枢57PresynapticnAChRsinducereleaseofanumberofneurotransmittersPostsynapticnAChRsdepolarizeneurons,increasetheirfiringrate,andcancontributetolong-termpotentiation58重要的中枢作用兴奋效应直接--兴奋2.间接？钙依赖效应与N受体的钙通透激活邻近的电压依赖性钙离子通道细胞内钙参与效应。59试述中枢尼古丁型乙酰胆碱受体的结构和功能特点Question4Characteristicsofcentralnicotinereceptors:

*Structure，subunits,*highlypermeabletoCa++.consequentlyactivatevoltagegatedCa++channels.*Facilitationofglutamatergicneurotransmissionsby….sensitiveto….

*FacilitationofGABAergicandglycinergicneurotransmission

by…

Insensitiveto…..

602----Thereinforcingandcognitionenhancingeffects7-----Sensorygating4-----AnalgesiceffectsnAChR的中枢功能61？Summaryofmodulatoryeffectsofacetylcholine(ACh)oncorticalcircuitdynamics.ACh与学习记忆的关系62IncreasedAChbooststheprocessingofextrinsicafferentprojections,suppressesintrinsicprojections,andlowersthethresholdfortheinductionofLTP.ReducedAChboostsprocessingofintrinsicprojections,raisesthethresholdfortheinductionofLTPandincreasesthelikelihoodthatLTDisinducedActivationdynamicsandplasticityinModelofthetafunction.InhibitoryoscillationsconvertdifferencesintheAmountofexcitationreceivedbycellswithinanetworkintoatime(phase)code.Threeexamplecellsareshown,eachreceivingadifferentamountofexcitatoryinput:0.0—thiscellreceivesnoinputandneveractivates,itincursnoLTPorLTD;0.3—thiscellreceivesmoderateinputandactivatesonlyduringthetroughoftheoscillations,itincursLTDasaresult;and0.6—thiscellreceivesstronginputandactivatesduringmorethanhalfoftheoscillation,itincursLTPasaresult.ThetarhythmismodulatedbycholinergicandGABAergicinputsfromthemedialseptum,andincreasesinacetylcholineareassociatedwiththetaoscillations.Hippocampal

twoseparatefrequencycomponents,acholinergic-independent,movement-relatedthetarhythmat8–9Hz(type1)alowerfrequency6–7Hzcholinergic-dependentcomponent(type2)63RoleofnAChRsindevelopmentThedifferentsubtypesofneuronalnAChRsareknowntobedevelopmentallyexpressedintheratbrainand(particularlyfortheα7subtype)areknowntohaveimportantrolesinthedevelopmentofthehippocampalcircuitry.α7receptorsignaling---thematurationandsurvivalofadult-bornneurons,transformationofGABAergiccurrentsfromexcitatoryinearlydevelopmenttoinhibitorysynapseThecognitivedeficitsassociatedwithADmayberelatedtodysfunctionoftheα7nAChRs.α7nAChRcanundergorapidonsetofdesensitization（channelcloseseveninthecontinuedpresenceofanagonist）.therapeuticdrugsthatpotentiateα7receptorsthroughtheremovalofdesensitization(e.g.,PNU-120596)arecurrentlybeingdevelopedtotreatAlzheimer'sdiseaseandotherneurologicalInthebrain(andinparticularthehippocampus),nicotineorAChactivationoftheα7nAChRblockedthereleaseofproinflammatorycytokines.64胶质细胞？Site1: UptakeofcholineSite2: Biosynthesisofacetylcholine(ChAT)，VesicleAcetylcholineTransporter(VAChT).Site3: ReleaseofAch(Note:Thisisnotagoodsiteforthedesignofcholinergicdrugs).Site4: MetabolismofAChbyacetylcholinesterase(AChE)..Site5: PostsynapticandPresynapticreceptors(maintargetfordrugaction).65乙酰胆碱系统的干预？乙酰胆碱能神经元的分布？受体结构和功能特点中枢乙酰胆碱的功能SectionI:Histamine组胺Recognitionofhistamineasanintercellularmessenger:注射组胺—过敏(allergy)，呼吸窘迫抗组胺药广泛应用于临床抗组胺药物的镇静作用—组胺唤醒Arousal

中枢作用？DistributionPeripheral:mastocyte,basicyte.Central:Neuronalhistamineintuberomammillarynucleus(TMN).Non-neuronalhistamine:gliacell,endothelialcell肥大细胞，嗜碱性细胞Histamine不易通过BBB中枢外周独立Chapter12Otherneurotransmitters66？神经营养，神经免疫，脑血流，BBB渗透性调节，等H2-receptorantagonists

asdrugscuringpepticulcerMechanismofactionCompetitivelyblockthehistamine(H2)receptorofacid-producingparietalcells

renderingcellslessresponsivetonotonlyhistaminebutalsotothestimulationofacetylcholineandgastrin.Alsoupto90%inhibitionofvagalstimulatedandgastrinstimulatedacidsecretion.

胃泌激素泌酸细胞FourFDA-approved:Cimetidine西咪替丁（Tagamet®）Ranitidine雷尼替丁（Zantac®）Famotidine法莫替丁（Pepcid®）Nizatidine尼扎替丁（Axid®）Roxatidine罗沙替丁H2-receptorantagonists671.Histaminetransportandmetabolisminneurons组氨酸脱羧酶，HDC组氨-N-甲基转移酶HNMT单胺氧化酶，醛脱氢酶213456甲基组胺68VMAT-2locatedpostsynapticallyandinglia失活形式HAD抑制剂：-氟甲基组氨酸，-FMH2.Histaminergicneurons神经元集中，投射广泛（脑的腹侧部为多）突触:dendrites(predominately),cellbody(less)递质共存常见（GABA,P物质）tuberomammillarynucleus(TMN)69乳头体核结节核JCompNeurol.2010Nov15;518(22):4591–4611.Histidinedecarboxylase(HDC),melanin-concentratinghormone(MCH),andorexin/hypocretins(ORX)70BrainhistamineduringdevelopmentIntherat,theliveristhemainsiteofhistaminesynthesisduringlatestagesoffetaldevelopment,althoughanextensive,transienthistamine-containingneuronalsystemcanbefoundintherapheareaofthebrainduringthisperiod.Thissystemisfirstdetectableonembryonicday14(E14),andatE16,histamineandserotoninshowmarkedcoexistenceintheraphearea.ByE18,histaminelevelsarealreadydiminishedinneuronsoftherapheregion.Histamine-containingmastcellspopulatetheratbrainatE18–E19,andthenumberofthesecellsincreasesuntilpostnatalday4.Therattuberomammillarynucleus(TMN)neuronsarebornbetweenE13andE18,andthatHDC组胺脱羧酶isfirstdetectableintheseneuronsonE18.IntracellularhistamineimmunofluorescencecanbedetectedinTMNneuronsonE207172ProminentsourcesoftheafferentprojectionstoTMtheinfralimbiccortex,lateralseptumandpreopticnucleus.adrenergiccellgroupsC1–C3,noradrenergicgroupsA1–A3,andfromserotonergicgroupsB5–B9,Themainterminalareasofthehistaminergicprojectionsarealsoslightlydifferentindifferentspecies,buttheycoveressentiallyallareasoftheCNS.下边缘皮质:regionintheventromedialprefrontalcortex2.Histaminergicneurons4)Firingproperties:Spontaneouslyactive:pace-makerproperty.

缓慢去极化—动作电位

自发放电机制:persistentsodiumcurrent，voltage-gatedcalciumcurrent.b.Lowfiringfrequency放电频率低:LongerAPduration动作电位时程长.Obviousafterhyperpolariztion(AHP):后超极化明显

机制：voltage-gatedKcurrent,calcium-dependentKcurrent.e.H3autoreceptorsregulate

thefiringrate:inhibitionofVDCCs.I-clampV-clampH3激动剂的抑制效应(H3receptorantagonist)噻普酰胺<组胺H3受体拮抗药>反向激动组氨能神经元的分布电活动特点和机制.Question753.Histaminergicreceptors组胺受体H1-4,为G蛋白偶联受体。H1-3分布于CNS。H1，H2兴奋;H3抑制(H3多亚型，Splicing)H4肥大细胞，白细胞，骨髓组织。

原位杂交BindingH1H2H3磷脂酰二肌醇H1-Gq/11磷脂酶C

三磷酸肌醇，甘油二酯

抑制钾电导H2—Gs腺苷酸环化酶H3—Gi/o抑制腺苷酸环化酶

抑制钙离子通道

自身抑制，抑制其他递质释放

组胺受体信号通路H1receptors.DepolarizationofaneuronofthepontinereticularformationthroughblockofaK+conductance.H3receptors.Decreaseoffieldexcitatorypostsynapticpotentialinthedentategyrusofthehippocampusevokedbyperforantpathstimulation.Histaminereducedthereleaseofglutamateinthispathway.H2receptors.Blockofthelong-lastingafterhyperpolarizationafterCa2+-inflow(calcium-dependentK+conductance)andblockoftheaccommodationofactionpotentialfiringinahumanhippocampalpyramidalcell.79InteractionsofthehistamineH3receptorwithdopaminereceptors804.HistamineandthefunctionoftheCNS1)ArousalwakefulnessH1受体有关证据：1.组胺能神经元活动随睡眠觉醒周期波动2.组胺释放有昼夜节律3.损毁或抑制TM神经元导致嗜睡4.脑内注射组胺或H1受体激动剂可延长清醒，缩短睡眠。H1拮抗剂阻断这些效应。

H3拮抗剂有利觉醒81ThehistaminergicTMNnetworkisanessentialcomponentofthesleep–wakeregulatorysystemVentrolateralpreopticnucleus82GABA4.HistamineandthefunctionoftheCNS脱水stressVasopressinreleaseHistamine-FMH,H3agonists,postsynaptichistmineantagonists(-)2)MaintenanceofendohomeostasisWaterbalance:H1receptor→vasopressinFeeding下丘脑腹内侧核（饱中枢）

三叉神经核（咀嚼控制）

对leptin功能具有permissiveactionThermalregulation（双向变化，先降后升）

下丘脑视前区H1降低体温调定点下丘脑后部H2散热Cardiovascularregulation

升血压，心率减慢

H2受体-动脉压力感受器反射

兴奋交感神经，释放儿茶酚胺；促释放AVP833)Learningandmemory:peoplepredisposedtoallergysmarter?4.HistamineandthefunctionoftheCNS4)Emotionandanxiety5)Painmodulation脑内组胺参与焦虑情绪形成外周介导伤害性感受器，介导痛觉在中枢起镇痛作用脑内组胺系统可能是对威胁做出反应的系统脑内组胺系统的兴奋可激活交感系统，释放应激相关激素。组胺参与神经系统疾病的机制。846）Localizationofhistaminereceptorsindifferenttypesofcellsinthebrainthatarepotentiallyinvolvedinblood–brainbarrierpermeabilityandmultiplesclerosis.Hreceptorsinbrainneurons,astrocytes,endothelialcellsandimmunocompetentcellsformacomplexsystemattheinterfaceofbraincapillariesandtheneuropile.Brainendothelialcellsexpressallfourtypesofhistaminereceptors.Astrocytes,whichsurroundbraincapillarieswiththeirendfeet,expresshistamineH1receptors(H1Rs)andH2Rs.HistaminergicandotherneuronswithterminalsaroundtheastrocyteendfeetcontainpresynapticH3Rs.CirculatingactivatedTlymphocytesexpressatleastH1Rs,andpossiblyalsoH2RsandH4Rs.Mastcells,whichexpressH1Rs,H2RsandH4Rs197,arefoundonlyinlimitedperivascularareasoftheratbrain(medianeminenceandthalamus)andarepotentiallyimportantinthehumanbrainandapossiblesourceofH4Rs.85SectionII:nitricoxideRobertFFurchgott,born1916Dept.ofPharmacology,SUNYHealthScienceCenterNewYorkLouisJIgnarro,born1941Dept.ofMolecularandMedicalPharmacologyUCLASchoolofMedicineLosAngelesFeridMurad,born1936Dept.ofIntegrativeBiologyPharmacologyandPhysiology,UniversityofTexasMedicalSchool,HoustondemonstratedthattherelaxationofbloodvesselsdescribedbyFurchgottwasduetoasubstanceproducedintheendothelium,whichhisgroupcalledendothelium-derivedrelaxingfactor(EDRF).In1987,IgnarrodemonstratedthatEDRFwasnitricoxide.86FurchgottandZawadzkishowedthattherelaxationofbloodvesselsdependedonanintactendothelium.showedthatnitroglycerinecausedbloodvesselstorelax,andthatthiswascausedbythereleaseofnitricoxidegas1.Biosynthesisandenzyme底物：L-精氨酸,

O2,NADPH产物：胍氨酸，NO酶：nitricoxidesynthase,NOS.NO合酶NO是极不稳定的脂溶性小分子，可迅速扩散Whenexposedtooxygen,NOisconvertedintoNO2.2NO+O2→2NO2Inwater,NOreactwithoxygenandwatertoformHNO2.4NO+O2+2H2O→4HNO2血液中血红蛋白是NO的主要清除剂（scavenger），也是NO的储存和运输工具87NameGene(s)DescriptionNeuronalNOS(nNOSorNOS1)NOS1ProducesNOinneuronaltissueinboththecentralandperipheralnervoussystem.NeuronalNOSalsoperformsaroleincellcommunicationandisassociatedwithplasmamembranes.InducibleNOS(iNOSorNOS2)NOS2A,NOS2B,NOS2CCanbefoundintheimmunesystembutisalsofoundinthebrainandcardiovascularsystem.EndothelialNOS(eNOSorNOS3orConstitutive/cNOS)mNOS

NOS3GeneratesNOinbloodvesselsandisinvolvedwithregulatingvascularfunction.AconstitutiveCa2+dependentNOSprovidesabasalreleaseofNO.eNOSisassociatedwithplasmamembranessurroundingcells.?88nNOS,eNOS是Ca2+-钙调蛋白依赖性酶，为基本型

cNOS(constitutiveNOS)iNOS不依赖Ca2+-钙调蛋白2.Cellactions无储存囊泡扩散传递作用机制：1.激活鸟苷酸环化酶（guanylylcyclase,GC）2.修饰蛋白质的含铁辅基，巯基，和芳香族氨基酸—参与炎症和细胞损伤等病理过程第二信使激活蛋白激酶cGMP-dependentproteinkinase(PKG)additionalsecondmessengersystemscAMP-dependentkinasePKA89注意：它可以扩散到其他细胞90效应：促进突触功能，促进LTP3.FunctionsofNOinCNS（1）Modulationofneurotransmissionexertslong-lastingeffectsthroughregulationoftranscriptionfactorsandmodulationofgeneexpression（2）Leaningandmemory:

modulationofsynapticactivity,neuralplasticity，LTPandmemoryfunctions.（3）RegulationofneuronalsurvivalanddifferentiationNOdonors具有促进记忆。调节LTP，LTDNOdonorsareinuseinclinicalmanagementofcardiovasculardiseases.AmongNOdonors,molsidomine(脉导敏)hasahighbioavailability,along-lastingdurationofaction,likelycrossesthebloodbrainbarrier(BBB)9192亚硝基化92NO在神经系统的主要作用机制QuestionWithlowconcentrationsNOisneuroprotectiveandmediatephysiologicalsignaling(e.g.,neurotransmissionorvasodilatation),whereashigherconcentrationsmediateimmune/inflammatoryactionsandareneurotoxiclowconcentrationshigherconcentrationsNOGlu,GABAAch,5-HT,histamine,catecholamineModulationofneurotransmission93SectionIII:PurineandPyridine嘌呤和嘧啶类分子可作为神经递质Druryetal1929:vasodilatation.（adenosine,AMP）Gillespie1934:adenosine,AMP----bloodpressureATP----bloodpressuredifferentreceptors?Holton1953:releaseofATPatsensoryneuralterminals—neurotransmitter?Burnstock1972:conceptofpurinergicnerve（肠道神经肌接头）.Burnstock1978:P1,P2receptorsadenosine,ATP\ADPATPactsaseitherthesoletransmitter