国外文献硫化氢

INTRODUCTIONHYDROGENSULFIDE(H2S)isgenerallythoughtofintermsofapoisonousgas.However,relativelyhighendogenouslevelsofH2Shaverecentlybeenmeasuredinthebrainsofrats,humans,andbovine(30,60,79).AsH2Sischemicallyaveryactivegas,endogenousH2Smayhaveaphysiologicalfunction.Recently,ithasbeenshownthatphysiologicalcon-centrationsofH2SspecificallypotentiatetheactivityofN-methyl-D-aspartate(NMDA)receptorandaltertheinductionoflong-termpotentiation(LTP)inthehippocampus,asynap-ticmodeloflearningandmemory(1).H2Scanalsoregulatethereleaseofcorticotropin-releasinghormonefromthehy-pothalamus(58).Twoothergases,nitricoxide(NO)andcar-bonmonoxide(CO),areendogenouslyproducedbyenzymeslocalizedinthebrain(28,77).BothNOandCOhavealsobeenproposedasretrogrademessengersinhippocampalLTP(10,34,52,61,64,83).Theseobservationssuggesttheneu-romodulatoryroleofH2Sinthebrain(1,62).Glialcellshavebeenconsideredtobethenonexcitablesup-portiveelementsinthenervoussystem,buttheyarenowre-gardedaselementsthatrespondtoneuronalactivity,aswellasmodulatesynapticactivity(36).Oneclassofglia,astrocytes,makesneurotransmittersandexpresseshormonereceptors.Anumberofconditions,includingneurotransmittersandame-chanicalstimulation,evokeincreasesinintracellularCa2+inastrocytesthatpropagateintoneighboringastrocytesasinter-cellularCa2+waves(11,17,40,50).Ca2+waveshavebeenwellcharacterizedinculturedastrocytes,aswellasacutelyiso-latedhippocampalslices(20,25,40,50).Neuronsinteractwithglia,andthetwocommunicatewitheachother(20,51,55).NeuronalactivityevokesglialCa2+waves(20),andconverselyglialCa2+wavesdriveneuronalactivity(51,55).Glialcellsarethereforeintegralmodulatoryelementsinsynaptictrans-mission(4),andH2Smaybeinvolvedintheglialsignaltrans-duction.Therearetwoformsofglutamatetoxicity:receptor-initiatedexcitotoxicity(14)andnon–receptor-mediatedoxidativeglu-tamatetoxicity(47).Oxidativeglutamatetoxicity,recentlyrenamedoxytosis(70),isawell-studiedprogrammedcell-deathpathwaythatisindependentofionotropicglutamatere-ceptors(44,47,70).Ithasbeenobservedinprimarycultures795NationalInstituteofNeuroscience,Tokyo,Japan.PhysiologicalRolesofHydrogenSulfide:SynapticModulation,Neuroprotection,andSmoothMuscleRelaxationHIDEOKIMURA,YASUONAGAI,KENUMEMURA,andYUKAKIMURAABSTRACTNearly300yearshavepassedsincethefirstdescriptionofthetoxicityofhydrogensulfide(H2S)in1713.Al-thoughmanystudieshavebeendevotedtoitstoxicity,verylittleattentionhasbeenpaidtounderstandingitsnormalphysiologicalfunction.RelativelyhighconcentrationsofendogenousH2S,however,haverecentlybeendiscoveredinanimaltissues,anditspossiblefunctionasabiologicalmessengerhasbeenproposed.H2SenhancestheactivityofN-methyl-D-aspartatereceptorsandfacilitatestheinductionofhippocampallong-termpotentiation,asynapticmodelformemory.H2SalsoincreasesintracellularconcentrationsofCa2+ingliaandinducesCa2+waves,whichmediateglialsignaltransmission.Basedonaccumulatingevidenceforthere-ciprocalinteractionsbetweengliaandneurons,ithasbeensuggestedthatgliamodulatesynaptictransmis-sion.Therefore,H2Smayregulatesynapticactivitybymodulatingtheactivityofbothneuronsandglia.Inad-ditiontoaroleinthesignaltransduction,H2Sprotectsneuronsfromoxidativestressandinsmoothmuscleitmayfunctionasarelaxant.H2S,thetoxicgas,maythereforebeusedasamultifunctionalsignalingmecha-nismundernormalphysiologicalconditions.Antioxid.RedoxSignal.7,795–803.ForumReviewANTIOXIDANTS&REDOXSIGNALINGVolume7,Numbers5&6,2005©MaryAnnLiebert,Inc.13910C31.pgs4/5/054:38PMPage795ofneuronalcells(48),neuronalcelllines(21,46,47),andbrainslices(78).Oxidativestressisresponsibleforneuronaldamageanddegenerationinbraindisorders,includingstroke,epilepsy,andAlzheimer’sdisease(18,56).Glutamatesharesanaminoacidtransporterwithcystine,anditcompeteswithcystinefortransportintocells(7).Therefore,elevatedextra-cellularglutamateinhibitsthetransportofcystinethatistheprimarysourceofintracellularcysteinenecessaryforgluta-thionesynthesis.H2Sincreasestheactivityof
-glutamylcys-teinesynthase(
-GCS)andcausestherecoveryofcystinetransportsuppressedbyglutamate,resultinginanincreaseinthelevelsofglutathioneinneurons(42).Thus,H2Smayfunc-tionasaneuroprotectantagainstoxidativestress.Whenacetylcholineisappliedtothethoracicaorta,theen-dothelialcellsreleaseendothelial-derivedrelaxingfactor(EDRF)(26).EDRFrelaxessmoothmuscleandhyperpolarizessmoothmusclecells(24).NOisarelaxingfactoridentifiedasEDRF(53,54).However,insomebloodvessels,alackofcorrela-tionhasbeennotedbetweentheeffectofNOandthatofEDRFtohyperpolarizethevascularsmoothmusclecells(24).An-otherunidentifiedfactororcomponentofEDRF,whichhy-perpolarizessmoothmuscle,isthoughttobereleasedfromendothelialcellsandisdesignatedendothelial-derivedhyper-polarizingfactor(EDHF).Inadditiontothesefactorsre-leasedfromendothelialcells,non–endothelium-derivedrelax-ingfactorshavebeenproposed(29).Low-molecular-weightS-nitrosothiolintermediatesmayalsocontributetotherelax-ationofcoronarysmoothmuscle,vascularsmoothmuscle,carotidarteries,andthecerebralartery(12,24,29,49).Cys-tathionine
-lyase(CSE),whichcanproduceH2S,hasbeenidentifiedinsmoothmuscle.Thefollowingparagraphsout-lineinmoredetailthepossibleroleofH2Sasasynapticmod-ulatorinthecentralnervoussystemandasarelaxantinsmoothmuscle.CHEMICALPROPERTIESOFH2SH2Sisacolorless34molecularweightgasthatisheavierthanair.OnegramofH2Sdissolvesin242mlofwater,94.3mlofethanol,or48.5mlofdiethylether(57).H2Seasilypenetratesbiologicalmembranes.Inphysiologicalsaline,ap-proximatelyone-thirdoftheH2Sexistsastheundissociatedform(H2S),andtheremainingtwo-thirdsexistsasHSatequilibriumwithH2S(57).NaHShasbeenwidelyusedforstudiesofH2SinsteadofH2Sgasforthefollowingreasons(9,43,79).NaHSdissociatestoNa+andHSinsolution,thenHSassociateswithH+andproducesH2S.ItdoesnotmatterwhethertheH2SsolutionispreparedbybubblingH2SgasorbydissolvingNaHS.TheuseofNaHSenablesustodefinetheconcentrationsofH2SinsolutionmoreaccuratelyandreproduciblythanbubblingH2Sgas.Theinfluenceof<1mMNa+onelectrophysiologicalexperimentsisnegligible,becausebasicsaltsolutioncontains150mMNa+.NaHSatconcentrationsof<1mMdoesnotchangethepHofbasicsaltsolution.LikeH2S,bothNOandCOarecolorlessgasesandeasilypenetratebiologicalmembrane.ThemolecularweightofNOandCOis30and28,respectively.NOisalittleheavierthanair,whereasCOislighter.At20°C,4.6mlofNOand2.3ml796KIMURAETAL.ofCOaredissolvedin100mlofwater.NOisafreeradicalandproducestheextremelytoxichydroxylradicalwhenitcombineswithsuperoxide(63).COisareducingagentlikeH2S.Withthosedifferencesandsimilarities,H2S,NO,andCOelicitseveraleffects;someofthemareopposite,whereasothersarequitesimilar.H2SPRODUCTIONEndogenousH2Scanbeproducedfromcysteinebypyri-doxal5-phosphate-dependentenzymes,includingcystathio-nine-synthetase(CBS)andCSE.CBSmRNAisexpressedinthebrain,expeciallyinhippocampusandcerebellum,whereasCSEmRNAisnotdetectable(1).TheproductionofH2SfrombrainhomogenatesissuppressedbyCBS-specificinhibitors,aminooxyacetateandhydroxylamine,whereasitisnotsup-pressedbyCSE-specificinhibitors,DL-propargylglycineand-cyano-L-alanine(1).TheH2SproductionisenhancedbyaCBSactivator,S-adenosyl-L-methionine.TheseobservationssuggestthatCBSisacandidateenzymefortheproductionofH2Sinthebrain.CSEisexpressedintheileum,portalvein,andthoracicaorta.ThehomogenatesofthesetissuesproduceH2Sinthepresenceofcysteine,andthisproductionisblockedbyCSE-specificinhibitors(38,82).TheproductionofH2Sfromho-mogenizedvasculartissuesisup-regulatedbysodiumnitro-prusside(SNP)inaconcentration-dependentmanner,andS-nitroso-N-acetylpenicillamine(SNAP),anotherNOdonor,increasesthetranscriptionallevelofCSE(81).OtherenzymesinvolvedinthetransaminativepathwayofmethioninecatabolismhavealsobeenproposedtoproduceH2Sinmammals,andtheirregulationmayalsobeinvolvedinthenormalphysiologicalfunctionofH2S(74).REGULATIONOFNEURONALACTIVITYBecauseH2Sisproducedinthebrain,H2Smayplayaroleinsynaptictransmission.Werecentlyfoundthatphysiologi-calconcentrationsofH2SmodifytheinductionofLTPinadose-dependentmanner.AlthoughNaHSatconcentrationsof<130µMoraweaktetanicstimulationalonedoesnotinduceLTP,simultaneousapplicationofbothstimulationsinducesLTP(1).ThetimingofapplicationofH2SwithaweaktetanicstimulationisanimportantfactortofacilitatetheinductionofLTP.WhenNaHSisapplied10minbeforeorafteraweaktetanicstimulation,facilitationofLTPinductiondoesnotoccur.NOandCOincreaseintracellularcyclicGMP,whereasH2Sdoesnot(1,63).TheobservationthatNOandCOinduceLTPevenwhenNMDAreceptorsareblocked(83)supportstheideathatNOandCOactasretrogrademessengersatsynapses(52,61,64).Incontrast,H2SwithaweaktetanicstimulationdoesnotinduceLTPinthepresenceof2-amino-5-phospho-novalerate,aspecificblockerfortheNMDAreceptor(1),suggestingthattheinductionofLTPbyH2Srequirestheacti-vationofNMDAreceptors.HippocampalLTPinducedbyatetanicstimulationrequirestheactivationofNMDAreceptors(35).H2Salonedoesnot13910C31.pgs4/5/054:38PMPage796induceanyapparentcurrents,butsignificantlyincreasestheNMDA-inducedinwardcurrent(1).TheenhancingeffectofH2SontheNMDAresponseisconcentration-dependentinthesamerangeasitsLTP-facilitatingeffectandisspecifictoNMDAreceptors.Therefore,H2SmayenhancetheinductionofLTPbyactivatingNMDAreceptors.Disulfidebondsplayaroleinmodulatingthefunctionofmanyproteins,includingNMDAreceptors(3,71).Itisthere-forepossiblethatH2SinteractswithdisulfidebondsorfreethiolsinNMDAreceptors.Theirreversiblethiol-protectingagentdithiothreitol(DTT)withaweaktetanicstimulationsignifi-cantlyfacilitatestheinductionofLTP.H2Swithaweaktetanicstimulation,however,stillinducesLTPevenaftertreatmentwithDTT,demonstratingthatDTTdoesnotoccludetheef-fectofH2S(1).ItisthereforeunlikelythatthethiolredoxsitesintheNMDAreceptorcontributelittle,ifatall,tothepotentiatingeffectofH2SontheinductionofLTP.H2SINCREASESINTRACELLULARCa2+ANDINDUCESCa2+WAVESINASTROCYTESTheobservationthatH2Senhancestheinductionofhip-pocampalLTPsuggeststhatH2Smaymodulatesomeaspectsofsynapticactivity.AlthoughH2SenhancestheNMDAreceptor-mediatedresponsestoglutamateinneurons,theeffectsofH2Sonbraincellsintheabsenceofglutamatearenotwellunderstood.WerecentlyfoundthatH2SaloneinducesCa2+wavesinastrocytes(50)usingaCa2+imagingsystemwithCalciumGreen-1asaCa2+-sensitivefluorescentdye.FocalapplicationofH2SincreasedintracellularconcentrationsofCa2+inglialfibrillaryacidicprotein(GFAP)-positiveastro-cytes(50).AlthoughH2SenhancestheresponsesofneuronstoNMDA,significantCa2+responsestoH2Sapplieddirectlytoneuronswerenotobserved.H2Smaythereforemodulatesynapticactivitybydirectlyenhancingtheresponsestogluta-mateinneuronsandindirectlybyinducingCa2+wavesinas-trocytes(Fig.1).ThereisadifferenceinthetimecourseoftheincreaseinintracellularCa2+betweentheastrocytesexposeddirectlytoH2SandthoseactivatedbythepropagatedCa2+waves.TheintracellularCa2+intheastrocytesexposedtoH2Ssharplyin-creasesandgraduallydecays,whereasthepropagatedCa2+wavesshowoscillationswithafasterdecay(50).TheinitialincreaseintheintracellularCa2+inducedbyH2Smaythere-foreberegulatedbyadifferentmechanismthanthepropa-gatedCa2+waves.GlialcellsinprimaryculturesareGFAP-negativeduringthefirst10days(72),andthencellsbecomeGFAP-positiveandA2B5-negativeastrocytes.CellsstartrespondingtoH2Sat6days,andtheresponsesreachamaximumlevelat~30days(50).TheresponsestoH2Sobservedinculturesofastro-cytesalsooccurinhippocampalslices(50).Ithasbeendiffi-culttoidentifyneuronsandgliainbrainslicesduringelectro-physiologicalrecordingorimaging,forviableslicescannotbestainedforspecificcellmarkers.Recently,ithasbeenfoundthatincreasesintheintracellularconcentrationsofCa2+arespecificallyinducedinastrocytesbylowexternalconcentra-PHYSIOLOGICALROLESOFH2S797tionsofK+(19).Byusingthischaracteristicofastrocytes,wecandefinethecellsthatrespondtoH2Sinhippocampalslicesasastrocytes.BecauseastrocytesinacutebrainslicesrespondtoH2S,thepossibilitythatresponsestoH2Smaybethearti-factcausedbycellculturecanbeexcluded.TherequirementofseveraldaysinculturebeforeastrocytesrespondtoH2SmaybeduetotheexpressionofproteinsthatarenecessaryforrespondingtoH2Sortheformationofcell–celljunctions.RESPONSESTOH2SREQUIREBOTHEXTRACELLULARCa2+ANDINTRACELLULARCa2+STORESGlutamateandATPareknowntoinduceCa2+wavesinas-trocytes(17,33).TheincreaseinintracellularCa2+inducedbyglutamateisdependentonextracellularCa2+,whereasthatinducedbyATPisonlydependentonintracellularCa2+stores(17,23,41).TheincreaseinintracellularCa2+inducedbyNaHSisgreatlysuppressedintheCa2+-freemedium,whereastheresponsetoATPisintact.H2SincreasestheinfluxofCa2+similarlytothatcausedbyionomycin,aCa2+ionophore(50).ResponsestoH2Sarealsosuppressedbythapsigargin,acom-poundthatdepletesintracellularCa2+stores,butthesuppres-sionofresponsestoH2SismuchlessthanthatofresponsestoATPorglutamate.H2SincreasesintracellularconcentrationsofCa2+,largelybyinducingCa2+influx,andtoalesserextentthroughthereleasefromintracellularCa2+stores.AsH2SincreasesintracellularCa2+,itispossiblethatH2SmayactivateachannelorareceptorassociatedwithachannelthatispermeabletoCa2+.Trivalentcations,La3+andGd3+,well-knownblockersofCa2+channels,potentlysuppressre-FIG.1.H2SinducesCa2+wavesinastrocytes.H2Sisre-leasedfromneuronsorgliasurroundingsynapsesandincreasestheintracellularconcentrationsofCa2+.ElevatedintracellularCa2+triggerstheinductionofCa2+wavesthatpropagatetotheneighboringastrocytesandmayreachandregulatethenextsynapse.13910C31.pgs4/5/054:38PMPage797sponsestoH2S(50).Rutheniumred,whichisablockerofryanodinereceptorsandinhibitsvoltage-gatedCa2+channels(15),alsosuppressesresponsestoH2S.Threeadditionalvoltage-dependentCa2+-channelblockers,flunarizine,nifedipine,and-conotoxinGVIA,allpotentlysuppressresponsestoH2S.AlthoughCa2+channelsareclearlyactivated,thetypeofCa2+channelsisdifficulttodeterminebecauseaT-typeblocker,flunarizine,anL-type,nifedipine,andanN-type,-conotoxin,blocktheeffectofH2Slesspotentlythanthenonspecificvoltage-dependentCa2+channelblockers,La3+andGd3+.Al-ternatively,La3+,Gd3+,andrutheniumredarealsopotentin-hibitorsofthetransientreceptorpotential(TRP)familyofchannelsthatarepermeabletoCa2+(16,65,73),andH2Smayactivatethesechannels.Mg2+andMDL-12,330AblockTRPchannels(64,76),andbothsubstancessuppressresponsestoH2S.Therefore,furtherworkisnecessarytoidentifythespe-cifictypeofCa2+channelthatisactivatedbyH2S.INVOLVEMENTOFH2SINCa2+WAVESINASTROCYTESINDUCEDBYNEURONALEXCITATIONInteractionsbetweenneuronsandgliamaymodulatesynap-tictransmission,forneuronalactivitycanevokeglialCa2+waves(20),andpropagatedCa2+wavesinglialcellsmaymodulateneuronalactivity(51,55).Afterneuronswereex-citedbyNMDA,Ca2+wavesoccurredinneighboringastro-cytes(50).TheCa2+wavesinducedbyNMDAwerecompletelysuppressedby10µMLa3+or10µMGd3+.H2Sreleasedinre-sponsetoneuronalexcitationmayincreaseintracellularCa2+andinduceCa2+wavesinneighboringastrocytes.Alternatively,asLa3+andGd3+blockCa2+wavesandalsoinhibitCa2+chan-nels,La3+andGd3+mayinhibittheexocytosisofglutamateorsomeotherfactorfromnerveterminalswhenneuronsarestimulatedbyNMDA.H2SASANEUROPROTECTANTThetoxiceffectofH2Sonthenervoussystemiswellknown(57),buttheprotectiveeffectofH2Sonneuronalcellshasnotevenbeenimagined.NOmaybeinvolvedingluta-mateneurotoxicity(63).Incontrast,sulfur-containingsub-stances,dimethylsulfoniopropionate(DMSP)anditsenzymaticcleavageproductdimethylsulfide(DMS),haverecentlybeenidentifiedasendogenousscavengersforhydroxylradicalsandotherreactiveoxygenspeciesinmarinealgae(69).Be-causeH2S,anendogenousreducingagent,isproducedbyoxi-dativestress(44),itispossiblethatH2Sfunctionsasanan-tioxidant.Toinvestigatethispossibility,theeffectofH2Sonoxytosiswasexaminedusingprimaryculturesofneurons.Primaryculturesofcorticalimmatureneurons,whichlackionotropicglutamatereceptorsduringtheirfirstfewdaysinculture(48),werepreparedfrom17-day-oldembryonicratbrainsandculturedfor1day.Mostoftheneuronsdiedwithin24haftertheapplicationof1mMglutamate,becausegluta-mateinhibitscystineuptakecausingoxidativestress-induced798KIMURAETAL.celldeath,aprocesscalledoxytosis(70).H2Sprotectscellsfromglutamatetoxicityinadose-dependentmanner(42).H2Salonecausedasignificantincreaseinsurvivalfollowingplating,protectingcellsfromthespontaneouscelldeaththatoccursinprimarycultures(2).Glutamatereducesintracellularglutathione(42),andglu-tathioneisthemajorendogenousantioxidant(31).H2Saloneincreasesthelevelsofthereducedformofglutathione(GSH)andtheoxidizedformofglutathione(GSSG)forseveralhours.H2Salsoreinstatesintracellularglutathioneloweredbygluta-mate(42).GSHcanprotectcellsfromoxidativestress,andH2SincreasestheGSHlevelsbothinuntreatedcellsandincellswhereGSHisnormallydepletedbyglutamate.ItislikelythatH2Sincreasesglutathionelevelsinsteadoffunctioningdirectlyasanantioxidant.Theendogenouslevelsofglutathione(1–8mM)(32)aremuchgreaterthanthoseofH2S(50–160µM)(57).Therefore,H2Sdoesnotitselfrescuecellsfromoxi-dativestress,butH2Sinducestheproductionofapotentan-tioxidant,glutathione.Cellscanberescuedfromoxidativestressbymechanismsthatareeitherdependentonorindependentofglutathionemetabolism.Forexample,antioxidantssuchasvitaminEpro-tectneuronalcellsfromoxytosisbyactingdirectlyasantioxi-dantsevenwhentheintracellularglutathionelevelsaredecreased(47,62).Incontrast,dihydroxyphenylglycine,anagonistofgroupImetabotropicglutamatereceptors,protectsneuronsbyup-regulatingglutathione(59).BecauseH2Srescuesneu-ronsbyincreasingtheaccumulationofglutathione,thepro-tectionfromoxytosisbyH2Sbelongstothelatterclassofmechanisms.TherequirementofglutathioneforcellsurvivalinducedbyH2Sisalsosupportedbyanotherobservation.Aspecificinhibitorof
-GCS,buthioninesulfoximine(31),dose-dependentlysuppressedboththelevelsofglutathioneandcellsurvivalinducedbyH2S(42).ItispossiblethatH2Senhancestheactivityof
-GCStoin-creasetheproductionof
-glutamylcysteine(
-GC).WefoundthatH2Sdoesindeedincreasethelevelsof
-GC,leadingtotheincreaseinthelevelsofglutathione.InthepresenceofH2S,thelevelsof
-GCincellsareincreasedmorethantwo-foldofthoseincellsintheabsenceofH2S.Eveninthepres-enceofglutamate,H2Sincreasesthelevelsof
-GCincellsapproximatelytwofold(42).Theincreasein
-GCinducedbyH2Sisnotcausedbythetranscriptionalregulationof
-GCS,buteitherbythedirectactivationoftheenzymeorthroughatranslationalmechanism.Glutathioneissynthesizedfromcysteinethatisproducedfromcystinetransportedintocellsfromtheoutside(7).Oxy-tosisiscausedbytheblockadeofthecystine/glutamatean-tiporterthatcouplestheimportofcystineandtheexportofglutamate(6,47).Thetransportofcystineintoprimaryneu-ronsissignificantlyincreasedbyH2S,andeveninthepres-enceofglutamateH2Ssignificantlyreversedtheinhibitionofcystinetransportbyglutamate(42).TheH2S-inducedrecov-eryofglutamate-suppressedcystinetransportmaythereforebeinvolvedintheincreasedproductionofglutathioneandneuroprotection.Thecystineuptakebythecystine/glutamateantiporterxcmediatesoxytosis(13).Thespecificinhibitorforxc,gluta-mate,significantlysuppressesthecystineuptake,andthisin-13910C31.pgs4/5/054:38PMPage798hibitionissignificantlyreducedbyH2S,suggestingthatan-tiporterxcmaybeinvolvedinthecystinetransportrecoveredbyH2S(42).Thisisalsosupportedbythefollowingobserva-tions:(a)EndogenouslevelsofcysteineareincreasedinthepresenceofH2S.(b)Ateachconcentrationofextracellularcystinetested,theglutathionelevelsareincreasedbygreaterthantwofoldinthepresenceofH2Srelativetothoseintheab-senceofH2S.(c)Whentheextracellularconcentrationsofcystinearedecreased,glutathionelevelsaredecreasedinboththepresenceandabsenceofH2S,indicatingthattheenhanc-ingeffectofH2Sontheglutathionelevelsisdependentontheextracellularconcentrationsofcystine(42).BecauseH2Sisareducingagent,itispossiblethatH2Sre-ducescystinetocysteineandenhancesthetransportofcys-teinethatistransportedbytheASC(alanine,serine,andcys-teine)transporter.TheinhibitorsfortheASCtransporter,alanineandserine,donotsignificantlyinhibitthecysteineuptake,nordotheysignificantlyinhibitthecysteineuptakeinthepresenceofH2S,excludingthepossibilitythatH2Sin-creasesthetransportofcysteinebyenhancingtheactivityoftheASCtransporter.Ascellssynthesizelittlecysteinethem-selves(8),H2Smustfunctionbyenhancingcystinetransport,leadingtotheincreaseinthelevelsof
-GCandglutathione(Fig.2).H2Sisanactivemoleculeandhasastrongeffectonseveraltargets.Forexample,H2Spotentiatestheinductionof