The Language of Calcium Signaling

Annu. Rev. Plant Biol. 2010.61:593-620. Downloaded from arjournals.annualreviews.orgby China Agricultural University on 07/12/10. For personal use only.¨Kudla,2andDaleSanders1AntonyN.Dodd,1Jorg

1

DepartmentofBiology,UniversityofYork,YorkYO105YW,UnitedKingdom;

email:ad542@york.ac.uk,ds100@york.ac.uk

¨Botanik,Universit¨¨MolekulareEntwicklungsbiologiederPflanzen,InstitutfuratMunster,

¨48149Munster,Germany;email:jkudla@uni-muenster.de

2

Annu.Rev.PlantBiol.2010.61:593–620FirstpublishedonlineasaReviewinAdvanceon

January25,2010

TheAnnualReviewofPlantBiologyisonlineatplant.annualreviews.org

Thisarticle’sdoi:

10.1146/annurev-arplant-070109-104628c2010byAnnualReviews.Copyright󰀁

Allrightsreserved

1543-5008/10/0602-0593$20.00

KeyWords

calcium,signaltransduction,membranetransport,systemsbiology

Abstract

Ca2+signalsareacoreregulatorofplantcellphysiologyandcellularresponsestotheenvironment.Thechannels,pumps,andcarriersthatunderlieCa2+homeostasisprovidethemechanisticbasisforgenerationofCa2+signalsbyregulatingmovementofCa2+ionsbetweensubcel-lularcompartmentsandbetweenthecellanditsextracellularenviron-ment.TheinformationencodedwithintheCa2+transientsisdecodedandtransmittedbyatoolkitofCa2+-bindingproteinsthatregulatetranscriptionviaCa2+-responsivepromoterelementsandthatregulateproteinphosphorylation.Ca2+-signalingnetworkshavearchitecturalstructurescomparabletoscale-freenetworksandbowtienetworksincomputing,andthesesimilaritieshelpexplainsuchpropertiesofCa2+-signalingnetworksasrobustness,evolvability,andtheabilitytoprocessmultiplesignalssimultaneously.

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Contents

INTRODUCTION..................EvolutionofCa2+Signaling........CELLULARFUNCTIONS

OFCa2+SIGNALS................Organ-andCell-TypeSpecificityofAbioticStressSignaling.......RegulationofStomatalAperture....Plant-PathogenInteractions........NodulationandOtherSymbioses...TheCircadianClock

andPhototransduction..........ControlofPolarTipGrowth

byTip-FocusedCa2+Gradients.TheSelf-Incompatibility

Response.......................TRANSPORTSYSTEMSTHAT

ENCODECa2+SIGNALS........EnergizedSystems:

Ca2+-PumpingATPases.........EnergizedSystems:

Calcium–ProtonExchangers....

594595595595595596596597598598599599600

CalciumEntrytotheCytosol.......CyclicNucleotide–Gated

Channels.......................Glutamate-Receptor-Like

Channels.......................Two-PoreChannels................AnnexinsasNovelPlant

Ca2+-PermeableChannels......PERCEPTIONANDDECODINGOFCa2+SIGNALS................ConnectingCa2+with

Transcription...................ConnectingCa2+withProtein

Phosphorylation................2+

CaSIGNALINGSYSTEMS........Scale-FreeNetworkArchitecture...Bow-TieNetworkArchitecture.....PredictiveModels

ofNetworkFunction............SimulationofCa2+HomeostasisandDynamics..................

601601602602603603604606608608609610611

Annu. Rev. Plant Biol. 2010.61:593-620. Downloaded from arjournals.annualreviews.orgby China Agricultural University on 07/12/10. For personal use only.INTRODUCTION

Ca2+isanastonishinglyversatilesignalingionthatispoisedatthecoreofasophisticatednet-workofsignalingpathways.Thesepathwaysintegrateinformationfrombioticandabioticsourcesandhavearesultantimpactongeneexpressionandcellphysiology.Inplants,cal-ciumsignalstaketheformoftransientincreasesincytosolicfreeCa2+(specifically,theactiv-ityofcytosolicfreeCa2+,[Ca2+]cyt)thatarisefromthefluxofCa2+intothecytosol,fromtheexternalmediumandfromsubcellularcom-partmentsinwhichtheconcentrationofCa2+ishighcomparedwiththecytosol.Stimulus-induced[Ca2+]cytincreasesinplantcellsof-tenoccurasrepetitiveoscillationsorspikingof[Ca2+]cytwherethefrequency(period),am-plitudeandshape(e.g.sinusoidal,square-wave)oftheCa2+increasearedeterminedbythena-tureofthestimulus.Itisthoughtthatstimulus-

[Ca2+]cyt:activityofcytosolic-freeCa2+

specifictemporalchangesin[Ca2+]cytenabletheiontoencodestimulus-specificinformationwithinthisso-calledcalciumsignature,andthusdefinethenatureandmagnitudeofthere-sponse(4,108).Anadditionallevelofregula-tionandspecificityisachievedbyCa2+-bindingproteinsthatfunctionasCa2+signalsensors,whichsenseCa2+alterationsbyCa2+bindingtodomainssuchasEFhands(10,98,141).TheseCa2+-bindingproteinsdecodeandre-laytheinformationencodedwithincalciumsignatures.Diverseproteinsencompassingcellulartransporters,enzymaticandsignalingproteinsincludingproteinkinases,andtran-scriptionfactorsaretargetsofcalcium-bindingproteins(44,136).TheinterplaybetweenCa2+signaturesandCa2+sensingtherebycon-tributestothestimulusspecificityofCa2+signaling.Here,weidentifyemergingfunc-tionsforCa2+signalinginplants,examinethe

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membranetransportmechanismsthatcontrolCa2+movementwithinthecelltherebydrivingCa2+signaling,andexplorehowCa2+-bindingproteinsrecognizespecificCa2+increasesinordertotranslatetheseintospecificcellularre-sponses.Finally,weconsiderthenewtypesofknowledgeconcerningcellsignalingthathaveemergedfromstudiesoftheintegratedfunc-tioningofentireCa2+signalingnetworks.

EvolutionofCa2+Signaling

Maintenanceof[Ca2+]cytatsubmicromolaractivitieswouldhavebeenanearlycon-straintduringtheevolutionofcells.Inter-.ymediarymetabolismbasedonenergycon-lnotainedwithinphosphoanhydrideesters(e.g. esuphosphate-phosphatebondswithinATP)re- lanquiresthatfreeCa2+besustainedatalowlevelosreotherwiseprecipitationofcalciumsaltsensuesp roasaresultofthelowsolubilityproductofCa2+F .withP0i(139).Thisconstraintdrovetheevo-/12lutionoftransportsystemsthatexportCa2+1/7fromthecytosol.Intheearliestunicellularor-0 noganisms,calciumhomeostasiswouldhavere- ytiquiredexportacrosstheplasmamembrane.Insrevalleukaryotes,sequestrationsystemshavealsoinUevolvedatendomembranes.Importantly,the larevolutionoftransportsystemsthatmaintainex-utlutremelylowcytosolicfreeCa2+createdacel-cirglularenvironmentfortheevolutionofasignal-A aingmechanismthatelevatescytosolicfreeCa2+niChveryrapidlybycapitalizingupontheenormous ybelectrochemicalpotentialdifferenceforCa2+acrossmembranesystemsthatseparate“stores”ofCa2+fromthecytosol(139).

CELLULARFUNCTIONSOFCa2+SIGNALS

Ca2+signalsregulatealargenumberofabi-oticstressresponses(108),aswellasstomatalaperture(121),self-incompatibilityduringfer-tilization(49),interactionswithpathogenicandsymbioticmicroorganisms(103,124),andthedevelopmentoftip-growingstructuressuchaspollentubesandroothairs(63).Ca2+signalsalsoparticipateinlightandcircadiansignaling(39,72,147,149).Wehighlightrecentadvances

inthefunctionsofCa2+signalsthatraiseim-portantquestionsforfutureresearch.

Organ-andCell-TypeSpecificityofAbioticStressSignaling

Ca2+elevationswithstimulus-specificproper-tiesareevokedbyextracellularsodium,osmoticstress,oxidativestress,lowtemperature,ozone,andmechanicalcues(108).Dose-dependentre-lationshipsbetweentheconcentrationofex-ternalNaClandNaCl-induced[Ca2+]cytspikemagnitudeinArabidopsisroots(155)recentlydemonstratedthatinformationconcerningabi-oticstimulusstrengthisencodedwithinthis[Ca2+]cytsignal.Stress-inducedCa2+signalshaveintriguingcelltype–specificproperties.[Ca2+]cytoscillationswithdifferentpropertiesoccurinthepericycleandendodermisaf-terchallengebyNaClorosmoticstresswithmannitol.Mannitolcausesrepetitive[Ca2+]cytincreasesintheendodermiswithapeakin[Ca2+]cytevery20–30s,comparedwithasus-tained[Ca2+]cytincreaseinthepericycle(76),buttheoutcomeofthedifferentcalciumsig-naturesinthesecelltypesintermsofcellularacclimationtoabioticstressremainsunknown.Analternativeexplanationforthedifferentcell-specificCa2+signaturesoftheendodermisandpericycleisthatthesecelltypesexperiencedif-feringlevelsofexposuretothestressasare-sultoftheirlocationwithintherootstructure,andsothedifferentCa2+signaturesinthecelltypesarecausedbydifferingstimulusmagni-tudes.Whethercelltype–specificCa2+signalscausecelltype–specificstressresponsesremainsanimportantandopenquestion.

RegulationofStomatalAperture

Ca2+signalsarecoreregulatorsofstom-atalaperture(121).Informationencodedin[Ca2+]cytoscillationsalonecanprogramstom-atalaperturebecauseartificiallyimposedos-cillationsinguardcell[Ca2+]cytclosestom-ata,andthe[Ca2+]cytoscillationfrequencyandamplitudedeterminesteady-stateaperture(4).Thegreatestdegreeofsteady-stateclo-sureiscausedbyartificial[Ca2+]cytincreases

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calmodulin-bindingtranscriptionfactor(strictly,calmodulin-bindingtranscriptionthathaveaperiodof10minutesandwheneachincreaselastsforapproximately5minutes(4),whichiscomparablewithABA-induced[Ca2+]cytoscillationsinguardcellsthatclosestomataandhaveperiodsof6to8minutes.AnemerginghypothesisisthatpreexposureofguardcellstoABAandCOincreasesthesen-comparedwiththoseinducedinthecytosol(e.g.harpincauses5minand150minin-creasesincytosolicandnuclear[Ca2+],re-spectively)andtheCa2+increasesmeasuredfromcellculturesaresustainedratherthanoscillatory(86).MAMP-induced[Ca2+]in-creasesleadtothecombinedCa2+-dependentactivator)

.ylno esu lanosrep roF .0/121/70 no ytisrevinU larutlucirgA aniCh yb2sitivityofCa2+sensorstosubsequentCa2+in-creases(71,148).Forexample,guardcellpre-exposuretoABAincreasesboththemagnitudeofS-typeanioneffluxcurrentsandthedown-regulationofK+incurrentsinresponsetoCa2+(148).Theauthors(71)thereforeproposethatspecificstimuliprimespecificCa2+sensorssothatthesensorismorereadilyactivatedbyanincreasein[Ca2+]cyt.Themechanisticba-sisfortheprimingofCa2+sensorsbyABAandCO2isunclearbutcouldinvolvedirectinterac-tionsbetweenCa2+sensor(s)andanABA/CO2-responsiveproteinorproteinkinase,oralterna-tivelytheconvergenceofCa2+-dependentandCa2+-independentcomponentsofABAsignal-ingdownstreamfromCa2+increases.Stomatalclosureisattenuatedbutnotpreventedbysup-pressionofABA-induced[Ca2+]cytoscillations(148).ThisdoesnotnecessarilyindicatethatthereisaCa2+-independentpathwaytostom-atalclosure,becauseifCa2+sensorsareprimed,resting[Ca2+]cytmightbesufficienttoactivateguardcellionefflux.Thisisconsistentwithre-portsofABAactivationofanionchannelsintheabsenceof[Ca2+]cytincreases(91).

Plant-PathogenInteractions

Ca2+

signalsareanearlyresponsebycellstothepresenceofpathogenicandsymbioticmi-croorganisms.Surprisingly,defenseresponsesarebothsuppressedandactivatedbyCa2+sig-nals,whichsuggeststhatCa2+-responsivebutantagonisticsignalingmechanismsarepresent.Moleculeswithmicrobe-associatedmolecu-larpatterns(MAMPs)mobilizeCa2+frombothextracellular(apoplast)andintracellu-lar(vacuole/endoplasmicreticulum)storesofCa2+andcausealterationsinnuclear[Ca2+].TheincreasesinnuclearCa2+thatarein-ducedbyspecificMAMPsareprolonged

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activationofmitogen-,salicylicacid(SA)–,andwound-activatedproteinkinases(86,103).Incontrasttothegeneralprinciplethatstimulus-inducedCa2+increasescanencodestimulus-specificinformation,itisproposedthatMAMP-specificpatternsof[Ca2+]cytin-creaseareunusualbecausetheydonoten-codeMAMP-specificinformation.Thisispri-marilybecauseprolonged[Ca2+]cytincreasesinducesimilardefenseresponsesirrespectiveoftheelicitor(103andreferenceswithin).IncontrasttoMAMP-inducedCa2+inductionofdefenseresponses,Ca2+signalsalsosup-pressSA-mediatedacquisitionofsystemicac-quiredresistance(41).ThepositiveregulatorofbasalresistanceandSAlevels,ENHANCEDDISEASESUSCEPTIBILITY1(EDS1),isre-pressedfollowingCa2+/calmodulinbindingtotheCa2+/calmodulin-bindingtranscriptionac-tivator(CAMTA)CAMTA3(41).Incombina-tionthesestudiessuggestthattheintegrationofCa2+signalingwithdefenseresponsesisex-traordinarilycomplexandcouldincoroporateseveralindependentsignalingpathways.

NodulationandOtherSymbioses

Nitrogen-fixingbacteriainproximitytolegumerootssecretenodulation(Nod)fac-tors.Nodfactorscauseperinuclear[Ca2+]cytspikinginrootepidermalcells,whichinitiatescellularinternalizationofrhizobiaandrootnoduledevelopment(123).ThecoreNodfactorreceptorcomprisestheNODFACTORRECEPTOR1(NFR1)/NFR5heterodimerandisrequiredforNodfactor–induced[Ca2+]cytspikingandmembranedepolariza-tion(123).InteractionsoccurbetweenABAandNodfactorsignalingupstreamofCa2+spiking(38),soitwouldbeinterestingtodiscoverwhetherinositol1,4,5-trisphosphate

Annu. Rev. Plant Biol. 2010.61:593-620. Downloaded from arjournals.annualreviews.org(InsP3),whichmobilizesCa2+andparticipatesinABAsignaling,isinvolvedinthisinteraction.Nodfactor–inducedCa2+spikesresultinCa2+/calmodulinbindingtotheCa2+/calmodulin–dependentproteinkinase(CCaMK)DOESN’TMAKEINFECTIONS3(DMI3)inMedicagotruncatula(123).ThisactivatesDMI3whichpromotesearlynodulation(ENOD)genes.ENODgenesareactivatedbyinductionof(a)theGRAS-familydomaintranscriptionfactorsNSP1andNSP2thattogetherformaDNA-bindingcomplexthatbindstheAATTTpromotermotif,and(b)theERF-subfamilytranscriptionfactorERN(65,123).

.yln[Ca2+]cyttransientsalsooccurinplantcellso eduringtheformationofsymbioticrelationshipssu labetweenplantsandothermicro-organisms.no2+s[Ca]cyttransientsoccurduringdevelopmentrepofsymbioseswithotherarbuscular-mycorrhizal roF(AM)fungi(82,120)andafterexposureto .0cellwallextracts(CWEs)fromthegrowth-/121promotingfungusPiriformosporaindica(158)./70 Thesesignalsinteractwith,butarenotiden-no yticalto,defensesignalingbecausebothP.in-tisredicaCWEsandMAMPsincreaseexpressionvinofdefense-relatedMAPKINASE6(MPK6),U lbutCWEsdonotcausedownstreamde-arutfenseresponsesandinsteadincreasethetran-luciscriptabundanceofCYCLICNUCLEOTIDErgAGATEDCHANNEL10(CNGC10),CNGC13, aniCALMODULIN-LIKEPROTEIN42(CML42),Ch andCML38(158).ThisimpliesthatCa2+sig-ybnalingisacommonfeatureofplant-microbeinteractions.

TheCircadianClockandPhototransduction

Ca2+signalscontributetoredlight(RL),bluelight(BL),andUV-Bsignaling.Ca2+signal-ingduringphytochrome-mediatedRLpho-totransductionhasbeenreviewedelsewhere(147,149)soherewefocusontheinvolve-mentofCa2+inBLsignaling.BLandRLcausebrief(60s)[Ca2+]cyttransientswithoutapparentoscillations(13,149)andtheBLspectrumcauses[Ca2+]cyttransientmaxima

atthe440nmand470nmwavelengths.BLcausesCa2+influxthroughplasmamembrane(lanthanum-sensitive)voltage-gatedCa2+channelsbutdoesnotcauseCa2+re-leasefromtheER(thapsigargin-insensitive)(13).ThisCa2+increaseismediatedbyBL-activationofphototropinbluelightphotore-ceptors(PHOTs)ratherthancryptochromebluelightphotoreceptors(CRYs)(13,58,59).BLCa2+signalsarealsorequiredforBLinhibitionofseedlinggrowth(46).Sev-eralproteinsmightparticipateinsensingBL-inducedCa2+increases.Ca2+-bindingproteinsthathavebeenlinkedtoBLincludeSHORTUNDERBLUELIGHT1(SUB1),anEF-hand–containingproteininvolvedincontrolofHY5-mediatedseedlingde-etiolationbyphy-tochromeandcryptochrome(55).However,sinceSUB1isinvolvedinCRYandPHYsig-naling,butCRYsdonotappeartomediateBL-inducedCa2+increases(13),theinvolvementofSUB1withlightinducedCa2+signalsmightre-lateprimarilytothedecodingofphytochrome-mediatedCa2+alterations.PLASTIDMOVE-MENTIMPAIRED1(PMI1)hasregionswithhomologytobindingdomainsforinteractionwithC-domainCa2+-bindingproteinsandisrequiredforBL-inducedchloroplastrearrange-ment(34).Incontrasttohigherplants,inthebryophytePhyscomitrellapatensBL-induced[Ca2+]cytincreasesaremediatedbybothCRYsandPHOTs(156).ThisraisestheintriguingpossibilitythatinhigherplantsCRYsmightcontributetoBL-inducedCa2+signals,butthisisnotalwaysdetectedwiththeaequorin-basedtechnologyusedforCa2+measurements.Fu-turecomparativestudiesinvolvingthemea-surementofBL-inducedCa2+increasesinsin-glecellscouldexpandourunderstandingofwhetherCRYsareassociatedwithBL-inducedCa2+signalsinhigherplantsorwhetherthismechanismwaslostduringtheevolutionofhigherplants.

Circadianoscillationsof[Ca2+]cytoccurincontinuouslightandarecontrolledbythemolecularcircadianoscillator(72,168).Underconstantlightthereisasinusoidalvariationin[Ca2+]cytover24hthatisestimated

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Annu. Rev. Plant Biol. 2010.61:593-620. Downloaded from arjournals.annualreviews.org.ylno esu lanosrep roF .0/121/70 no ytisrevinU larutlucirgA aniCh ybtoreachpeakconcentrationsof300–700nMbetweenthemiddleandendofthesubjectiveday(72,96).Similar[Ca2+]cytvariationsoccurunderlight–darkcycles(96)butdonotpersistundercontinuousdarkness,requiringlightinputviaPHYTOCHROMEB(PHYB),CRYPTOCHROME1(CRY1),andCRY2(168).CircadianrhythmsofCa2+arethoughttobepositioneddownstreamofthecalcium-mobilizingmoleculecyclicADPribose(cADPR)(39).Inlight–darkcycles,thereisarhythmofADPribosylcyclaseactivityinEuglenagraciliswithpeakactivityduringthelightperiod(106);incontinuouslight,circa-diancADPRfluctuationsoccurinArabidopsis(39).InArabidopsis,perturbationofcircadianCa2+oscillationsorcADPRsignalingaltercircadianclockfunction,whichsuggeststhatCa2+/cADPRformsafeedbackloopwithintheclockbecausethecircadianclockisrequiredforcircadian[Ca2+]cytoscillationstooccur(39,168).AswithmanyCa2+signalsinplants,thedownstreamCa2+-bindingproteinsthatdecodecircadian[Ca2+]cytoscillationsareunidentified.Itisnotknownwhethercircadian[Ca2+]cytdynamicsaredistributeduniformlywithinthecytosolorarealternativelyanaggregationoffrequency-oramplitude-modulated[Ca2+]cytspikes.Theextensivecrosstalkbetweencircadiantimingandstresssignalingnetworks(39)indicatesthatitwillbeimportantinthefuturetodiscoverwhethercircadian[Ca2+]cytoscillationsparticipateinabioticstressresponses,particularlygiventhecontributionofcADPR-mediatedCa2+releasetoabscisicacidsignaling.

ControlofPolarTipGrowthbyTip-FocusedCa2+Gradients

Tip-focusedCa2+gradientsareimportantde-terminantsofpolarityintip-growingcellssuchasroothairs,pollentubes,fungalhyphae,andalgalrhizoids(63).Here,weconsiderresearchdevelopmentsinCa2+signalingduringroothairextensionbecausetherehavebeensev-eralrecentdevelopmentsinourknowledgeofCa2+signalinginthiscelltype.TheNADPH

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oxidaseROOTHAIRDEFECTIVE2(RHD2,alsoAtRBOHC)islocalizedtotheplasmamembraneofthegrowingtipofroothairs(152).RHD2producesreactiveoxygenspecies(ROS)thatstimulatehyperpolarization-activatedCa2+channelsofunknownmolecularidentity,leadingtoformationofatip-focusedCa2+gradient(47).Thisisthoughttotar-getthecytoskeletonandsecretoryapparatustothegrowingtip.Polarityisproposedtobeself-sustainedthoughpositivefeedback,inwhichROS-inducedCa2+influxmaintainsel-evatedCa2+attheroothairtip,whichre-sultsinsynergisticactivationofRHD2bybothCa2+bindingtotwoEF-handsonRHD2andCa2+-dependentphosphorylationoftwoserineresiduesonRHD2(152).Consistentwiththishypothesis,thereareoscillationsintheelevatedtip-focused[Ca2+]cytgradientandinroothairextension,separatedbyalagofapproximately5s(112).TheoscillationsareproposedtoarisefromaburstofroothairextensioncausingapulseofCa2+influxthatsubsequentlyinducesROSproduction,furtherCa2+influxandthenextpulseofgrowth(112).Thismodelisdependentuponthelocaliza-tionofRHD2andrelevantchannelstothetipsothatCa2+influxoccursonlyinthisre-gion,butthemechanismscontrollingthisdis-tributionareunclearandthisrepresentsanimportantareaforfutureresearch.Annexins,whichcangenerateCa2+-permeableconduc-tances(85),areconcentratedintip-growingstructures(114)andareanattractivepoten-tialregulatorofroothairpolarity.TheRhoGTPaseGDPdissociationinhibitor(RhoGDI)SUPERCENTIPEDE1(SCN1)regulatestip-focusedROSproduction(18),andtheRopGTPaseROP2mightdosoaswell(73).

TheSelf-IncompatibilityResponse

Ca2+signalsareinvolvedinreproductiveself-incompatibilityinpoppy(Papaverrhoeas).Topreventinbreeding,self-producedpollenthatsharesthesameS-alleleasthestigmaisrecognizedbythegrowingpollentubewhenitdevelopsonthestigma.Thiscauses

Annu. Rev. Plant Biol. 2010.61:593-620. Downloaded from arjournals.annualreviews.orgtheself-incompatibility(SI)responsethatstopspollentubegrowthandpreventsself-fertilization.Inpoppy[Ca2+]cytalterationsactasanearlysignalinpreventionofself-fertilizationandactivateseveralinhibitorymechanisms.Withinsecondsofpollentubechallengewithself-(i.e.,incompatible)pistilS-proteins(PrsS),[Ca2+]cytinthepollentubeshankincreasesfrom∼200nMto1.5μMforseveralminutesandtheoscillatorytip-focused[Ca2+]cytgradientdissipates(48).Arti-ficial[Ca2+]cytelevationwithinthepollentubemimicstheSIresponse(49).ThepollenSIdeterminantistheplasmamembraneproteinPrpSandthisinteractswiththepistilself-.ylndeterminantPrsStotriggertheSIresponseo ewhenpollenPrpSinteractswithpistilself-su lPrsS(164).ThemolecularidentityoftheCa2+anoschannelsthatcauseCa2+influxduringtherepSIresponseremainstobediscovered.The roFSIresponsealsoinvolvesCa2+/calmodulin- .0dependentinhibitoryhyperphosphorylationof/121thesolubleinorganicpyrophosphatasesPr-/70 p26.1aandPr-p26.2b.Thisisproposedtocauseno yPitoincreaseduringtheSIresponseandsoin-tisrhibitpollentubemetabolism(33).TheSICa2+evinsignalalsopromotescaspase(cysteine-asparticU lprotease)-likeactivity,whichisacomponentarutofmechanismscausingprogrammedcelldeathluci(153).

rgA aniChTRANSPORTSYSTEMSTHAT ybENCODECa2+SIGNALS

Calciumtransportsystemshavetomaintainlow[Ca2+]cytagainstasignificantelectrochem-icalpotentialdifferenceforCa2+(i.e.,notonlyaconcentrationdifferencebutalsoanelec-tricalpotential)andthusareenergized(141).InplantsenergizationisaccomplishedeitherthroughCa2+pumpspoweredbyATPhydrol-ysisorthroughCa2+-H+antiporterspoweredbyaproton-motiveforce(141).AconventionalviewoftheseenergizedsystemsinplantcellsisthattheyprovidethehomeostaticbackgroundagainstwhichCa2+-releasechannelsoperatetransientlytoelevatefree[Ca2+]cyt(139).Open-ingofsuchchannelsshouldthereforeprovide

atleasttheinitialspikefortheelevationof[Ca2+]cyt.Ingeneral,thisparadigmremainsin-tact.However,asdiscussedinthenextsection,researchinvolvingmutantsingenesencodingenergizedtransportsystemshasyieldedintrigu-ingresultsdemonstratingthatenergizedtrans-portofCa2+fromthecytosolmightprovidemuchmorethanahousekeepingbackgroundtoCa2+signaling.

EnergizedSystems:

Ca2+-PumpingATPases

ATP-dependentexportofCa2+fromthecy-tosolisaccomplishedbyP-typeATPasesoftheP2class.P2Ca2+-pumpingATPasescom-prisetwodistinctclades.InArabidopsistheseareER(endoplasmicreticulum)-typeCa2+-ATPases(ECAs)oftheP2Agroup,andAUTO-INHIBITEDCa2+-ATPases(ACAs)oftheP2Bgroup.TwomajorfeaturesdistinguishECAsfromACAs(17).First,anN-terminalcytosolicdomainpresentonlyinACAsbindscalmod-ulinthatisboundtoCa2+,andthisinteractionactivatesCa2+pumping(8).Second,therearedifferencesinmembrane-locatedresiduesthatarethoughttobeinvolvedinCa2+binding.ThislatterdifferencemightaccountforthefactthatinsertionalmutantsinatleasttwoofthefourArabidopsisECAgeneshaveMn2+-aswellasCa2+-relatedphenotypes.Thus,whileplantslackingtheER-localizedECA1pump(166)andthoselackingtheGolgi-orendosome/post-Golgi-localizedECA3(93,111)exhibitgrowth-sensitivephenotypestolowCa2+concentrations,allmutantsalsoex-hibitphenotypeswithrespecttoMn2+.There-fore,thisgroupofCa2+-ATPasesseemstobeinvolvedprincipallyindeliveryofcationstoin-tracellularcompartmentswherethereisare-quirementforsecretionorasacofactorforen-zymaticactivity,ratherthanincytosolicCa2+homeostasisandsignalingperse.

Bycontrast,ACApumps,whichcomprisea10-membergenefamilyinArabidopsis,areemergingaspotentialkeyplayersinplantCa2+signaling.Hintsatthisrolecomefromex-pressionprofiling.Forexample,ACA12and

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Annu. Rev. Plant Biol. 2010.61:593-620. Downloaded from arjournals.annualreviews.org.ylno esu lanosrep roF .0/121/70 no ytisrevinU larutlucirgA aniCh ybACA13transcriptsaredramaticallyupregulatedbypathogenstress(17).Furthermore,tran-scriptabundanceoftheclosely-relatedACA8andACA10isdifferentiallyregulatedbycold(142),whereastranscriptsofACA8andACA9arebothacutelyupregulatedbyABA(21).ACAs8,9,and10areplasmamembranelo-calized(16,142,143),anddistinctrolesinsig-nalinganddevelopmenthavebecomeapparent.T-DNAinsertionalmutantsintheACA9geneexhibitpartialmalesterility,consistentwithex-pressionprimarilyinpollen(143).Thisfind-ingneednotofitselfindicateakeysignalingroleforACA9,despitethecentralfunctionofCa2+indictatingpollentubegrowthandguid-ance(63):Itispossiblethatageneraldisrup-tionofcytosolicCa2+homeostasisinaca9mu-tantsimpactsthephenotypesofreducedpollentubegrowthanddischargeofspermcellsintoovules.

However,anintriguingphenotypeofaca10mutantssuggeststhatACApumpsplaycriti-caldevelopmentalroles.Acompactinflores-cence(cif)phenotypeinArabidopsisisspecifictoaca10mutantsbutnottoaca8oraca9mutants(53).Nevertheless,overexpressionofACA8inanaca10backgroundwillcomplementthecifphenotype,suggestingthatdifferencesinex-pressionamongmembersofthissubgroupofP2BATPasescanimpactdevelopment.

ACApumpsarealsosubjecttocomplexposttranslationalregulation,includingactiva-tionbycalmodulin,regulationbyacidicphos-pholipids(15),andinthecaseoftheER-localizedACA2,phosphorylation(68).Thesemultiplemodesofcontrol,differentialintracel-lularlocations(e.g.,ACA4andACA11localizetovacuoles;52,88),anddifferingtissue-specificexpressionofACAsarechallengingintermsofunderstandingtheextenttowhichACAshavespecificrolesinCa2+signaling.InPhyscomitrellaanACA-typedeletionofCa2+-ATPasegenere-sultsinenhancedsensitivitytoNaClandthisisassociatedwithaberrantregulationof[Ca2+]cyt(134).Todate,therehavebeennosuchstudiesinhigherplants,makingthisafruitfulareaforfurtherinvestigation.

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EnergizedSystems:

Calcium–ProtonExchangers

WithrespecttoP2ATPases,calcium-protonexchangersarelow-affinitycytosolicexportsys-tems,coupledtothethermodynamicallydown-hillexchangefluxofH+.Itislikelythattherearesixbonafidecalcium–protonexchang-ers,knownasCATIONEXCHANGER1to-6(CAX)(146),encodedintheArabidopsisgenome.CAXtransportersaremembersoftheMajorFacilitatorSuperfamilyandarepredictedtohave11transmembranedomains(TMDs).Wheremembranelocationhasbeencharacter-ized,inthecasesofCAX1toCAX4,thelocal-izationisvacuolar(146).

InArabidopsis,CAX1andCAX3appeartobeprominentinCa2+homeostasis.cax1mutantsexhibitdevelopmentalreductionsinlateralrootlengthandnumber,adramaticreductioninthelengthoftheprimaryinflo-rescence(24),andincreasedcapacityforcoldacclimationassociatedwithenhancedexpres-sionofCBF/DREB1(20).AlthoughCAX1ismorestronglyexpressedinshoottissueandCAX3moresoinroots,cax1/cax3doublemu-tantshavesignificantlymoreseverephenotypesthaneitherofthesinglemutants,includingleaftipnecrosisandioniccontent(25).cax3mu-tantsarealsomoresusceptibletosaltstress(171).

CAXtransporters,likeACApumps,aresub-jecttoposttranslationalregulationinplantsthroughanautoinhibitoryN-terminus(110)andpossiblyalsothroughregulatoryprotein–proteininteractions(23,26).Incombinationwithcaxmutantphenotypes,thisposttrans-lationalregulationsuggestsanacuteroleforCAXsinCa2+homeostasis.Acriticalcurrentquestionrevolvesaroundthenatureofthemu-tantphenotypesoftheseenergizedcytosolicexportsystems:AretheymerelydisruptedinCa2+homeostasis,asupregulationofalterna-tiveCa2+transporterscanimplyinsomemu-tants(24,25),oristhereamorefundamentalroleinCa2+signaling?

WhetherenergizedCa2+transportsys-temsaremorethanbackgroundplayersin

Annu. Rev. Plant Biol. 2010.61:593-620. Downloaded from arjournals.annualreviews.orgtheCa2+signalingtoolbox,and,likePCAIinnicotinicacidadeninedinucleotidephosphatePhyscomitrella,playanactiveroleinshaping(NAADP;118).

Ca2+signals,willonlybeestablishedoncemea-InsP3participatesinpollentubeorientation,surementsof[Ca2+]cythavebeenperformedinsaltandhyperosmoticstresssignaling,ABAsig-mutantslackingthesetransportsystems.

nalingandgravitropism,whilecADPRmedi-atestheactivationofsomedefensegenesandCalciumEntrytotheCytosol

functionsinABAandcircadiansignaling(39,141).Thesefindingsconfirmthephysiologi-PassivereturnflowofCa2+downtheelectro-calrelevanceofthetwoligandsand,incom-chemicalpotentialgeneratedbyATPasesandbinationwithresultsdemonstratingthatInsP3CAXsisthoughttobetheprimarydriverforandcADPRmobilizeCa2+,suggestthepres-Ca2+signaling(141).ThisfluxoccursthroughenceofreceptorsthatalsofunctionasCa2+ionchannels.Forexample,plasmamembranechannels,asisthecaseinmammaliancells.Ca2+-permeablechannels,whichareinnormalHowever,homologuesofmammalianInsP3conditionsrelativelyinactive,areactivatedbyreceptorandryanodinereceptor(therecep-.ylnABAorbyROSinguardcells(117,127),twotorforcADPR)arenotencodedbyhighero estimulithateffectstomatalclosure.ROSalsoplantgenomes,andthemolecularidentitiesofsu lactivateCa2+-permeablechannelsattheplasmatheInsPa3-andcADPR-activatedCa2+-releasenosmembraneofroothairsduringCa2+-regulatedpathwaysinhigherplantsremainunknown.repcellexpansion(47).TheseROS-relatedactiva-Theabsenceofthismolecularhandlehasim- roFtioneventsmightinvolveextracellularATPsig-pededprogressinunderstandingtherolesof .0naling(36).However,dependingonthestimu-InsP3andcADPRinplantCa2+signaling./121lus,Ca2+signalscanbegeneratedacrossmem-Untilrelativelyrecently,themoleculariden-/70 branesotherthantheplasmamembrane:ColdtitiesofplasmamembraneCa2+-permeableno yshockinducesmobilizationofvacuolarCa2+channelsandthosenotcontrolledbyligandsattisr(79),whileNodfactorsgenerate[Ca2+]cytsig-endomembraneswereunknown.ForwardandevinnalsthatemanatefromtheperinuclearregionreversegeneticapproacheshavenowyieldedU lERoflegumeroothairs(123).

specificinformationonthemolecularidenti-arutElectrophysiologicalstudies,particularlytiesandphysiologicalrolesofsomeplantCa2+-luciduringthe1990s,establishedthatavarietyofpermeablechannels(161).

rgAdifferentCa2+-permeablechanneltypesexist aniinplants(reviewedin35,141).TheplasmaChCyclicNucleotide–GatedChannels

membranepossessesCa2+-permeablechannelsybwitharangeofvoltage-dependencies:someArabidopsispossessesalargegenefamilyof20areactivatedbymembranehyperpolarizationmembersthatencodecyclicnucleotide-gatedorbydepolarization,andsomearevoltage-channels(CNGCs)(105).Thesechannelshaveinsensitive.InaccordwiththenotionthatsixTMDsandaporedomain,andproba-Ca2+canbemobilizedacrossendomembranes,blyassembletetramericallytoformthepore.voltage-dependentchannelsalsoresideintheSomeplantCNGCsareCa2+-permeablewhenvacuolarmembraneandER.Additionally,elec-expressedheterologously(90,157),althoughtrophysiologicalapproacheswithintactvac-somearealsopermeabletomonovalentionsuolesandradiometricapproachesusingmem-(9,89).Besidesacyclicnucleotide-bindingdo-branevesicleshaveestablishedthepresencemain,CNGCsalsobindcalmodulin(144).Allofligand-gatedCa2+-permeablepathwaysatCNGCsstudiedtodatelocalizetotheplasmaendomembranes.Secondmessengerssuchasmembrane(7,54,157).

InsP3andcADPRreleaseCa2+fromthevac-MutantsinArabidopsisCNGC2,CNGC4,uolarlumen(e.g.,5).Bothligandsalsoliber-CNGC11,andCNGC12haveaberrantregula-ateCa2+fromtheER(116,119),alongwith

tionofpathogendefenseresponses(9,29,170),

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601

Annu. Rev. Plant Biol. 2010.61:593-620. Downloaded from arjournals.annualreviews.org.ylno esu lanosrep roF .0/121/70 no ytisrevinU larutlucirgA aniCh ybandcngc2mutantsadditionallylackacAMP-gatedCa2+currentattheplasmamembraneofguardcells(3).ThemannerinwhichCNGCsareactivatedduringdefensesignalinghasyettobedetermined.Amorediverseroleformem-bersoftheCNGCfamilyhasbeenindicatedincngc18mutants,whicharedefectiveinpollentubegrowth(50).Glutamate-Receptor-LikeChannels

Plantscontainhomologuesofanimalionotropicglutamatereceptorsthatfunctionasnonselectivecationchannelsatpostsynapticmembranes.TheGLUTAMATERECEPTOR(GLR)genefamilyinArabidopsiscomprises20members,eachofwhichencodesaproteinwiththreepredictedTMDs.Theentirechannelisprobablyformedasatetramerorpentamer(32).

Glutamate,aswellasfiveotheraminoacidsandevenglutathione,appliedtoArabidopsisseedlingsgeneratesaninwardcurrentandacy-tosolicCa2+spike,andbothresponsesareat-tenuatedinglr3.3mutants(37,132).DifferentmembersoftheGLRfamilyresponddiffer-entlytoactivatingligands(150),butitisnotclearwhichligandsarephysiologicallyactive.Nevertheless,exogenousglutamateandglycinehaverolesinprocessesasdiverseashypocotylelongation(43)andtheregulationofCandNmetabolism(74).

ForbothGLRandCNGCionchannels,thepotentialformembersoflargegenefamiliestoformheteromultimericcomplexesmightexplainthediversityofplantplasmamembraneCa2+-permeablechannelsthathavebeenreportedinelectrophysiologicalstudies.However,anoteofcautionisalsonecessary.ChannelsthatdepolarizeamembranewhenactivatedmightcontributetoacytosolicCa2+responsemerelybyactivatingsomeothervoltage-sensitivepathway.OneexampleforwhichthisisalmostcertainlythecaserelatestoperinuclearCa2+spikingduringNod-factorperception.CASTORandPOLLUX(inLotus)andDMI1(inMedicago)arenucleus-localizedchannels,andmutantslackNod-factor-602

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inducedCa2+spiking.However,allthreechannels,whenstudiedheterologously,havecharacteristicsthatsuggesttheyareregulatorsofCa2+-permeablechannelsbutdonotthem-selvesformthephysiologicalpathwayforCa2+release(22,129).Indeed,perinuclearCa2+spikinginMedicagocanbeelicitedindmi1mu-tantsbymastoparan,aG-proteinagonist(151).

Two-PoreChannels

TheArabidopsisgenomecontainsasinglemem-beroftheTWO-PORECHANNEL(TPC)family,TPC1.Theproteinispredictedtohave12TMDsandincorporatetwoporedomains(hencethename),andislikelytoformahomo-dimer.AcytosolicloopbetweenTMDs6and7includestwoputativecalcium-bindingEF-handsanda14-3-3bindingdomain,andTMDs4and10havepositivelychargedresiduesthatsuggestthechannelshouldbevoltagegated(128).

TPC1localizesinArabidopsistothevac-uolarmembrane,andmutantslackactivityoftheso-calledslowvacuolar(SV)channel(128)thatdominatesthevacuolarmembraneconduc-tanceathigh[Ca2+]cyt(62).SV/TPC1channelsappeartobeexpressedubiquitously(62).TheTPC1proteinisunusuallyhighlyexpressedforachannelprotein,appearinginanumberofvacuolarproteomicsanalyses(19,165).Elec-trophysiologicalstudiesdemonstratethatthisCa2+-activatedchannelisCa2+permeable(6,162),suggestingthatthechannelprovidesapathwayforCa2+-inducedCa+release.Thishasbeenconfirmedinacarefulstudyinvolvingpatchclampelectrophysiologycombinedwithnoninvasiveionfluxmeasurementsusingion-selectivemicroelectrodes(131).

DeletionmutantsinTPC1aredefectiveintwoCa2+signalingpathways—Ca2+-inducedstomatalclosureandABA-delayedgermination(128)—butnotinaselectiverangeofothertypesofCa2+signaling(135),demonstrat-ingthestimulusspecificityofCa2+-permeablechannelactivation.Aconstitutivelyactivemu-tantofTPC1(fou2)exhibitsjasmonateover-production(14).OnewaythatTPC1channel

Annu. Rev. Plant Biol. 2010.61:593-620. Downloaded from arjournals.annualreviews.orgactivationmightoccuratthevacuolarmem-braneisillustratedinFigure1(140,162).

AnnexinsasNovelPlantCa2+-PermeableChannels

Annexinproteinspurifiedfrommaizecanfunc-tionasCa2+-permeablechannelswhenincor-poratedintoplanarlipidbilayersandcanalsoelicitelevationsof[Ca2+]cytwhenaddedtopro-toplasts(85).Thepurifiedproteinalsohasper-oxidaseactivity,anditissuggestedthatannexinsmightformplasmamembraneCa2+-permeablechannelsduringstressresponses.

.ylno PERCEPTIONANDDECODINGesu OFCa2+SIGNALS

lanosTheincreasesincytosolicandnuclearfreecal-repciumthatoccurduringsignaltransductionare roFdetectedbycalciumsensorproteins.Proteins .0involvedintheperceptionanddecodingof/121Ca2+signalsarepresentinthecytosolandnu-/70 cleus,andarebothfreeandattachedtomem-no ybranes.ThelargenumberofcalciumsensortisrproteinswithdifferentCa2+-bindingcharacter-evinistics,subcellularlocalizationsanddownstreamU lsignalinginteractionsisthoughttoprovideaaruttoolkitthatenablesthedecodingofinforma-lucitionwithinCa2+oscillationsandspikesandthergAprocessingofthisinformationintoalterations aniincellfunction.

Ch Calciumsensorproteinsareclassifiedasybeithersensorrelaysorsensorresponders(141).SensorresponderproteinssuchasCa2+-dependentproteinkinases(CDPKs)combinewithinasingleprotein(a)asensingfunction,mediatedbycalcium-bindingdomainsthatoftencauseCa2+-inducedconformationalchanges,and(b)aresponseactivity(e.g.,kinaseactivity).Incontrast,sensorrelayproteinssuchascalmodulinalsocontainmultiplecalcium-bindingdomainsandusuallyundergoCa2+-inducedconformationalchangesbutlackothereffectordomains(Figure2).TotransmittheCa2+signal,sensorrelayproteins

“limitless” VacuoleCa2+VacuolarmembraneCytosolInsP3limited ER+Ca2+InsP2+3RCaInsP3R−−cADPR+cADPR-RCa2+cADPR-R+TPC1 (SV)Ca2+PNAADP+Ca2+NAADP-RH+Ca2+CAXs+Ca2+ATPER membraneADPECAs+Figure1

Ca2+-inducedCa2+releaseinplantcellsinvolvesthevacuoleandER.ThevacuoleandERstoredifferentquantitiesofCa2+andtheirmembranesystemsaresensitivetodifferentcombinationsofsmallmolecules.TriggerCa2+,

releasedthroughligand-activatedCa2+channels,mightactivatetheTPC1/SVchannel(a)directlythroughbindingtotheEF-hands,(b)indirectlythroughmembranedepolarizationresultingfromcytosol-directedmovementofCa2+,or(c)throughelicitingCa2+-activatedK+channels(notshown).ThisdualformofactivationwouldtriggerregenerativeCa2+release,forwhichsomekindofnegativefeedback—perhapsthroughkinaseinhibition—wouldberequired.Abbreviations:cADPR,cyclicadenosinediphosphateribose;cADPR-R,receptorforcADPR(unknowninplants);CAX,Ca2+/H+

antiporter(cationexchanger);ECA,ER-typeCa2+ATPase;InsP3,inositol1,4,5-trisphosphate;InsP3R,receptorforinositol1,4,5-trisphosphate

(unknowninplants);NAADP,nicotinicacidadeninedinucleotidephosphate;NAADP-R,receptorforNAADP;TPC1,TWO-PORECHANNEL1.

www.annualreviews.org•Ca2+Signaling603

Annu. Rev. Plant Biol. 2010.61:593-620. Downloaded from arjournals.annualreviews.orgStimulusAKT1CBL1/9.ylno esu lanosrep roF .0/121/70 no ytisrevinU larutlucirgA aniCh ybCDPK:

Ca2+-dependentproteinkinase

604

CIPK23CBL1/4K+CAMDiverseproteinstargetNa+CIPK24Ca2+CAMsSOS1H+CBLs/CIPKsCAM7CIPK24CBL10Light-inducible genesUnknownCAMNa+CAMTA1/3CAMCold-inducible genesCCaMKNucleusVacuoleCDPKRSGCDPKsCPK3/6CDPKanion channelsS-typeoxidases

NADPHFigure2

AnarrayofmechanismsdecodeCa2+signalsandelicithighlyspecificresponsesthatdependonspatialandtemporal[Ca2+]cytvariations.Abbreviations:CAM,calmodulin;CAMTA,Ca2+/calmodulin-bindingtranscriptionactivator;CBL,calcineurinB-likeprotein;CCaMK,calcium/calmodulin-dependentkinase;CDPK,Ca2+-dependentproteinkinase;CIPK,CBL-interactingproteinkinase;CPK,proteinencodedbyCALCIUMDEPENDENTPROTEINKINASEgenefamily;RSG,promoterofREPRESSIONOFSHOOTGROWTH;SOS1,theNa+/H+antiporterSALTOVERLYSENSITIVE1.

mustthereforeinteractwithtargetproteinsdefinedCa2+signaturesintospecificdown-andregulatetheiractivity(98).Althoughthisstreamreactionsandarediscussedindetailconceptoffunctionalclassificationwasini-here.

tiallyappliedtotheconversionofCa2+sig-nalsintophosphorylationresponses,itsrel-evancefortheregulationoftranscriptionalConnectingCa2+withTranscription

processesbyCa2+signalsisbecomingappar-ThemechanismsofCa2+-dependenttran-ent.WhileCa2+bindingtoCALMODULIN7scriptionalregulationinvolvenumeroussignal(CAM7)appearstoresultindirectpromotertransducersincludingCa2+-bindingproteinsinteractionandregulation,othercalmodulins(69).However,despitetheimportanceofarelikelytomediategeneregulationviainter-definedCa2+signaturesduringreactionsactingCAMTAsthatfunctionastranscriptionalto,e.g.,distinctabioticstressconditions(co)regulators.Metabolicandbiosyntheticpro-suchascold,drought,andsalinity(108),thecesseslikebrassinosteroidsynthesisareimpor-molecularidentityofthosegenessubjecttotanttargetsofdirectCa2+-dependentmodula-Ca2+-dependentregulationandthemoleculartion(42),butCa2+-dependentphosphorylationmechanismsmediatingCa2+-responsivegeneandCa2+-dependentgeneregulationrepresentexpressionhaveremainedlittleunderstood.themajorcellularcurrenciesforconverting

Inpart,thisisbecauseofthedifficultyin

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Annu. Rev. Plant Biol. 2010.61:593-620. Downloaded from arjournals.annualreviews.orgdistinguishingstress-dependentCa2+re-sponsesfromstress-dependentbutCa2+-independentreactions(45,115).Theinduc-tionofdefinedartificialCa2+transientsbytheuseofthecalmodulinantagonistsWP7andSKF-7171allowedidentificationof230Ca2+-responsivegenesthatweredifferentiallyexpressed1hpoststimulus(75).Consideringthatthisstudycoveredonly25%ofknownArabidopsisgenes,theseresultssuggestthatapproximately3.3%ofArabidopsisgenesaresubjecttoregulationbyCa2+.ManyoftheCa2+-regulatedgenesidentifiedbythisstudywereknownearlystress-inducedgenes.Impor-tantly,thisinvestigationestablishedthatknown.ylnABRE(abscisicacid–responsiveelement)-o erelatedcis-promoterelementsaresufficienttosu laconfertranscriptionalregulationinresponsenostocytosolicCa2+signatures.SinceABREsarereppresentinthepromoterofC-REPEAT/DRE roFBINDINGFACTOR(CBForDREB1)tran- .0scriptionfactorsthatfunctionasmasterregula-/121torsofabioticstressresponses(45),thesefind-/70 ingspointtoadirectinterconnectionbetweenno yCa2+regulationoftranscriptionandabiotictisrstressresponsesbutraisethequestionofhowevinCa2+signalsaretransducedtothetranscriptionU lmachinery.TheanswermaybeprovidedinarutpartbythefunctionofCAMTAproteins.

luciCAMTAsareafamilyofeukaryoticCa2+-rgAdependentcalmodulin-bindingtranscription anifactorswithsixmembersinArabidopsis(44).Ch Thesetranscriptionfactorsshareaconservedybdomainstructure,includingaC-terminalcalmodulin-bindingdomainthatmediatesin-teractionswithcalmodulinandanN-terminalCG-1domainthatmediatesbindingtoDNAcis-elements(CAMTAbindingsites),thelatterincludingABREsandadditionalCGCGele-ments(44).CAMTAgeneexpressioninAra-bidopsisrespondsrapidlyandtransientlytovar-iousstresses(e.g.,cold,salinity)andhormones(e.g.,ABA,jasmonicacid)(169),suggestingtheirinvolvementinmultiplesignaltransduc-tionpathwaysthatarecriticalforplantstresstolerance.FirstinsightsintothephysiologicalfunctionofplantCAMTAproteinswerepro-videdbyareversegeneticanalysisofArabidopsisCAMTA3functionthatrevealedacriticalroleforthisproteininsuppressingplantre-sponsestopathogenssuchasPseudomonassy-ringaeandBotrytiscinerea(51).Importantly,arecentstudy(40)providedevidenceforadi-rectlinkbetweenCa2+signaling(viaCAMTA1andCAMTA3)andcoldtoleranceinplantsbydiscoveringthattheseCAMTAproteinsbindtoregulatoryelements(CAMTAbindingsites)inthepromoteroftheDREB1c/CBF2gene.WhilstcoldinductionofCBF2andothercold-inducedgenesisreducedinasinglecamta3mutant,camta1/camta3doublemutantsareimpairedintheircoldacclimationtofreezingtolerance(40).

ThesefindingsestablisharoleforCa2+

/calmodulin-regulatedCAMTAtran-scriptionfactorsincontrollingtheCBFregulonofcold-regulatedgenesandpromotingfreez-ingtolerance.Moreover,theysuggestamodelinwhichCAMTAsmayfunctiondirectlyinthetransductionofcold-inducedcytosolicCa2+signaturesintotheregulationofgeneexpressionthroughinteractionwithoneormoreofthesevenArabidopsisCa2+/calmodulinsensors(109).Furtherinvestigationswillneedtoaddressexactlyhowchangesin[Ca2+]cytleadtochangesinnucleartranscription.

CalmodulinsareprototypicalCa2+sensorrelayproteins,andtheirgenomics,structuralproperties,andfunctionalprincipleshavebeenreviewedcomprehensively(98,109).Asur-prisingtwisttoourviewaboutcalmodulinfunctioninplantswasprovidedbyarecentstudyofCALMODULIN7(CAM7)fromAra-bidopsis(84).InArabidopsissevengenesencodefourCAMisoforms,ofwhichCAM1/CAM4differbyfouraminoacidsubstitutionsfromCAM7,whereasCAM2/3/5andCAM6differbyoneaminoacidfromCAM7(109).Kush-wahaetal.(84)establishedthatCAM7,butnotCAM2/3/5,isatranscriptionalregulatorthatinteractsdirectlywithpromotersofsev-erallight-induciblegenes.cam7mutantsdidnothavephotomorphogenicgrowthalterations,mostlikelyduetooverlappingfunctions,butcam7mutantshadreducedexpressionoflight-induciblegenes.Conversely,overexpression

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Annu. Rev. Plant Biol. 2010.61:593-620. Downloaded from arjournals.annualreviews.orgCIPK:CBL-interactingproteinofCAM7causedanincreaseinexpressionoflight-induciblegenesandhyperphotomor-phogenicgrowth.ThesefindingssuggestthatthecalciumsensorCAM7translatescytosoliccontributestofullactivationofthekinases(100).

ThefirstinvivoevidenceforCDPKfunc-tionwasobtainedbysuppressionofNtCDPK2kinase

.ylno esu lanosrep roF .0/121/70 no ytisrevinU larutlucirgA aniCh ybCa2+signaturesintogeneexpressionthroughDNAbinding.However,futureworkneedstoinvestigatewhetherthisrequirestheinteractionofCAM7withadditional(transcriptionfactor)proteinsandexactlyhowtheinterconnectionbetweencytosolicCa2+signaturesandnucleargeneregulationisachieved.

ConnectingCa2+withProteinPhosphorylation

Phosphorylationcascadesregulatedbykinasesandphosphatasesareprimarydownstreamin-terpretersofCa2+signals.Ca2+transientsareperceivedandtransmittedbyCa2+-dependentkinasesandphosphatases.Theseproteinscanalterbiochemicalfunctiondirectlyandrapidlythroughreversiblephosphorylation,andalsocausealterationsingeneexpressionbymodu-latingtranscriptionfactoractivity(139).PlantshaveauniquerepertoireofCa2+-dependentproteinkinasesthatcomprisethefamiliesofCCaMKs(Calcium-Calmodulin-DependentKinases),CDPKs(Calcium-DependentProteinKinases),andCIPKs(CBL-InteractingProteinKinases)thatformanintricatecellularnetworkfordecodingCa2+signalsandregulatingcel-lularprocesses,includingionhomeostasis(seeFigure2)(10,141).WhileCDPKsandCCaMKsaretypicalsensorresponders,theCIPKsaretargetsofCalcineurinB–like(CBL)sensorrelayproteins(notethatCCaMKsareabsentfromtheArabidopsisgenome).

TheArabidopsisgenomeencodes34CDPKsand8additionalCDPK-relatedkinases(66).ThebiochemistryandregulationofCDPKshavebeenreviewed(60,61,100).Activa-tionofCDPKsisassumedtooccurafterbindingofCa2+totheC-terminalEF-hand-containingregulatorydomain,causingconfor-mationalchangesthatrelievetheactivesiteofthekinasedomainfrommaskingbyanau-toinhibitorydomain.ThisprocessisparalleledbyautophosphorylationoftheCDPKsthat

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byviral-inducedgenesilencing(VIGS)inNico-tianabenthamiana(137).CDPK-silencedplantshadareducedanddelayedhypersensitivere-sponseafterrace-specificAvr9elicitationinagene-for-geneinteraction,andlackedanac-companyingwiltingphenotype.Remarkably,furtheranalysisofNtCDPK2functionsuggeststhatelevatedCDPKsignalinginhibitsstress-inducedMAPKactivation,andthisinhibi-tionrequiresethylenesynthesisandperception(101).ThisindicatesthatCDPKandMAPKpathwaysdonotfunctionindependentlyandconcertedregulationofbothpathwayscon-trolsresponsespecificitytobioticandabioticstress.

Reversegeneticanalyseshavesubstantiallyextendedourknowledgeonthephysiolog-icalfunctionofseveralCDPKs.ArabidopsisCALCIUMDEPENDENTPROTEINKI-NASE3(CPK3)andCPK6functioninABAregulationofstomatalclosureandmodulateguardcellS-typeanionchannels(113).Inaddition,CPK4andCPK11arecriticalforABAresponsivenessofguardcellsandtheyphosphorylatetheABA-responsivetranscrip-tionfactorsABSCISICACIDRESPONSIVEELEMENT-BINDINGFACTOR1(ABF1)andABF4invitro(172).Experimentsinto-baccorevealedthatCDPK1regulatesthetran-scriptionfactorREPRESSIONOFSHOOTGROWTH(RSG)inresponsetogibberellins(70),andworkinpotatosuggeststhatseveralCDPKsregulateROSproductionbyNADPHoxidases(80).Together,thesefindingsindicatecriticalrolesforCDPK-mediatedCa2+signal-inginaverydiversearrayofprocesses.How-ever,itwillbemostimportanttodiscoverthemechanisticbasisforhowspecificCDPKscon-tributetothedecodingofspecificCa2+signa-tures(seeFigure2).

TheCBLproteinfamilyandtheirinter-actingkinases(CIPKs)separateCa2+-bindingfunctionality(sensorrelayfunction)andkinaseactivity(responseactivity)intotwoflexible,

Annu. Rev. Plant Biol. 2010.61:593-620. Downloaded from arjournals.annualreviews.orgcombinablemodules.Thisallowsforthefor-mationofacomplexanddynamicCa2+-decodingsignalingnetwork.Sincethediscov-eryofCBLsandCIPKsinArabidopsis(83,145),advancesinourknowledgeofthestructuralfeatures,evolution,andfunctionalprinciplesofthisCa2+-decodingsystemhavebeenre-viewed(10,11,97–99,163).CBLproteinshavesignificantsimilaritytotheregulatoryBsub-unitofcalcineurinandneuronalcalciumsen-sor(NCS)proteinsfromanimalsandyeast(83).CBLscontainfourCa2+-bindingEF-handdo-mainsthatarearrangedwithinvariantspacing(81).CIPK-typekinasescompriseaconservedN-terminalkinasedomainwithhighsimilar-.ylnitytoyeastSNF1,andaC-terminalregula-o etorydomainthatisseparatedfromthekinasesu ldomainbyavariablejunctiondomain.Withinanostheratherdivergentregulatorydomain,therepconservedNAFdomainisrequiredandsuffi- roFcientforinteractionwithCBLs(1).Moreover,a .0protein-phosphataseinteraction(PPI)domain/121thatmediatesCIPKinteractionwithPP2C/70 phosphatasesispresentintheC-terminusofno ythesekinases(122).ItisassumedthatCBLtisrbindingtotheNAFdomainofCIPKsreleasesevintheC-terminal(autoinhibitory)domainfromU lthekinasedomain,therebytransformingthearutkinaseintoanactivestate(56).Comprehen-lucisivebioinformaticanalysesofbothproteinfam-rgAilieshaveidentified10CBLsand26CIPKsin anitheArabidopsisgenome,and10CBLsand30Ch CIPKsinrice(1,81,163).SingleCBLandCIPKybgenesarepresentinseveralspeciesofgreenalgae,whilePhyscomitrellacontainsfourCBLsandsevenCIPKsandthegenomeofthefernSelaginellamoellendorfiihasfiveCBLsandfiveCIPKs(11,163).ThesefindingssuggestthattheevolutionofplantswasaccompaniedbytheevolutionofcomplexityoftheCBLandCIPKproteinfamilies.

Spatialspecificityisanimportantaspectofcellularinformationprocessing.LocalizationstudiesofArabidopsisCBLproteinsrevealedthatfourCBLsarepresentattheplasmamem-brane,fourarelocalizedtothevacuolarmem-brane,andtwoarepresentinthecytoplasmandnucleus(12,28,31,77,163).ThissuggeststhatCBL-CIPKcomplexescouldfunctionasfastresponderstolocalCa2+releaseeventsfrominternalandexternalstoresandthatthespatialseparationofdistinctCBL-CIPKcom-plexescontributestospatialspecificityinCa2+signaling.Fortheplasmamembrane–localizedCBL1,duallipidmodificationbymyristoy-lationandS-acylationarerequiredforbothitsfunctionanditslocalizationtotheplasmamembrane.CBL1localizationisachievedbyatwo-steptargetingprocessinwhichinitialmyristoylationresultsinlocalizationtotheen-doplasmaticreticulum(ER)andsubsequentS-acylationiscrucialforER-to-plasmamem-branetrafficking(12).

MostCIPK-GFPfusionproteinshavecy-tosolicandnuclearlocalization(11,31,163).However,CBL-CIPKinteractionanalysesus-ingbimolecularfluorescencecomplementation(BiFC)revealedthatCIPKsaretargetedtodif-ferentcompartmentsofthecellbytheirre-spectiveinteractingCBLproteins(12,28,31,160).Forexample,CIPK1istargetedtotheplasmamembranebyCBL1orCBL9(28,160)butuponinteractionwithCBL2theresultingCBL2/CIPK1complexesareexclusivelyvacuo-larmembrane-localized(12).

Initialinsightsintothephysiologicalfunc-tionofCBLsandCIPKscamefromfor-wardgeneticscreens.TheCBLcalciumsen-sorSOS3(AtCBL4)andtheCIPK-typekinaseSOS2(AtCIPK24)appeartobepartofaCa2+-regulatedsignalingpathwaythatspecificallymediatessaltstressadaptationbyregulatingtheNa+/H+antiporterSOS1(seeFigure2)(57,94,95).RecentstudiesrevealedthatthecalciumsensorCBL10alsointeractswithandactivatesthekinaseCIPK24(77,133).CBL10/CIPK24complexesarevacuolarmembrane-localized,therebysupportingthefunctionalconceptthatalternativecomplexformationofCIPK24ki-naseswitheitherCBL4orCBL10createsadual-functionkinasewithseparatefunctionsattheplasmaandvacuolarmembranes(seeFigure2).WhileCBL4/CIPK24complexesmediateNa+extrusionviatheregulationoftheH+/Na+antiporterSOS1attheplasmamem-brane,formationofCBL10/CIPK24resultsin

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ReversegeneticshasgreatlyadvancedourunderstandingofCBLsandCIPKsandrevealedcrucialfunctionsofdistinctCBLpro-teinsandCIPKsformineralnutrition,aswellasresponsestoabioticstressesandtoABA.Anal-ysisofaCIPK3loss-of-functionalleleestab-lishedthatthiskinaseregulatesABAresponsesduringseedgerminationandregulatesABA-inducedgeneexpression(78).TwoindependentreversegeneticanalysesofCBL1functionrevealedthatCBL1isacentralintegratorofresponsestodrought,cold,andsalinity(2,27).WhilethemutantstudiesofCBL1revealedanABA-independentfunctionofthisproteininseveralabioticstressresponses,lossoffunctionofthecloselyrelatedCa2+sensorCBL9rendersplantshypersensitivetoABA(125).AlternativecomplexformationbetweenthekinaseCIPK1andeitherCBL1orCBL9me-diatesABA-dependentandABA-independentresponses(31).CBL9alsoappearstocomplexwithCIPK3formodulatingABAresponses(126).

TheCBL/CIPKsystemalsoregulatesK+homeostasis.CIPK23istargetedtotheplasmamembraneandisactivatedbythetwohighlyrelatedCa2+sensorsCBL1andCBL9(28,167),andthecomplexesregulatetheactivityoftheshaker-likeK+channelARABIDOPSISK+TRANSPORTER1(AKT1).CIPK23in-teractsexclusivelywithAKT1andnootherK+transportersfromArabidopsis(87).BesidestheregulationofK+uptakeinroots,theCa2+-decodingCBL1/CBL9/CIPK23moduleisin-volvedinstomatalregulationunderdehydrat-ingconditions(28).

ThefindingsofallthesestudiesindicatethattheCBL-CIPKnetworkisacentralandcriti-calsystemfordecodingCa2+signalsinresponsetoabroadvarietyofstimuli.ItisalsobecomingapparentthateachCBLandeachCIPKrep-resentsamultifunctionalsignalingcomponentthatcanundergoalternativeproteininterac-tions,determiningtheflowofinformationpro-cessingthroughthissignalingsystem.There-fore,elucidatingthemechanisticfactorsthat

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determinethe“decisionmaking”inthisflexibleinteractionnetworkwillbeofeminentimpor-tancetofurtherourunderstandingofCa2+-decodingmechanisms.

Ca2+SIGNALINGSYSTEMS

Ca2+signalingnetworksarecomplexandso-phisticated.Predictionofnetworkfunctionisoftennonintuitiveduetothehighdegreeofin-terconnectivitybetweennetworkcomponents.Here,we(a)considersystems-basedinvestiga-tionsofnetworkarchitecture,and(b)discussthemodelingof[Ca2+]alterationsduringthegenerationanddecodingofCa2+signals.

Scale-FreeNetworkArchitecture

Somesignalingnetworksareproposedtohavepropertiessimilartoscale-freenetworksincomputing.Scale-freenetworkshavemanyin-terconnectednodes(i.e.,signalingintermedi-ates).Asmallnumberofthenodesareveryhighlyconnectedandcalledhubs(64).Scale-freenetworksarerobusttonoderemoval,aresensitivetohubremoval,andcanpro-cessmultiplesignalssimultaneously(64).Intheguardcell,theextensiveconnectivityofCa2+withothernetworkcomponentsandde-pendencyofstomatalclosureuponstimulus-inducedCa2+alterationsimplythatCa2+isahub(64).Theparadigmofscale-freenetworkarchitectureisnotaformalismofnetworkfunc-tionbutprovidesatoolfordevelopmentofmathematicalmodels,advancesunderstandingoftheevolutionarybasisofthenetwork,andal-lowsidentificationofoptimalmanipulationtar-getsforresearchoragriculturalpurposes.

Knowledgeofinterconnectivitiesbetweenalargenumberofnodes(>1000)isnecessarytoconcludescale-freearchitecture(64).AnAra-bidopsiswhole-genomenetworkderivedfromtranscriptomedatahasscale-freepropertiesbutisnotcompletelyscale-free(102).Thisnet-work(102)reflectsgeneregulationandsodidnotspecificallyincorporateCa2+.Interestingly,thecold-regulatedsubnetworkincludesknownanduncharacterizedproteinslinkedtoCa2+

Annu. Rev. Plant Biol. 2010.61:593-620. Downloaded from arjournals.annualreviews.orgsignaling(102).TranscriptsassociatedwithBow-TieNetworkArchitecture

Ca2+signalingalsooccupyseparateandwell-connectednodeswithinsubnetworksassociatedPlantCa2+signalingnetworkshavecharacter-withERstressresponses(CALRETICULIN2),isticsofbow-tienetworksinneuralnetworkbioticstress(CAX3),jasmonicacid/ethylenecomputing(30,130)(Figure3).Thesenet-signaling(Ca2+-bindingTSK-ASSOCIATINGworksconnectdiverseinputsandoutputsbyPROTEIN1),andsalicylicacidmetabolismandprocessinginformationthroughasmallnumberpathogenresponses(calmodulin-bindingpro-ofcoreintermediatesknownasthehiddenlayer,teinencodedbyAt1g73805)(102).WhenCa2+usingparametersthatbecomedefinedduringsignalingisconsideredwithingenenetworks,networktraining(Figure3a).TheparametersgenesassociatedwithCa2+signalingappearthatdefinerelationshipsbetweeninputsandthetooccupyindependentpositionswithinsev-hiddenlayer,andbetweenthehiddenlayeranderalsubnetworks.Thismightderivefromtheoutputs,causeclassification,wherebyaspecificcapacityofCa2+signalstoencodespecificity,setofinputsleadstoaspecificsetofoutputs.whichallowsthesesignalstooccupymultipleInsignaling,classificationoccurswhenaspe-.cificCa2+signatureisdefinedbytheinputpa-ylnpositionswithinthenetwork.Scale-freenet-orameterset,andalsoduringsubsequentCa2+ eworkarchitectureisalsoausefulparadigmwithsusignaturedecodingintoastimulus-specificout- lwhichtoconsidersmallernetworks.Forexam-anput.Forexample,severalabioticstimulicauseosple,theCBL/CIPKCa2+sensorrelaysystemr[Ca2+]cytandROSalterations,withdifferentep(10)isproposedtohavescale-freearchitecture rpropertiesthatinducestimulus-specifictran-oFbecausethemajorityofCBLsinteractwitha .scriptsets(Figure3b).WhetherCa2+signalsin0smallnumberofCIPKs,whilealimitednum-/1plantcellsperformneuralnetwork–likeclassi-21berofhublikeCBLs(e.g.,CBL2)interactwith/7ficationhasnotbeenformallytested,although0 manyCIPKs(10).Thisprovidesthecapac-nthisappearstobethecaseforCa2+andcGMPo yitytoprocessmultiplesignalssimultaneouslytsignalinginsomeanimalcells(130).Thisarchi-isrthoughformationofalternativeCBL/CIPKetectureisproposedto(a)controlcellfunctionvincomplexes,dependingonlocalizationandcon-Uefficientlybecausealterationsinrelativelyfew lcentrationofCa2+alterationsandlocalizationaintermediatescanevokeavarietyoflarge-scalerutofCBL/CIPKs(31,160).

luoutputalterations,(b)beevolvablebecausenew

cirgA ania

Input layer

bStimuliCh ybyz2+ClassificationHidden layerCaROSATPxOutput layerTranscripts

Figure3

(a)Bow-tiefeedforwardneuralnetworkarchitectureinwhichdiverseinputsregulatediverseoutputsbyprocessing(classification)withinacorehiddenlayer.(b)TranslationofthisconcepttoplantCa2+signalingwithclassificationinvolvingspatiotemporalvariationsinCa2+,ROS,andATP.Conceptfrom(130).Abbreviations:ROS,reactiveoxygenspecies;ATP,adenosinetriphosphate.

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PredictiveModelsofNetworkFunction

Thedynamicinteractionswithinmanysignal-ingnetworksarewellcharacterized,butquan-titativedescriptionsofnetworkfunctionarein-.frequent(67).Here,weconsidersimulationsofylnnetworksthatincludeCa2+signaling.

o esOnemodelforABA-inducedstomatalclo-u lasurehasgeneratednewquestionsconcerningnosrCa2+signalingintheguardcell(92).Inthisep modelinteractionsofsignalingintermediatesroF aredescribedwithBooleanlogic,withtheul-.0/1timateoutcomethattheporeiseitheropenor21/7closed(92).Themosthighlyconnectedcompo-0 nnentsare[Ca2+]cyt(12interconnections),pHcyto yt(9interconnections),andplasmamembranede-isrepolarization(9interconnections).Withinthisvinnetworkthereareatleasttwosemiindepen-U ladentpathwaysconnectingABAperceptionwithrutlstomatalclosure,involvingchangesin[Ca2+]cytucirandpHcyt,respectively(92).OnehypothesisgA formedfromthismodelisthatstomataareaniclosedbyABA-induced[Ca2+]cytincreases,butCh y[Ca2+]cytincreasesarenotaprerequisiteforbstomatalclosure(92).Testingthishypothesis

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Figure4

(a)Arbuscular-mycorrhizal(AM),and(b)Nod-factor-induced[Ca2+]cytspikinginroothairs;from(82).(Copyright2008NationalAcademyofSciences,U.S.A.)

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revealedthatABAcausesslowandpartialstom-atalclosurewhen[Ca2+]cytincreaseswereex-perimentallyprevented(148).TheBooleanmodelincludesOST1,ABI1,andphospholi-paseDascomponentsoftheclosurepath-waythatarerelativelyCa2+independent(92).However,inhibitionofABA-inducedclosureintheABA-insensitivemutantsost1–2andabi1–1ismorepronouncedwhen[Ca2+]cytincreasesareprevented,andacomparableresponseoccurredintheABA-hyposensitivepldα1mutant,suggestingthattheCa2+-dependentABAsignalingpathwayisdomi-nantorthataCa2+-independentmechanismprimesthesignalingnetworktoCa2+increases(148).

Severalcircadianclocktranscriptsareup-ordownregulatedbycADPR,suggestingthatcADPRorCa2+affectscircadianclockfunction(39,138).Toinvestigatethis,parameterswithinanexistingmodelforthecircadianclockwereconstrainedtoforcethesimulatedabundanceoftheclocktranscriptsCCA1/LHY,GIandTOC1toadoptthefoldchangescausedbyinduc-tionofcADPRsynthesis(39,138).Thesim-ulationspredictedthat(a)temporaryparame-terconstraints(inductionofcADPRsynthesis)wouldcausetransientalterationsinclockfunc-tion,(b)continuousparameterconstraint(con-stitutivecADPRsynthesis)wouldalterthecir-cadianperiod,dependingonthemodelparam-etersconstrained,and(c)formanyparameterpairs,aninvertedparameterconstraint(inhibi-tionofcADPRsynthesis)wouldcausealongersimulatedperiod(39).ItwassubsequentlyfoundthatmanipulationofcADPRsynthesiscanaltercircadianclockfunction(39).FuturemodelingmayuncovercandidatemechanisticlinksbetweencADPR/Ca2+andthecircadianclock.

PropertiesofCa2+oscillationsthoughttoconferspecificityincludetheperiod,ampli-tude,andwaveform;theseareamenabletomathematicalanalysis.Arbuscular-mycorrhizal(AM)fungicauseirregularpatterningofCa2+spikingcomparedwithconsistentlyrepetitiveCa2+oscillationsinducedbyNodfactor(com-pareFigure4awith4b)(82).Theauthors

Annu. Rev. Plant Biol. 2010.61:593-620. Downloaded from arjournals.annualreviews.orginvestigatedmathematicallywhetherAM-inducedCa2+spikesareunpredictable(stochas-tic)ordeterministicbutwithchaoticprop-erties,andconcludedfrommultiplemeasuresthatbothAM-andNod-inducedCa2+spikeshaverecurrentproperties.Thevariablepat-terningofAM-inducedCa2+spikesisthere-forelikelyduetochaoticratherthanstochasticpropertiesofthesystem(82).Thissuggeststhatthetransportprocessescausingtheoscillationshavechaoticregulatorypropertiesthatallowslightdifferencesinthestimulustoevokehighlydifferentiatedoutputresponses(82),aconclu-sionthatmayhelpexplainhowmanydistinctCa2+signaturescanbecausedbyasmallsetof.ylnchannels.

o esu lanoSimulationofCa2+HomeostasissreandDynamics

p ro+FClassicalsimulationsofstimulus-inducedCa2 .0oscillationsinanimalcellsparameterizetwoor/121moreCa2+stores,aCa2+releasemechanism,/70 cytosolicCa2+-scavengingCa2+ATPases,andno ymembraneleakcurrents(154).ThesemodelstisrsimulateCa2+oscillationswithpropertiessim-evinilartoCa2+oscillationsinanimalcells.MoreU lsophisticatedmodelsincorporatefeaturesarutsuchastheligandbindingkineticsofCa2+lucireleasechannels(154).ImportantdifferencesrgAbetweenplantandanimalcellsrequireincor- aniporationintosimulations.cADPRandInsP3Ch arethoughttoactivateseparateCa2+storesinybanimalcells,whereascommoncADPR-andInsP3-sensitiveCa2+storesexistinplantcellsbecausethevacuolarmembraneiscADPR-andInsP3-sensitive(5),whereasERmembranesareInsP3-,cADPR-,andNAADP-sensitive(seeFigure1)(5,116,118,119).ThenotionofanERstorethatcontainsfinitequantitiesofCa2+thatfunctionsincombinationwithavacuolarstorecontainingvirtuallylimitlessCa2+wasincorporatedwithinasimulationofABA-induced[Ca2+]cytoscillations(159).Thestudyconcludedthat[Ca2+]cytoscillations

withcomparablepropertiesareevokedbyABAconcentrationsthatspanseveralordersofmagnitudebecausethedifferentkineticsofCa2+scavengingCa2+ATPasesandCa2+/H+antiportersmeanthatathigh[ABA],Ca2+/H+antiportersremoveCa2+fromthecytosolandallow[Ca2+]cytoscillations;whereas,atlow[ABA],[Ca2+]cytoscillationscanoccurwithonlyCa2+-ATPaseactivity(seeFigure1)(159).Thelongperiodof[Ca2+]cytoscillationsinplantcellscomparedwithanimalcellsmightarisefromdifferencesintherateofactivationbyInsP3ofInsP3-sensitiveCa2+channels(strictly,relieffromCa2+inhibitionofthechannelbyInsP3),anddifferentCa2+signaturesmayarisefromvariationsinthisparameter(159).ThesimulationassumedthatCa2+releasewasentirelymediatedbycADPRandInsP3-gatedchannels,sofuturesimulationsincorporat-ingregulatorykineticsofTPC1-mediatedCa2+release(128)wouldbeinformative(seeFigure1).ThecontributionofextracellularCa2+influxtostimulus-inducedCa2+signals,whichisimportantinatleastthoseguardcellsthatarerelativelyinsensitivetoABA(104),couldprovidefurtherinformationconcerningthecontributionofeachCa2+storetoCa2+oscillations.

Four-dimensionalsimulationofCa2+waveshasbeenperformedusingasatemplatethe3Dgeometryofmembranesystemsinanimalcellsfromtomographicelectronmicroscopy(107).Simulationspredictedthatregionsofclosemembraneproximityparticipateinfor-mationofsignalingmicrodomains.Applicationtoplantcellsseemsappropriategiventhedis-tinctivearrangementofalargecentralvacuolesurroundedbyarelativelysmall-volume,ER-containingcytosol,whichprovidesaverydif-ferenttopologyforthepropagationofCa2+signalscomparedwithanimalcells.Wesuggestthat,infuture,computationalapproacheswillbeessentialforadvancingourunderstandingofthecomplexintracellularlanguageofCa2+signaling.

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Annu. Rev. Plant Biol. 2010.61:593-620. Downloaded from arjournals.annualreviews.org.ylno esu lanosrep roF .0/121/70 no ytisrevinU larutlucirgA aniCh ybSUMMARYPOINTS

1.ManyenergizedtransporterspreviouslythoughttofunctiononlyinCa2+homeostasismayhavesignalingroles.2.SpecificCa2+signaturesaredecodedbyacomplextoolkitofCa2+-bindingproteinsthattranslatetheinformationencodedwithinCa2+signalsintophosphorylationeventsanddefinedtranscriptionalresponses.3.Ca2+-signalingnetworkscouldhavearchitecturalandfunctionalpropertiesthatarecom-parabletoscale-freenetworksandbow-tienetworks.

FUTUREISSUES

1.UnderstandthetransportandsignalingfunctionsofspecificgeneproductsthatarelikelytoformmultisubunitCa2+-permeablechannels.2.Identifygenesencodingligand-gatedchannelstoestablishthemechanisticbasisforcADPR,InsP3andNAADPsignalinginplantcellsandtheevolutionarybasisforthesemechanisms,particularlygiventheabsenceofanimalcADPRandInsP3receptorsfromtheplantgenome.3.Measure[Ca2+]cytinCa2+pumpandCa2+exchangermutantstopositiontheseproteinswithintheCa2+signalingnetwork.4.UnderstandthebiologicalsignificanceofthespatialdistributionofCa2+signalswithinsingleplantcellsduringsignaling.5.DeveloppredictivemodelsforCa2+signalsthatincorporatethekineticsandregulationofspecificgeneproducts.6.UnderstandhowcircadianCa2+oscillationsaredecoded:(a)WhatistheidentityoftheCa2+sensorprotein(s)thatareinvolvedinthispathway?(b)Whatarethedown-streammechanismsthatconvertthesignalsarisingfromactivationoftheseproteinsintoalterationsingeneexpressionorenzymeactivity?7.UncoverthefunctionalinterconnectionsbetweenthesystemsthatdecodeCa2+signalsandothercellsignalingsystemssuchasPP2C-typephosphatases,receptor-likekinases,andMAPKmodules.

DISCLOSURESTATEMENT

Theauthorsarenotawareofanyaffiliations,memberships,funding,orfinancialholdingsthatmightbeperceivedasaffectingtheobjectivityofthisreview.

ACKNOWLEDGMENTS

Weapologizetoresearcherswhoseworkisnotcitedduetospacelimitations.WethankDr.LorellaNavazioforcriticalreadingofourmanuscript.A.N.D.isgratefultotheRoyalSocietyfortheawardofaUniversityResearchFellowship.J.K.thanksDr.HillelFrommforhelpfuldiscussionsaboutCAMTAproteinsandDr.KenjiHashimotoforhelpwithFigure2.Workin

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Annu. Rev. Plant Biol. 2010.61:593-620. Downloaded from arjournals.annualreviews.orgtheJ.K.laboratorywassupportedbytheD.F.G.,theAlexandervonHumboldtfoundation,theD.A.A.D.,theG.I.F.,andtheH.F.S.P.

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AWanderingPathwayinPlantBiology:FromWildflowerstoPhototropinstoBacterialVirulence

WinslowR.Briggspppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppp1.yStructureandFunctionofPlantPhotoreceptorslno AndreasM¨oglich,XiaojingYang,RebeccaA.Ayers,andKeithMoffatppppppppppppppppppppp21esu laAuxinBiosynthesisandItsRoleinPlantDevelopment

nosrYundeZhaopppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppp49ep rFoComputationalMorphodynamics:AModelingFrameworkto .01UnderstandPlantGrowth

/21/VijayChickarmane,AdrienneH.K.Roeder,PaulT.Tarr,AlexandreCunha,

70 nCoryTobin,andElliotM.Meyerowitzppppppppppppppppppppppppppppppppppppppppppppppppppppp65o tyisFemaleGametophyteDevelopmentinFloweringPlants

revinWei-CaiYang,Dong-QiaoShi,andYan-HongChenppppppppppppppppppppppppppppppppppppppp89U larDoomedLovers:MechanismsofIsolationandIncompatibilityinPlants

utluKirstenBombliesppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppp109cirgAChloroplastRNAMetabolism

anihDavidB.Stern,MichelGoldschmidt-Clermont,andMaureenR.Hansonpppppppppppppp125C ybProteinTransportintoChloroplasts

Hsou-minLiandChi-ChouChiupppppppppppppppppppppppppppppppppppppppppppppppppppppppppp157TheRegulationofGeneExpressionRequiredforC4Photosynthesis

JulianM.HibberdandSarahCovshoffpppppppppppppppppppppppppppppppppppppppppppppppppppp181Starch:ItsMetabolism,Evolution,andBiotechnologicalModificationinPlants

SamuelC.Zeeman,JensKossmann,andAlisonM.Smithppppppppppppppppppppppppppppppp209ImprovingPhotosyntheticEfficiencyforGreaterYield

Xin-GuangZhu,StephenP.Long,andDonaldR.Ortppppppppppppppppppppppppppppppppppp235Hemicelluloses

HenrikVibeSchellerandPeterUlvskovppppppppppppppppppppppppppppppppppppppppppppppppppp263DiversificationofP450GenesDuringLandPlantEvolution

MasaharuMizutaniandDaisakuOhtappppppppppppppppppppppppppppppppppppppppppppppppppp291

AnnualReviewofPlantBiology

Volume61,2010

v

Annu. Rev. Plant Biol. 2010.61:593-620. Downloaded from arjournals.annualreviews.org.ylno esu lanosrep rFo .01/21/70 no tyisrevinU larutlucirgA anihC ybEvolutioninAction:PlantsResistanttoHerbicides

StephenB.PowlesandQinYupppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppp317InsightsfromtheComparisonofPlantGenomeSequences

AndrewH.Paterson,MichaelFreeling,HaibaoTang,andXiyinWangpppppppppppppppp349High-ThroughputCharacterizationofPlantGeneFunctionsbyUsingGain-of-FunctionTechnology

YouichiKondou,MiekoHiguchi,andMinamiMatsuipppppppppppppppppppppppppppppppppppp373HistoneMethylationinHigherPlants

ChunyanLiu,FalongLu,XiaCui,andXiaofengCaopppppppppppppppppppppppppppppppppppp395GeneticandMolecularBasisofRiceYield

YongzhongXingandQifaZhangpppppppppppppppppppppppppppppppppppppppppppppppppppppppppp421GeneticEngineeringforModernAgriculture:ChallengesandPerspectives

RonMittlerandEduardoBlumwaldppppppppppppppppppppppppppppppppppppppppppppppppppppppp443MetabolomicsforFunctionalGenomics,SystemsBiology,andBiotechnology

KazukiSaitoandFumioMatsudappppppppppppppppppppppppppppppppppppppppppppppppppppppppp463QuantitationinMass-Spectrometry-BasedProteomicsWaltraudX.SchulzeandBj¨ornUsadelpppppppppppppppppppppppppppppppppppppppppppppppppppp491MetalHyperaccumulationinPlantsUteKr¨amerpppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppp517ArsenicasaFoodChainContaminant:MechanismsofPlantUptakeandMetabolismandMitigationStrategies

Fang-JieZhao,SteveP.McGrath,andAndrewA.Mehargppppppppppppppppppppppppppppp535GuardCellSignalTransductionNetwork:AdvancesinUnderstandingAbscisicAcid,CO2,andCa2+SignalingTae-HounKim,MaikB¨ohmer,HonghongHu,NoriyukiNishimura,

andJulianI.Schroederppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppp561TheLanguageofCalciumSignalingAntonyN.Dodd,J¨orgKudla,andDaleSanderspppppppppppppppppppppppppppppppppppppppppp593Mitogen-ActivatedProteinKinaseSignalinginPlants

MariaCristinaSuarezRodriguez,MortenPetersen,andJohnMundyppppppppppppppppp621AbscisicAcid:EmergenceofaCoreSignalingNetwork

SeanR.Cutler,PedroL.Rodriguez,RuthR.Finkelstein,andSuzanneR.Abramspppp651BrassinosteroidSignalTransductionfromReceptorKinasestoTranscriptionFactors

Tae-WukKimandZhi-YongWangpppppppppppppppppppppppppppppppppppppppppppppppppppppppp681

viContents

Annu. Rev. Plant Biol. 2010.61:593-620. Downloaded from arjournals.annualreviews.orgDirectionalGravitySensinginGravitropism

MiyoTeraoMoritapppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppp705Indexes

CumulativeIndexofContributingAuthors,Volumes51–61ppppppppppppppppppppppppppp721CumulativeIndexofChapterTitles,Volumes51–61pppppppppppppppppppppppppppppppppppp726Errata

AnonlinelogofcorrectionstoAnnualReviewofPlantBiologyarticlesmaybefoundathttp://plant.annualreviews.org

.ylno esu lanosrep rFo .01/21/70 no tyisrevinU larutlucirgA anihC ybContentsvii

Annu. Rev. Plant Biol. 2010.61:593-620. Downloaded from arjournals.annualreviews.org