Pathways of Intracellular Signal Transduction.docx
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PathwaysofIntracellularSignalTransduction
PathwaysofIntracellularSignalTransduction
Mostcellsurfacereceptorsstimulateintracellulartargetenzymes,whichmaybeeitherdirectlylinkedorindirectlycoupledtoreceptorsbyGproteins.Theseintracellularenzymesserveasdownstreamsignalingelementsthatpropagateandamplifythesignalinitiatedbyligandbinding.Inmostcases,achainofreactionstransmitssignalsfromthecellsurfacetoavarietyofintracellulartargets—aprocesscalledintracellularsignaltransduction.Thetargetsofsuchsignalingpathwaysfrequentlyincludetranscriptionfactorsthatfunctiontoregulategeneexpression.Intracellularsignalingpathwaysthusconnectthecellsurfacetothenucleus,leadingtochangesingeneexpressioninresponsetoextracellularstimuli.
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ThecAMPPathway:
SecondMessengersandProteinPhosphorylation
Intracellularsignalingwasfirstelucidatedbystudiesoftheactionofhormonessuchasepinephrine,whichsignalsthebreakdownofglycogentoglucoseinanticipationofmuscularactivity.In1958,EarlSutherlanddiscoveredthattheactionofepinephrinewasmediatedbyanincreaseintheintracellularconcentrationofcyclicAMP(cAMP),leadingtotheconceptthatcAMPisasecondmessengerinhormonalsignaling(thefirstmessengerbeingthehormoneitself).CyclicAMPisformedfromATPbytheactionofadenylylcyclaseanddegradedtoAMPbycAMPphosphodiesterase(Figure13.18).Asdiscussedearlier,theepinephrinereceptoriscoupledtoadenylylcyclaseviaaGproteinthatstimulatesenzymaticactivity,therebyincreasingtheintracellularconcentrationofcAMP(seeFigure13.11).
Figure13.18
SynthesisanddegradationofcAMP.CyclicAMPissynthesizedfromATPbyadenylylcyclaseanddegradedtoAMPbycAMPphosphodiesterase.
HowdoescAMPthensignalthebreakdownofglycogen?
ThisandmostothereffectsofcAMPinanimalcellsaremediatedbytheactionofcAMP-dependentproteinkinase,orproteinkinaseA,anenzymediscoveredbyDonalWalshandEdKrebsin1968.TheinactiveformofproteinkinaseAisatetramerconsistingoftwocatalyticandtworegulatorysubunits(Figure13.19).CyclicAMPbindstotheregulatorysubunits,leadingtotheirdissociationfromthecatalyticsubunits.Thefreecatalyticsubunitsarethenenzymaticallyactiveandabletophosphorylateserineresiduesontheirtargetproteins.
Figure13.19
RegulationofproteinkinaseA.TheinactiveformofproteinkinaseAconsistsoftworegulatory(R)andtwocatalytic(C)subunits.BindingofcAMPtotheregulatorysubunitsinducesaconformationalchangethatleadstodissociationofthecatalytic(more...)
Intheregulationofglycogenmetabolism,proteinkinaseAphosphorylatestwokeytargetenzymes(Figure13.20).Thefirstisanotherproteinkinase,phosphorylasekinase,whichisphosphorylatedandactivatedbyproteinkinaseA.Phosphorylasekinaseinturnphosphorylatesandactivatesglycogenphosphorylase,whichcatalyzesthebreakdownofglycogentoglucose-1-phosphate.Inaddition,proteinkinaseAphosphorylatestheenzymeglycogensynthase,whichcatalyzesglycogensynthesis.Inthiscase,however,phosphorylationinhibitsenzymaticactivity.ElevationofcAMPandactivationofproteinkinaseAthusblocksfurtherglycogensynthesisatthesametimeasitstimulatesglycogenbreakdown.
Figure13.20
RegulationofglycogenmetabolismbyproteinkinaseA.ProteinkinaseAphosphorylatesbothglycogensynthaseandphosphorylasekinase.Glycogensynthase(whichcatalyzesglycogensynthesis)isinhibitedbythisphosphorylation,whereasphosphorylase(more...)
Thechainofreactionsleadingfromtheepinephrinereceptortoglycogenphosphorylaseprovidesagoodillustrationofsignalamplificationduringintracellularsignaltransduction.Eachmoleculeofepinephrineactivatesonlyasinglereceptor.However,eachreceptormayactivateuptoahundredmoleculesofGs.EachmoleculeofGsthenstimulatestheenzymaticactivityofadenylylcyclase,whichcancatalyzethesynthesisofmanymoleculesofcAMP.SignalamplificationcontinuesaseachmoleculeofproteinkinaseAphosphorylatesmanymoleculesofphosphorylasekinase,whichinturnphosphorylatemanymoleculesofglycogenphosphorylase.Hormonebindingtoasmallnumberofreceptorsthusleadstoactivationofamuchlargernumberofintracellulartargetenzymes.
Inmanyanimalcells,increasesincAMPactivatethetranscriptionofspecifictargetgenesthatcontainaregulatorysequencecalledthecAMPresponseelement,orCRE(Figure13.21).Inthiscase,thesignaliscarriedfromthecytoplasmtothenucleusbythecatalyticsubunitofproteinkinaseA,whichisabletoenterthenucleusfollowingitsreleasefromtheregulatorysubunit.Withinthenucleus,proteinkinaseAphosphorylatesatranscriptionfactorcalledCREB(forCRE-bindingprotein),leadingtotheactivationofcAMP-induciblegenes.SuchregulationofgeneexpressionbycAMPplaysimportantrolesincontrollingtheproliferation,survival,anddifferentiationofawidevarietyofanimalcells.
Figure13.21
CyclicAMP-induciblegeneexpression.ThefreecatalyticsubunitofproteinkinaseAtranslocatestothenucleusandphosphorylatesthetranscriptionfactorCREB(CRE-bindingprotein),leadingtoexpressionofcAMP-induciblegenes.
Itisimportanttorecognizethatproteinkinases,suchasproteinkinaseA,donotfunctioninisolationwithinthecell.Tothecontrary,proteinphosphorylationisrapidlyreversedbytheactionofproteinphosphatases.Someproteinphosphatasesaretransmembranereceptors,asdiscussedintheprecedingsection.Anumberofothersarecytosolicenzymesthatremovephosphategroupsfromeitherphosphorylatedtyrosineorserine/threonineresiduesintheirsubstrateproteins.Theseproteinphosphatasesservetoterminatetheresponsesinitiatedbyreceptoractivationofproteinkinases.Forexample,theserineresiduesofproteinsthatarephosphorylatedbyproteinkinaseAareusuallydephosphorylatedbytheactionofaphosphatasecalledproteinphosphatase1(Figure13.22).ThelevelsofphosphorylationofproteinkinaseAsubstrates(suchasphosphorylasekinaseandCREB)arethusdeterminedbyabalancebetweentheintracellularactivitiesofproteinkinaseAandproteinphosphatases.
Figure13.22
RegulationofproteinphosphorylationbyproteinkinaseAandproteinphosphatase1.ThephosphorylationoftargetproteinsbyproteinkinaseAisreversedbytheactionofproteinphosphatase1.
AlthoughmosteffectsofcAMParemediatedbyproteinkinaseA,cAMPcanalsodirectlyregulateionchannels,independentofproteinphosphorylation.CyclicAMPfunctionsinthiswayasasecondmessengerinvolvedinsensingsmells.ManyoftheodorantreceptorsinsensoryneuronsinthenoseareGprotein-coupledreceptorsthatstimulateadenylylcyclase,leadingtoanincreaseinintracellularcAMP.RatherthanstimulatingproteinkinaseA,cAMPinthissystemdirectlyopensNa+channelsintheplasmamembrane,leadingtomembranedepolarizationandinitiationofanerveimpulse.
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CyclicGMP
CyclicGMP(cGMP)isalsoanimportantsecondmessengerinanimalcells,althoughitsrolesarenotasclearlyunderstoodasthoseofcAMP.CyclicGMPisformedfromGTPbyguanylylcyclasesanddegradedtoGMPbyaphosphodiesterase.Asdiscussedearlierinthischapter,differenttypesofguanylylcyclasesareactivatedbybothnitricoxideandpeptideligands.StimulationoftheseguanylylcyclasesleadstoelevatedlevelsofcGMP,whichthenmediatebiologicalresponses,suchasbloodvesseldilation.TheactionofcGMPisfrequentlymediatedbyactivationofacGMP-dependentproteinkinase,althoughcGMPcanalsoacttoregulateothertargets,includingionchannels.
Thebest-characterizedroleofcGMPisinthevertebrateeye,whereitservesasthesecondmessengerresponsibleforconvertingthevisualsignalsreceivedaslighttonerveimpulses.ThephotoreceptorinrodcellsoftheretinaisaGprotein-coupledreceptorcalledrhodopsin(Figure13.23).Rhodopsinisactivatedasaresultoftheabsorptionoflightbytheassociatedsmallmolecule11-cis-retinal,whichthenisomerizestoall-trans-retinal,inducingaconformationalchangeintherhodopsinprotein.RhodopsinthenactivatestheGproteintransducin,andtheαsubunitoftransducinstimulatestheactivityofcGMPphosphodiesterase,leadingtoadecreaseintheintracellularlevelofcGMP.ThischangeincGMPlevelinretinalrodcellsistranslatedtoanerveimpulsebyadirecteffectofcGMPonionchannelsintheplasmamembrane,similartotheactionofcAMPinsensingsmells.
Figure13.23
RoleofcGMPinphotoreception.AbsorptionoflightbyretinalactivatestheGprotein-coupledreceptorrhodopsin.TheαsubunitoftransducinthenstimulatescGMPphosphodiesterase,leadingtoadecreaseinintracellularlevelsofcGMP.
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PhospholipidsandCa2+
Oneofthemostwidespreadpathwaysofintracellularsignalingisbasedontheuseofsecondmessengersderivedfromthemembranephospholipidphosphatidylinositol4,5-bisphosphate(PIP2).PIP2isaminorcomponentoftheplasmamembrane,localizedtotheinnerleafletofthephospholipidbilayer(seeFigure12.2).AvarietyofhormonesandgrowthfactorsstimulatethehydrolysisofPIP2byphospholipaseC—areactionthatproducestwodistinctsecondmessengers,diacylglycerolandinositol1,4,5-trisphosphate(IP3)(Figure13.24).DiacylglycerolandIP3stimulatedistinctdownstreamsignalingpathways(proteinkinaseCandCa2+mobilization,respectively),soPIP2hydrolysistriggersatwo-armedcascadeofintracellularsignaling.
Figure13.24
HydrolysisofPIP2.PhospholipaseC(PLC)catalyzesthehydrolysisofph