细胞生理2.ppt

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1、细胞生理细胞生理2vDefinition and identification of neurotransmittervDiscovering of neurotransmitter vCategory and distribution of neurotransmittervDefinition of modulatorvCoexistence of transmittervMetabolism of transmitterSection Outline1.Neurotransmitter1.1 Definition and identification of neurotransmitte

2、rnDefinition:A chemical released from a presynaptic terminal diffuses to another neuron where it causes excitation or inhibition.nIs synthesised,stored,and released from neuronsnActivates receptors to produce an effect on the post-synaptic cellnHas agonist or antagonist to mimic or block its effects

3、nHas its action terminated1.1 Definition and identification of neurotransmitterA chemical substance that:nIn the night of Easter Saturday,1921,I awoke,turned on the light,and jotted down a few notes on a tiny slip of paper.Then I fell asleep again.It occurred to me at six oclock in the morning that

4、during the night I had written down something most important,but I was unable to decipher the scrawl.That Sunday was the most desperate day in my whole scientific life.During the next night,however,I awoke again,at three oclock,and I remembered what it was.This time I did not take any risk;I got up

5、immediately,went to the laboratory,made the experiment on the frogs heart,described above,and at five o clock the chemical transmission of nervous impulse was conclusively proved.-quoted from Loewi,O.,From the Workshop of Discoveries,Lawrence:University of Kansas Press,1953.Otto Loewi 1921Otto Loewi

6、1873-1961He connected two frogs hearts by a solutionThe electrical stimulation of the first heart affected the second through the solutionConcluded that there was a chemical released that affected the second heart Frogs and hearts*Awarded 1936 Nobel Prize in Physiology or Medicine1.3 Category and di

7、stribution of neurotransmitterBiogenic AminesAmino AcidsPeptidesOthersAcetylcholine MonoaminesSerotonin CatecholaminesNoradrenaline/NorepinephrineDopamineAdrenaline/EpinephrineSubstance PATPNitric OxideGlutamateGABAAcetylcholine,AChnIn CNS:vDistribution:motor neuron,the ascending reticular activatin

8、g system,thalamus,striatum,hippocampus.vEffects:most of them are excitatory.In PNS:nDistribution:Cholinergic fibers includes:vSomatic nerve fibers(neuromuscular junction)vANS preganglionic fibervParasympathetic postganglionic fibervA few sympathetic postganglionic fibernEffects:excitatory or inhibit

9、ory which depends on its receptorAcetylcholine,AChMonoamine neurotransmitternNoradrenalin,NA and adrenalin,AnDopamine,DAnSerotonin,5-HTAdrenergic pathwayDopaminergic pathwaySerotoninergic pathwayPeptides neurotransmitternEnkephalinn-endorphinnDynorphinnSubstance PnNeurotensinAmino acid neurotransmit

10、tersnExcitatory amino acid,EAAvGlutamatevAspartatenInhibitory amino acid,IAAvGABAvGlycinenGlutamate is the major excitatory neurotransmitter which plays an important role in learning and memorynGABA is the major inhibitory neurotransmitter which plays anxiolytic,antiepileptic and anticonvulsant effe

11、cts Amino acid neurotransmittersPurine neurotransmitternPurines neurotransmitter:inhibitory neurotransmitter,ATPNitric oxideOthersnCarbon monoxide,COnHistamine1.4 Definition of modulatornCharacteristics of neuromodulatorvGenerated and released by neuron or glia cellvModulate presynaptic neurotransmi

12、tter releasevModulate postsynaptic response 1.5 Coexistence of transmitternDales principle:nCoexistence of transmitter:vNA and neuropeptide YvAch and VIP1.6 Metabolism of transmitternAch1.6 Metabolism of transmitternNAnNA1.6 Metabolism of transmitterDopamine,DA1.6 Metabolism of transmitter2.Neurotra

13、nsmitter receptorvCholinergic receptorvAdrenergic receptor vReceptor of neurotransmitter in CNSvPresynaptic receptorSection OutlineReceptornCharacteristics of binding of ligand and receptor:vSpecificityvSaturabilityvReversibilityAgonist and antagonistBasis of Neuropharmacology Agonists and Antagonis

14、tsnAgonistsnStructurally similar to neurotransmitter to activate receptornAntagonistsnAntagonists block receptornDiverse structures often unrelated to neurotransmitterAbout neurotransmitter receptor nDifferent subtypes of receptornPre-and postsynaptic receptor Presynaptic autoreceptornIonotropic rec

15、eptor G-protein coupled receptor Enzyme coupled receptornDesensitization 2.1 Cholinergic receptornMuscarinic receptor,MnNicotinic receptor,NMuscarinic receptornDistribution:Membrane innervated by most parasympathetic postganglionic fiber and few sympathetic postganglionic fiber.nSubtypes:M1,M2,M3,M4

16、,M5nG-protein coupled receptornMultiple effects:nAntagonist:atropineNicotinic receptornNeuron-type nicotinic receptor,N1 vLocated at postsynaptic membrane of both sympathetic and parasympathetic ganglia vLigand gated ion channelvAntagonist:tubocurarine(N1 and N2)hexamethonium Nicotinic receptornMusc

17、le-type nicotinic receptor,N2vLocated at end plate of neuromuscular junction vLigand gated ion channelvAntagonist:tubocurarine(N1 and N2)decamethonium nreceptorv1 receptorv2 receptornreceptorv1 receptorv2 receptorv3 receptor2.2 Adrenergic receptorreceptornActionv1 receptor:mainly excitatoryv2 recept

18、or:autoreceptornAntagonistvreceptor:phentolamine (1 2)v1 receptor:prazosinv2 receptor:yohimbinereceptorvActionv1 receptor:excitatoryv2 receptor:inhibitoryvAntagonistvreceptor:propranolol v1 receptor:practololv2 receptor:butoxamine2.3 Receptor in CNSnDA receptorn5-HT receptornGlutamate receptornGABA

19、receptornGlycine receptornPeptide receptornPurine receptornHistamine receptorDopamine receptornG-protein coupled receptornSubtypes:DA1,DA2,DA3,DA4,DA5nAction:DA1,DA5cAMP DA2,DA3,DA4 cAMP nAntagonist:DA receptor:pimozide DA1 receptor:SCH23390 DA2 receptor:butyrophenonesSerotonin receptorn7 families,5

20、-HT1-7n14 structurally and pharmacologically distinct subtypes v5-HT1A,5-HT1B,5-HT1D,5-HT1E,5-HT1Fv5-HT2A,5-HT2B,5-HT2Cv5-HT3:ligand-gated ion channelv5-HT4v5-HT5A,5-HT5Bv5-HT6v5-HT7nAntagonist:5-HT:cinanserin5-HT1A:spiperone,methiothepin5-HT3:ICS20930Serotonin receptorGlutamate receptornSubtypes of

21、 glutamate receptornNMDAnAMPA&KainatenMetabotropicGlutamate receptorGlutamate ReceptorsAMPA receptorNMDA receptorGlutamate is important for learning and memorynHigh densities of NMDA and AMPA receptors in the hippocampusnRole for glutamate receptors in long term potentiationnGlutamate receptor antag

22、onists inhibit LTP and learning and memorynAMPA receptor potentiators enhance LTP and learning and memoryField EPSPsHigh-frequency stimulationGABA receptornGABA-A receptor ionotropic receptornGABA-B receptor metabotropic receptornGABA-C receptor ionotropic receptorIonotropic GABA-A receptorAntagonis

23、t:vBicucullinevPicrotoxinGABA-A receptors mediate fast inhibitory synaptic potentialsn7 transmembrane domain Structural model of GABA-B receptor GiCa2+GiCa2+BaclofenPresynaptic GABA-B receptorGiGiK+K+Postsynaptic GABA-B receptorIonic mechanism of GABA-B receptorGlycine receptornStrychnine sensitive:

24、Cl-channel,IPSPnStrychnine insensitive:modulate glutamate receptor2.4 Presynaptic receptorGABAB1GABAB2glutamatergic terminalGABAergic terminalglutamatergic terminalGABAergic terminalGP dendriteGP dendritePresynapticPostsynaptic GABAB receptorsauto-GABAB receptorshetero-GABAB receptorsSummary-Neurotr

25、ansmissionAch receptornNicotinic receptors(nAchR),ligand-gated,located in autonomic ganglia(N1),neuromuscular junction(N2),Renshaw cell.nMuscarinic receptor:metabotropic.nM1 Gq IP3/DAG Ca2+,in brain,activates myenteric plexus.1.2 Discovering of neurotransmittervagus nerveelectricalstimulationHEART R

26、ATE SLOWSHEART RATE SLOWSsecreted chemical messenger“Vagusstoff”(acetylcholine)superfusateOtto Loewi1873-1961*Awarded 1936 Nobel Prize in Physiology or MedicinenExperiment on frog heart(1921)nAcetylcholine,AChnNorepinephrine,NE and Epinephrine,E (Catecholamine)nDopamine,DAn5-hydroxytryptamine,5-HTnH

27、istaminenAmino acids:glutamate,aspartate,-aminobutyric acid,glycinenPeptides:substance P,tachykinin,opioid peptide,brain-gut peptidenPurines:adenosine,ATPnOthers:nitric oxide,NO and carbon monoxide,CO1.3 Category and distribution of neurotransmitter1.1 Definition and identification of neurotransmitt

28、ernDefinition:A chemical released from a N.ending diffuses to another N.or effector C.where it causes Exc.or Inh.nCriteria:Synthesized or taken up by pre-S-N.nReleased in sufficient amount to cause Exc.or Inh.nSpecific receptor on the post-S-N.or effector cell.nMechanism for removal or inactivation.

29、nAgonist,antagonist to mimic or block its effects.nPharmacologist are able to develop drugs that regulate somatic,visceral activities,emotion,behaviors.1.1 Definition and identification of neurotransmitterAcetylcholine,AChnIn CNS:Cholinergic neurons are located in motor neuron,the ascending reticula

30、r activating system,thalamus,striatum,hippocampus.Most of them are excitatory.nAlzheimers disease:loss of cholinergic fiber in basal forebrain.nThe major NE-ergic cell group is locus ceruleus(LC,A6)which contributes most of axons of dorsal NE-ergic bundle in MFB,sending axons to cerebellum,cerebral

31、cortex,thalamus,hippocampus,hypothalamus,form part of ascending reticular activating system,regulates attention,arousal,circadian rhythms.Noradrenergic PathwaysDopamine,DAnNigrostriatal tract:substantia nigro pars compacta(SNc)axons caudate nucleus and putamen.This tract triggering of self-initiated

32、 movement and postural adjustments.nArcuate Nucleus axons median eminence release of PRLDopaminergic TractsDopaminenDA plays a role in movement,behavioral disorders.nParkinson disease:degeneration of DA-erginc neurons in SNc.nSchizophrenia,excess DA release,increased DA receptors,antipsychotic drugs

33、 function by blocking D2 receptors.SerotoninSerotoninSerotoninn5-HT plays a role in the following:v Mood control(drug that augment serotonergic transmission are used to treat depression,obsessive-compulsive behavior,schizophrenia).v Regulation of circadian rhythms.v Food intake.5-HT in Mental illnes

34、snWell known drug Prozat(fluxetine hydro-chloride),a serotonin reuptake inhibitor,is used in the treatment of depression.nIn the US,severe depression affects 18.8 million(9.5%)over 18 years of age and is almost always a factor in the more than 30000 suicides each year(NIMH,1998).Peptides neurotransm

35、ittern2 to 40 a.a.long,made in cell bodynLarger molecules,slow-acting(hundreds of ms),but substance P acts fast.nSP,CGRP,neurokinin A,neurotensin,endophin,enkephalin:involved in pain modulation and other functions.nAVP,VIP,CGRP:in control of cardiov.SnAVP,oxytocin:in response to stress.Glutamate is

36、important for learning and memorynHigh densities of NMDA and AMPA receptors in the hippocampusnRole for glutamate receptors in long term potentiationnGlutamate receptor antagonists inhibit LTP and learning and memoryn AMPA receptor potentiators enhance LTP and learning and memoryGABA-B receptorGABA

37、also activates a metabotropic receptor-termed the GABAB receptor.Like all GPCRs it is a seven transmembrane domain receptor.GABAB receptors can be located both pre-and post-synaptically.The two main effects of activating GABAB receptors is to close Ca2+channels and open K+channelsCa2+channel closure-inhibition of transmitter releaseK+channel opening-slow IPSPBaclofen is a selective GABAB receptor agonist,while CGP55845 is a selective GABAB receptor antagonist