Chapter9MotorSystem-1MuscleContractionandMotorUnitContentSkeletalMuscleContractionMotorUnitReference–TextBookP160-163P56–70P464P85–91P673-674SectionISkeletalMuscleContractionSignalTransmissionThroughNeuromuscularJunctionMolecularMechanismofMuscleContractionFactorsthatAffecttheEfficiencyofMuscleContractionPartI

SignalTransmissionThroughtheNeuromuscularJunction9SkeletalMuscleInnervation10IllustrationoftheNeuromuscularJunction(NMJ)11NewIonChannelPlayersVoltage-gatedCa2+channelinpresynapticnerveterminalmediatesneurotransmitterreleaseNicotinicAcetylcholineReceptorChannelinmuscleneuromuscularjunction(postsynapticmembrane,orendplate)mediateselectricaltransmissionfromnervetomuscle12NeuromuscularTransmissionSkeletalMuscleMyelinAxonAxonTerminal13NeuromuscularTransmission:StepbyStepNerveactionpotentialinvadesaxonterminal

-+------+++++++---++DepolarizationofterminalopensCachannelsLookhere++14K+OutsideInsideNa+Na+Na+Na+Na+Na+Na+Na+Na+Na+Na+Na+K+K+K+K+K+K+K+K+K+K+K+AChAChAChCa2+inducesfusionofvesicleswithnerveterminalmembrane.AChisreleasedanddiffusesacrosssynapticcleft.AChAChbindstoitsreceptoronthepostsynapticmembraneBindingofAChopenschannelporethatispermeabletoNa+andK+.Na+Na+K+MusclemembraneNerveterminalCa2+Ca2+15EndPlatePotential(EPP，終板電位)OutsideInsideMusclemembranePresynapticterminalMuscleMembraneVoltage(mV)Time(msec)-90mVVKVNa0ThresholdPresynapticAPEPPThemovementofNa+andK+depolarizesmusclemembranepotential(EPP)AChReceptorChannelsVoltage-gatedNaChannelsInwardRectifierKChannels16Meanwhile...OutsideInsideAChAChunbindsfromitsreceptorMusclemembraneAChsothechannelclosesAChAChNerveterminalAChishydrolyzedbyAChEintoCholineandacetateCholineAcetateCholineistakenupintonerveterminalCholineCholineresynthesizedintoAChandrepackagedintovesicleACh17StructuralReality18NeuromuscularTransmissionPropertiesofneuromuscularjunction1:1transmission:AnunidirectionalprocessHasatimedelay.20nm/0.5-1mseasilyaffectbydrugsandsomefactorsTheNMJisasiteofconsiderableclinicalimportance19ClinicalChemistryAchisthenaturalagonistattheneuromuscularjunction.Tubocurarineistheprimaryparalyticingredientincurare.TubocurarinecompeteswithAChforbindingtoreceptor-butdoesnotopenthepore.Sotubocurarineisaneuromuscularblockingagent.Tubocurarineandother,relatedcompoundsareusedtoparalyzemusclesduringsurgery.Carbacholisasyntheticagonistnothydrolyzedbyacetylcholinesterase.CarbacholandrelatedcompoundsareusedclinicallyforGIdisorders,glaucoma,salivaryglandmalfunction,etc.Suberyldicholineisasyntheticneuromuscularagonist.Relatedcompoundsareusefulintheneuroscienceresearch20AnticholinesteraseAgentsAnticholinesterase(anti-ChE膽堿酯酶抑制劑)agentsinhibitacetylcholinesterase（乙酰膽堿酯酶）prolongexcitationattheNMJ211.Normal:ACh

Choline+AcetateAChE2.Withanti-AchE:ACh

Choline+Acetateanti-AChEAnticholinesteraseAgents22Usesofanti-ChEagentsClinicalapplications(Neostigmine,新斯的明,Physostigmine毒扁豆堿)Insecticides(organophosphate有機磷酸酯)Nervegas(e.g.Sarin沙林，甲氟膦酸異丙酯。一種用作神經性毒氣的化學劑))23NMJDiseasesMyastheniaGravis（重癥肌無力）AutoimmunitytoAChreceptorFewerfunctionalAChreceptorsLow“safetyfactor”forNMtransmissionLambert-Eatonsyndrome（蘭伯特-伊頓綜合征，癌性肌無力綜合征）AutoimmunitydirectedagainstCa2＋

channelsReducedAChreleaseLow“safetyfactor”forNMtransmissionPratIIMolecularMechanismofMuscleContraction25StructureofSkeletalMuscle:

MicrostructureSarcolemma

（肌管系統）Transverse(T)tubuleLongitudinaltubule(Sarcoplasmicreticulum,SR

肌漿網)Myofibrils

（肌原纖維）Actin

肌動蛋白(thinfilament)Troponin

（肌鈣蛋白）Tropomyosin

（原肌球蛋白）Myosin

肌球蛋白(thickfilament)26WithintheSarcoplasmTransversetubules

（橫管）Sarcoplasmicreticulum-StoragesitesforcalciumTerminalcisternae-StoragesitesforcalciumTriad（三聯管）27Sarcomeres

bundleofalternatingthickandthinfilamentsjoinendtoendtoformmyofibrilsThousandsperfiber,dependingonlengthofmuscleAlternatingthickandthinfilamentscreateappearanceofstriations2829Thickfilament:Myosin(肌球蛋白，headandtail)Thinfilament:Actin肌動蛋白,Tropomyosin原肌球蛋白,Troponin(肌鈣蛋白calciumbindingsite)30MolecularMechanismofMuscularContractionTheslidingfilamentmodel

肌絲滑行MuscleshorteningisduetomovementoftheactinfilamentoverthemyosinfilamentReducesthedistancebetweenZ-lines31TheSlidingFilamentModelofMuscleContraction32ChangesintheappearanceofaSarcomereduringtheContractionofaSkeletalMuscleFiber33EnergyforMuscleContractionATPisrequiredformusclecontractionMyosinATPasebreaksdownATPasfibercontracts34NerveActivationofIndividualMuscleCells(cont.)35ActionpotentialalongT-tubulecausesreleaseofcalciumfromcisternaeofTRIADCross-bridgecycleExcitation/contractioncouplingBegincyclewithmyosinalreadyboundtoactin371.MyosinheadsformcrossbridgesMyosinheadistightlyboundtoactininrigorstateNothingboundtonucleotidebindingsite382.ATPbindstomyosinMyosinchangesconformation,releasesactin393.ATPhydrolysisATPisbrokendowninto:ADP+Pi

(inorganicphosphate)BothADPandPiremainboundtomyosin404.MyosinheadchangesconformationMyosinheadrotatesandbindstonewactinmoleculeMyosinisinhighenergyconfiguration415.PowerstrokeReleaseofPifrommyosinreleasesheadfromhighenergystateHeadpushesonactinfilamentandcausesslidingMyosinheadsplitsATPandbendstowardHzone.ThisisPowerstroke.

426.ReleaseofADPMyosinheadisagaintightlyboundtoactininrigorstateReadytorepeatcycle43THECROSS-BRIDGECYCLEATPADP+PiAlMA–MlATPAlMlADPlPiA+MlADPlPiRelaxedstateCrossbridgeenergisedCrossbridgeattachment

Tensiondevelops

Crossbridgedetachment

Ca2+presentA,Actin;M,Myosin44CrossBridgeCycle45RigormortisMyosincannotreleaseactinuntilanewATPmoleculebindsRunoutofATPatdeath,cross-bridgesneverrelease46ManycontractilecyclesoccurasynchronouslyduringasinglemusclecontractionNeedsteadysupplyofATP!47RegulationofContractionTropomyosinblocksmyosinbindinginabsenceofCa2+LowintracellularCa2+

whenmuscleisrelaxed48Ca+2

bindstotroponinduringcontractionTroponin-Ca2+pullstropomyosin,unblockingmyosin-bindingsitesMyosin-actincross-bridgecyclecannowoccur49HowdoesCa2+getintocell?ActionpotentialreleasesintracellularCa2+fromsarcoplasmicreticulum(SR)SRismodifiedendoplasmicreticulumMembranecontainsCa2+pumpstoactivelytransportCa2+intoSRMaintainshighCa2+inSR,lowCa2+incytoplasm50Ca2+ControlsContractionCa2+ChannelsandPumps

ReleaseofCa2+fromtheSRtriggerscontractionReuptakeofCa2+intoSRrelaxesmuscleStructuresinvolvedinECcoupling

-SkeletalMuscle-outinvoltagesensor?junctionfootsarcoplasmicreticulumsarcolemmaT-tubule52Dihydropyridine（DHP,雙氫吡啶）

ReceptorInt-tubulesofheartandskeletalmuscle

Nifedipine

andotherDHP-likemoleculesbindtothe"DHPreceptor"int-tubulesInheart,avoltage-gatedCa2+channelInskeletalmuscle,voltage-sensingproteinundergoesvoltage-dependentconformationalchanges

53Ryanodine(利阿諾定)ReceptorThe"footstructure"interminalcisternaeofSRFootstructureisaCa2+channelofunusualdesignConformationchangeorCa2+-channelactivityofDHPreceptorgatestheryanodinereceptor,openingandclosingCa2+channelsManydetailsareyettobeelucidated!

outinvoltagesensor(DHPreceptor)junctionalfoot(ryanodinereceptor)sarcoplasmicreticulumsarcolemmaT-tubuleSkeletalmuscleTheAP:movesdownthet-tubulevoltagechangedetectedbyDHP（雙氫吡啶）receptorsDHPreceptorisessentiallyavoltage-gatedCachanneliscommunicatedtotheryanodinereceptorwhichopenstoallowCaoutofSRactivatescontractionCardiacmuscleTheAP:movesdownthet-tubulevoltagechangedetectedbyDHPreceptors(Ca2+channels)whichopenstoallowsmallamountof(trigger)Ca2+intothefibreCa2+bindstoryanodinereceptorswhichopentoreleasealargeamountof(activator)Ca2+(CACR)Thus,calcium,notvoltage,appearstotriggerCa2+releaseinCardiacmuscle!outinvoltagesensor&Cachannel(DHPreceptor)junctionalfoot(ryanodinereceptor)sarcoplasmicreticulumsarcolemmaT-tubuleComparisonSkeletal

ThetriggerforSRreleaseappearstobevoltage(VoltageActivatedCalciumRelease-VACR)Thet-tubulemembranehasavoltagesensor(DHPreceptor)TheryanodinereceptoristheSRCareleasechannelCa2+releaseisproportionaltomembranevoltageCardiacThetriggerforSRreleaseappearstobecalcium(CalciumActivatedCalciumRelease-CACR)Thet-tubulemembranehasaCa2+

channel(DHPreceptor)TheryanodinereceptoristheSRCareleasechannelTheryanodinereceptorisCa-gated&CareleaseisproportionaltoCa2+

entry

57Summary:Excitation-ContractionCouplingPartIIIFactorsthatAffecttheEfficiencyofMuscleContraction59Tension張力andLoad負荷Theforceexertedonanobjectbyacontractingmuscleisknownastension.Theforceexertedonthemusclebyanobject(usuallyitsweight)istermedload.Accordingtothetimeofeffectexertedbytheloadsonthemusclecontractiontheloadwasdividedintotwoforms,preloadandafterload.60Preload前負荷Preloadloadonthemusclebeforemusclecontraction.Determinestheinitiallengthofthemusclebeforecontraction.Initiallengththelengthofthemusclefiberbeforeitscontraction.positivelyproportionaltothepreload.61TheEffectofSarcomereLengthonTensionTheLength–TensionCurveConceptofoptimallength62TypesofContractionsITwitch單收縮:abriefmechanicalcontractionofasinglefiberproducedbyasingleactionpotentialatlowfrequencystimulationisknownassingletwitch.Tetanus強直收縮:summationoftwitchesthatoccursathighfrequencystimulation63EffectsofRepeatedStimulationsFigure10.15641/sec5/sec10/sec50/sec65Afterload后負荷Afterload

loadonthemuscleafterthebeginningofmusclecontraction.reverseforcethatopposethecontractileforcecausedbymusclecontraction.doesnotchangetheinitiallengthofthemusclepreventmusclefromshortening66AfterloadisresistanceIsometric等長Lengthofmuscleremainsconstant.Peaktensionproduced.DoesnotinvolvemovementIsotonic等張Lengthofmusclechanges.Tensionfairlyconstant.InvolvesmovementatjointsResistanceandspeedofcontractioninverselyrelatedTypesofContractions(II)67IsotonicandIsometricContractio