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Powerd By 群友通讯录 交流 共享 互利 共赢72Hyperpolarization-activated (Ih) current in mouse vestibular primary neurons
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72Hyperpolarization-activated (Ih) current in mouse vestibular primary neurons
MEMBRANEANDCELLULARBIOPH；NEUROREPORT；Hyperpolarization-activa；mousevestibularprimaryne；ChristianChabbert,CAJean；INSERMU432,UM2cp089,plac；CA；CorrespondingAuthor；Received30May2001;ac
MEMBRANEANDCELLULARBIOPHYSICSANDBIOCHEMISTRYNEUROREPORTHyperpolarization-activated(Ih)currentinmousevestibularprimaryneuronsChristianChabbert,CAJean-MarieChambard,JeanValmier,AlainSansandGillesDesmadrylINSERMU432,UM2cp089,placeE.Bataillon,34095Montpellier,Cedex5,FranceCACorrespondingAuthorReceived30May2001;accepted27June2001Thepresenceofahyperpolarization-activatedinwardcurrent(Ih)wasinvestigatedinmousevestibularprimaryneuronsusingthewhole-cellpatch-clamptechnique.Incurrent-clampcon?g-uration,injectionofhyperpolarizingcurrentsinducedvariationsofmembranevoltagewithprominenttime-dependentrecti?ca-tionincreasingwithcurrentamplitudes.Thiseffectwasabolishedby2mMCs??or100ìMZD7288.Involtage-clampcon?guration,hyperpolarizationpulsesfromà60mVtoà140mVtriggeredaslowactivatingandnoninactivatinginwardcurrentthatwassensitivetothetwoblockers,butinsensitiveto5mMBa2??.ChangingNa??andK??concentra-tionsdemonstratedthatIhcurrentiscarriedbyboththesemonovalentcations.Thisisthe?rstdemonstrationofaIhcurrentinvestibularprimaryneurons.NeuroReport12:&2001LippincottWilliams&Wilkins.Keywords:Current-andvoltage-Cs??;Ih;VestZD7288INTRODUCTIONAhyperpolarization-activatedinwardcurrent(Ih),carriedbyK??andNa??ions,hasbeendescribedinanumberofneuronalandnon-neuronalcells[1].ThiscurrentisblockedbyextracellularCs??[2]andZD7288[3]butisinsensitivetoBa2??.Ih,onceactivated,inducesaslowdepolarizationofthecell.Inneurons,Ihisknowntobeinvolvedinsettingtherestingmembranepotential,andinprovidingpacemakerdepolarizationinducingrhythmicactivity[1].Discrepancyinthedischargepropertiesofvestibularprimaryafferentshaspreviouslybeenattributedtoadifferenceinthecompositionofmembraneioniccurrentsintheseneurons[4].Inthiscontext,werecentlydescribedalargevariabilityintheexpressionofoutwarddepolariza-tion-activatedK??currentsinvestibularprimaryneurons(VPN)[5].Thisobservationcouldexplaininpartthedifferenceindischargepropertiesoftheseneurons.How-ever,thepropertiesofIhmakeitaputativecandidateincontrollingdischargepropertiesinvestibularafferents.WethereforeinvestigatedwhetherIhwaspresentinVPNacutelyisolatedfrommiceusingthecurrent-andvoltage-clampcon?gurationsofthewhole-cellpatch-clamptech-nique.Wereportandcharacterizeforthe?rsttimeahyperpolarization-activatedinwardcurrentthatresemblesIhdescribedinotherneuronalpreparations[1].glucose10,MgCl21.FortheNa??-freesolution,NaClwasreplacedbyequimolarcholine-Cl.Patchpipettes(2and3Mù)were?lledwiththefollowingintracellularsolution(inmM):KCl135,EGTA10,HEPES25,MgATP3,NaGTP1,glucose10.ThepHofthesolutionswereadjustedto7.35andtheosmolarityto300mOsm/l.DatawererecordedwithanAxopatch200BandanalyzedwithPclampsoft-ware(AxonInstrument,ForsterCity,CA).Seriesresistanceintherange5±9Mùwere80%compensatedaftercancella-tionofthecapacitivetransients.Datapresentedarecor-rectedonlineforjunctionpotentials(à7mV).Incurrent-clampmode,actionpotentials(AP)wereelicitedwithbrief(1.5ms)depolarizingpulsesfromtherestingmembranepotential.Activationcurveswerebest?ttedwithasingleBoltz-mannfunctionoftheformI/Imax??1/(1??exp((VàV1/2)/k)).Timeconstants(?)werebest?ttedwithasingleexponentialfunctionoftheformA.exp(àt/?).Pooleddataaregivenasmean?s.d.Statisticalsigni?canceswereexaminedusingANOVA.ZD7288wasobtainedfromTocris,andallotherchemicalsfromSigma.RESULTSMATERIALSANDMETHODSWhole-cellrecordingsofhyperpolarization-activatedcur-rentswereperformedinVPNusinganisolationproceduredescribedpreviously[5].Thestandardextracellularsolu-tioncontained(inmM):NaCl135,KCl5,HEPES10,Recordingsweremadefromneuronswithameaninputresistanceof223.5?100.6Mùandameanmembranecapacitanceof16.0?6.5pF(n??93).Themeanrestingmembranepotentialoftheneuronsstudiedincurrent-clampexperimentswasà63.1?4.7mV(n??23).Wetestedtheeffectonmembranevoltageofhyperpolarizingcurrentinjections.Incontrolsolution,injectionofcurrentsin50pAincrementsupto300pAinducedvariationsofmembranevoltage,withprominenttime-dependentrecti?cationthat&LippincottWilliams&WilkinsVol12No1228August20012701NEUROREPORTincreasedwiththeamplitudeofthehyperpolarizingcur-rents(Fig.1aa,ca).Thetime-dependentrecti?cationwasemphasizedbyplottingtheamplitudeofthevoltagevariationstakenatthepeakandtheendofthecurrentinjections(Fig.1ab,cb).Inthepresenceof2mMCs??(Fig.1b)or100ìMZD7288(Fig.1d),thetime-dependentrecti?-C.CHABBERTETAL.(a)ab(b)a(c)a(e)10 msFig.1.Effectsofcurrentinjectionsonmembranevoltage.(aa±da)Variationsofmembranevoltageelicitedbytheinjectionofhyperpolariz-ingcurrents(à50toà300pA,à50pAincrements).(aa,ca)C(ba)2mMCs??;(da)100ìMZD7288.(ab±db)Plotofvoltageamplitudesasafunctionofthehyperpolarizingcurrent(squares,circles,10msbeforetheendofthecurrentinjection).(ab,cb)(bb)2mMCs??;(db)100ìMZD7288.(e,f)Solidtraces,actionpotentialelicitedby1.5ms400pAdepolarizingpulses.Dottraces:effectsofCs??(e)andZD7288(f).Notetheabsenceofchangeinthedepolarization,repolarizationphasesandthetrajectoryoftheAHP.cationofthemembranevoltagewasabolished.Therestingmembranepotentialoftherecordedneuronswasnotsigni?cantlyaffectedbytheseblockers(p.0.5,Cs??n??6,ZD7288n??9).Totestwhetherthehyperpolarization-activatedcurrentcontributestotheafterhyperpolarization(AHP)trajectory,2mMCs??(n??10)or100ìMZD7288(n??5)wereappliedonneuronsinwhichasingleactionpotentialwaselicitedbyshortdepolarizingpulses(Fig.1e,f).Nochangewasobservedeitherinthedepolarizationorrepolarizationphaseoftheactionpotential.TheamplitudeandthetrajectoryoftheAHPfollowingtheAPwerealsounaf-fectedbytheapplicationofthetwoblockers.Wethencharacterizedthehyperpolarization-activatedinwardcurrentusingthevoltage-clampcon?gurationfromaholdingpotentialofà60mV.Incontrolsolution,hyper-polarisingvoltagestepstoà70andà80mVevokedaninstantaneousinwardcurrent,whereashyperpolarizationsbelowà90mVactivatedaslowactivatinginwardcurrent(Fig.2aa±ca).Applicationsof2mMCs??(Fig.2ab)or100ìMZD7288(Fig.2bb)preventedtheactivationoftheslowactivatingcomponent,withoutaffectingtheinstanta-neousone.Applicationsof5mMBaCl2(Fig.2cb)abolishedtheinstantaneouscomponent,leavingtheslowactivatingcomponentunaffected.Inwardcurrentswereisolatedbysubtractingtracesevokedinthepresenceoftheblockersfromthoseelicitedincontrolexternalsolution(Fig.2ac±cc).Voltage-dependentsteady-stateactivationoftheinwardcurrentwasstudiedbyplottingthemeanrelativeampli-tudesofthesubtractedtailcurrentsagainstthetestvoltagepulses(Fig.2d).Instantaneoustailcurrentsweretakenatà110mV,avoltagelevelatwhichweassumethattheinwardcurrentsensitiveto2mMCs??istheonlyvoltage-activatedcurrentactivated,andwerenormalizedtothoseobtainedafterthemosthyperpolarizedpulse(à140mV).Thehalfactivationpotential(Vac(1a2))was109.9?à1.9mV,andk??11.1?2.1mV(n??8).RelativeactivationoftheinwardcurrentsensitivetoZD7288wasplottedonthesame?gure.InasetofsixneuronsVac(1a2)wasà112.5?0.8mV,andkwas8.1?0.7mV.TheseVac(1a2)valuesobtainedusingpharmacologicalisolationswerecomparedtothoseobtainedincontrolsolution,followingtheprocedurereportedpreviously[6].Theslowlyactivat-ingcomponentoftheinwardcurrentcouldtheisolatedfromtheinstantaneousoneby?ttingcurrenttraceswithsingleexponentialfunction.Itsvoltage-dependentsteady-stateactivationwasstudiedbyplottingnormalizedampli-tudeasafunctionofthetestpulses.ThisproceduregaveVac(1a2)ofà110.6?0.9mV,andkof10.0?0.9mV(n??11;Fig.2d).TheVac(1a2)valuesisolatedfollowingthethreedifferentproceduresdidnotdiffersigni?cantly(p.0.5).Thetimeconstantforactivation(?ac)oftheinwardcurrentsensitiveto2mMCs??plottedasafunctionofthetestpotential(Fig.2e)showedastrongvoltagedependencewithaslopeof29.1?2.4ms/mV(n??8).?acoftheinwardcurrentsensitivetoZD7288andthoseobtainedbythe?ttingmethodwere30.4?2.9ms/mV(n??6)and30.5?3.2ms/mV(n??11)respectively.Valuesfor?acob-tainedusingthethreedifferentproceduresdidnotdiffersigni?cantly(p.0.5).Nocorrelationbetweenthecapacitanceoftherecorded2702Vol12No1228August2001IhINPRIMARYVESTIBULARNEURONSNEUROREPORT(c)aI/Imax(d)(a)a(b)a0.1 nA(a)b1 sCsCl 2 mM(b)bZD μM0.2 nA1 s(c)bBaCl2 5 mM0.1 nA1 s(e)mV(a)c(b)c(c)cτ (s)?60 mV?110 mV?140 mVmVFig.2.Characterizationofthehyperpolarization-activatedinwardcurrent.(a±c)currenttracesevokedbyapplicationofhyperpolarizingvoltagepulsesbetweenà70andà140mVfromHPà60mV.(aa±ca)Controlsolution,(ab±cb)applicationof2mMCs??,100ìMZD7288,and5mMBa2??respectively.(ac±cc)subtractedtraces.(d)Plotofmeanrelativeamplitudeoftheinstantaneoustailcurrentsasafunctionofthetestvoltagepulses.(e)Plotofthetimeconstantforactivationoftheslowlyactivatinginwardcurrentasafunctionofthetestpotential.Inpanels(d)and(e)cirlclesindicateCs??-sensitivecurrent(n??8),squaresindicateZD7288-sensitivecurrent(n??6),trianglesindicatecurrentisolatedincontrolsolutionusingthe?ttingmethod(n??11),thesolidlinesrepresenttheBoltzmanandthebestlinear?tsrespectively.neuronsandtheamplitudeofthelargestcurrentwasnoticed(n??45),indicatingthatthehyperpolarization-acti-vatedcurrentisnotexpresseddifferentiallybetweenneu-rons.Theionicnatureofthiscurrentwasinvestigatedusingthemethoddescribedrecently[7].Reversalpotentialwasdeterminedincontrolsolution,andinsolutionsinwhichtheconcentrationsofNa??andK??hadbeenchanged.Theslowlyactivatinginwardcurrentwasmeasuredatdifferentlevelsbytheapplicationof2svoltagepulsesaroundthehalfactivationpotential.Voltagepulsesbetweenà90andà140mVwerethenapplied,andthecurrent-voltagerela-tionshipoftheinstantaneouscurrentwasestimatedbylinear?ts.Thereversalpotentialwasdeterminedfromtheintersectionofthelinear?ts.Theintersectionofthelinear?tsgaveareversalpotentialofà49.4?2.3mV(n??5)incontrolexternalsolution(Fig.3b),à62.0?1.6mV(n??4)inNa??-freesolution(Fig.3c),andà11.2?2.6mV(n??4)in20mMK??solution(Fig.3d).TheseresultsindicatedthatinVPN,thehyperpolarization-activatedinwardcurrentiscarriedbythemonovalentcations,Na??andK??.(a)abc?60 mV?110 mV(b)??mVnA0.5 mA?120 mV(c)(d)mVmVDISCUSSIONTheslowlyactivatinghyperpolarization-activatedinwardcurrentfoundinVPNsharesmostofthepropertiesthatde?neIhinotherneuronalpreparations,namelyaslowandvoltage-dependentactivation,absenceoftime-depen-dentinactivation,sensitivitytoCs??andZD7288,insensi-tivitytoBa2??andamixedcationscompositionofthecurrent[1].Inthatmatter,itdiffersfromtheotherhyperpolarization-activatedinwardcurrents(IKIR)whicharecarriedbyK??,andaresensitivetoBa2??[8].TheIhFig.3.Ionicnature,ofthehyperpolarization-activatedinwardcurrent.(a)Currenttracesinducedincontrolsolution,byapplicationsof2sconditioningvoltagepre-pulsesatà110,à120andà130mVfromHPà60mV,followedbyvoltagetest-pulsesbetweenà90andà140mVin10mVincrements.(b±d)Plotsofinstantaneouscurrentmeasuredimmediatelyaftertheprepulsesatà110(triangles),à120(circles),à130mV(squares),asafunctionoftestvoltages.In(b±d)solidlinesrepresenttheextrapolatedlinear?tstothedatapoints.Verticaldottedlinesshowthevoltageattheintersectionofthethreelinear?ts.Controlsolution(b),Na??-freesolution(c),K??-richsolution(d).foundinVPNdiffersfromthatdescribedinotherneuronalpreparationsinseveralspeci?ccharacteristics.First,itactivatesatamembranepotentialwhichisaround20mVmorehyperpolarizedthantheactualrestingmembraneVol12No1228August20012703NEUROREPORTpotentialmeasuredinthesecells.Moreover,applicationofCs??andZD7288didnotaffecttherestingpotential.Theseobservationsindicatethat,unlikeotherneuronalprepara-tions[7],IhfoundinVPNisnotinvolvedinsettingrestingmembranepotential.Secondly,fullactivationofIhinVPNrequiresseveralseconds,whereasitactivateswithin1sinanumberofotherneurons[1].Thispropertygivessomeinsightsintotheidenti?cationofthesubunitsthatunderlietheIhchannel.OfthefourmembersoftheHCNgenefamilythathavebeencloned,onlytwo(HCN2,HCN4)haveslowratesofactivation[9].Lastly,withahalf-activationvoltagearoundà110mV,theactivationrangeofIhinVPNisrelativelyhyperpolarizedcomparedtomostotherneuronsinwhichithasbeenmeasured[7].However,V1a2valuesbetweenà100andà120mVhavebeenre-portedinguineapigspiralganglionneurons[10],andmousecerebellarbasketcells[11].InVPN,althoughwetookspeci?ccareinestimatingV1a2,wecannotexcludethepossibilitythatourrecordingconditionsmaymodifythegatingpropertiesoftheIhchannel.AssumingthatsuchhyperpolarizedactivationthresholdandV1a2valuesreˉecttheinvivosituation,itisunlikelythatIhisactivatedduringtheAHPsince,inourrecordingconditions,AHPneverexceededà80mV(unpublishedobservations).Thissugges-tioniscon?rmedbytheabsenceofanyeffectoftheIhblockersontheAHP.AdditionalrolesforIhinextrinsicormetabolicregula-tionshavebeenproposedinotherneuronalmodels[1]becauseIhismodulatingbyneurotransmittersand/orextrinsicstimuliviatheintracellularcAMPandcGMP[12].SuchpossibilitiesneedtobeinvestigatedinVPN.AroleC.CHABBERTETAL.forIhinprotectingagainstexcessivehyperpolarizationscouldalsobeconsidered.CONCLUSIONThepresentstudyisthe?rstreportofahyperpolarization-activatedcurrentinvestibularprimaryneurons.ThiscurrentdisplaysmostofthepharmacologicalandkineticpropertiesreportedforIhinotherneuronalpreparations.InVPN,however,Ihdisplaysalowthresholdofactivation,andpharmacologicalstudiesindicatethatitisnotinvolvedinsettingrestingmembranepotential,norinshapingAHP.Itspresenceinallinvestigatedneurons,withoutvariationinitsexpression,suggeststhatitcouldbeinvolvedinextrinsicfunctionsormetabolicregulationsthatremaintobeinvestigated.1.PapeHC.AnnuRevPhysiol58,299±327(1996).2.HalliwellJVandAdamsPR.BrainRes250,71±92(1982).3.BoSmithRE,BriggsIandSturgessNC.BrJPharmacol110,343±349(1993).4.SmithCEandGoldbergJM.BiolCybem54,41±51(1986).5.ChabbertC,ChambardJM,SansAetal.JNeurophysiol85,(2001).6.PerkinsKLandWongRK.JNeurophysiol73,911±915(1995).7.BalRandOertelD.JNeurophysiol84,806±817(2000).8.KuboY,ReuvenyE,SlesingerPAetal.Nature364,802±806(1993).9.SantoroBandTibbsCR.AnnNYAcadSci868,741±764(1999).10.ChenC.HearRes110,179±90(1997).11.SouthanAP,MorrisNP,StephensGJetal.JPhysiol526,91±97(2000).12.IngramSLandWilliamsJT.Neuron13,179±186(1994).REFERENCESAcknowledgements:TheauthorsthankG.DayanithiandDrJ.Galeforcarefulreadingofthemanuscript.TheworkwassupportedbyDRED-UM2toC.C.andCNESgrant99-793.2704Vol12No1228August2001包含各类专业文献、应用写作文书、高等教育、文学作品欣赏、幼儿教育、小学教育、行业资料、专业论文、生活休闲娱乐、中学教育、72Hyperpolarization-activated (Ih) current in mouse vestibular primary neurons等内容。求心意(S)_国模吧_百度贴吧
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