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The ancient roots of calcium signalling evolutionary tree

Helmut Plattner

a,∗

, Alexei Verkhratsky

b,c,d

aFacultyofBiology,UniversityofKonstanz,78457Konstanz,Germany

bFacultyofBiologicalSciences,UniversityofManchester,ManchesterM139PT,UK

cAchucarroCentreforNeuroscience,IKERBASQUE,BasqueFoundationforScience,48011Bilbao,Spain

dUniversityofNizhnyNovgorod,NizhnyNovgorod603022,Russia

a r t i c l e i n f o

Keywords:

Antiporter ATPase Ca2+

Ca2+-ATPase Calcium Channel Evolution

a b s t r a c t

Molecularcascadesofcalciumhomeostasisandsignalling(Ca2+pumps,channels,cationexchangers, andCa2+-bindingproteins)emergedinprokaryotesandfurtherdevelopedattheunicellularstageof eukaryoteevolution.Withprogressiveevolution,mechanismsofsignallingbecamediversifiedreflect- ingmultiplicationandspecialisationofCa2+-regulatedcellularactivities.Recentgenomicanalysisof organismsfromdifferentsystematicpositions,combinedwithproteomicandfunctionalprobinginvig- oratedexpansioninourunderstandingoftheevolutionofCa2+signalling.Particularlyimpressiveisthe consistentroleofCa2+-ATPases/pumps,calmodulinandcalcineurinfromveryearlystagesofeukary- oticevolution,althoughwithinterspeciesdifferences.DeviationsinCa2+handlingandsignallingare observedbetweenvertebratesandfloweringplantsaswellasbetweenprotistsatthebasisofthetwo systematiccategories,Unikonta(forexamplechoanoflagellates)andBikonta(forexampleciliates).Only theB-subunitofcalcineurin,forinstance,ismaintainedtoregulatehighlydiversifiedproteinkinasesfor stressdefenceinfloweringplants,whereasthecompletedimericprotein,invertebratesuptohumans, regulatesgenetranscription,immune-defenceandplasticityofthebrain.Calmodulinissimilarlymain- tainedthroughoutevolution,butinplantsacalmoldulin-likedomainisintegratedintoproteinkinase molecules.Theeukaryoticcellhasinheritedandinventedmanymechanismstoexploittheadvantages ofsignallingbyCa2+,andthereisconsiderableoverallsimilarityinbasicprocessesofCa2+regulationand signallingduringevolution,althoughsomedetailsmayvary.

1. Bacterialinheritance:Ca2+regulationandprimaevalCa2+

signalling

Earlylifemayhaveemergedintheoceanorinlocalpartsof itunderalkalineconditionsthatfavouredrelativelylow(ina100s nMrange)Ca2+concentrations([1,2]thisspecialissue).Atthisearly stageCa2+permeationintoancestralcells,Ca2+handlingandCa2+

influenceonenergetic(andinparticulartherequirementoflow freeCa2+forATPmetabolism[3])madeCa2+ionscriticalforlife andforsignallingprocesses.

BacteriamaintainCa2+homeostasis[4,5]althoughrestinglevels offreecytosolicCa2+concentration([Ca2+]i)aresomewhathigher thanineukaryotes[6]andalthoughspecificmechanismsemployed bydifferentbacterialspeciesareyettobecharacterisedindetail.

Correspondingauthorat:DepartmentofBiology,UniversityofKonstanz,Room M1132,P.O.BoxM625,78457Konstanz,Germany.Tel.:+497531882228;

fax:+497531882168.

E-mailaddress:helmut.plattner@uni-konstanz.de(H.Plattner).

Somebacteriaexpressprimaryandsecondaryactivetransporters includingP-typeCa2+-transportATPasesofwhichseveralresemble theSarcoplasmicandEndoplasmicReticulumCa2+-ATPase(SERCA) ofeukaryotes [7,8].Thesepumps, togetherwithmechanosensi- tivechannels[9],Ca2+-activatedchannels[10],cationexchangers, suchasCa2+/H+andCa2+/Na+exchangers,anarrayofCa2+-binding proteins(CaBP),andabatteryofCa2+-activatedenzymes,which allarepresentinbacteria([11]thisspecialissue)formedthepri- mordialCa2+homeostaticandCa2+signallingsystem.Inbacteria whichlivetoday,changesin[Ca2+]i,regulatenumerousfunctions suchas,forexample,chemotaxis[6,12].Calmodulin-likeproteins arefoundinthegenomeofcertainGram-positivebacteria[13–15], inadditiontootherCaBPs[16].However,fastCa2+sensorswithC2 domains(suchasforexamplesynaptotagmins[17])havenotbeen reported.

Consideringthefrequentoccurrenceofgenetransferbetween ancestralorganisms, theearlyperiod of evolution of molecular cascadesresponsibleforcontrolovercellularCa2+remainsrather vagueandspeculative.EvengenuineCa2+signallinginbacteriahas beendebated[10].Apartfromtheserestrictionsitappearsthat

Konstanzer Online-Publikations-System (KOPS) URL: http://nbn-resolving.de/urn:nbn:de:bsz:352-0-280634

Erschienen in: Cell Calcium ; 57 (2015), 3. - S. 123-132

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bacteriaprophesiedseveralimportantmechanismsthathavebeen advancedandrefinedthroughouttheevolutionaryladder.

2. Frombacteriatotheeukaryotecell:requirementofCa2+

fortrafficking

Thereisconsiderableuncertaintyabouttheoriginoftheeukary- otic cell from archaebacteria or eubacteria [18], withdifferent scenariosbeingproposed[19,20].Eventheageof eukaryotesis disputed;theclassical(andprevailing)viewoftheiremergence(as witnessedbyfossils)∼2billionyearsago[21–24],isnotuniversally acknowledgedwiththedataonthepresenceofeukaryoticmark- ersinmucholder(∼3to∼3.5billionyears)fossils[25,26].Based ontheanalysisofeukaryoticsignatureproteins,theemergenceof a“chronocyte”,theintermediatedistinctfromArchaeaandeubac- teriahasbeencontemplated[27].Thetextbookviewhighlightsan archaebacterialancestorwhosegenomehasbeensequesteredby anothercellthroughinvaginationofthecellmembrane.Integration ofanarchaebacteriumintoaneubacteriumisanotherhypothetic scenario.TheCa2+regulatingandCa2+regulatedproteinsoutlined aboveareessentiallyknownfromeubacteria,whereasimportant proteinsofthenucleushaveorthologuesinsomearchaebacteria [28].

Byinfoldingof thecellmembrane withribosomesattached, theEndoplasmicReticulum(ER)couldhaveformed,followedby controlledblebbingandfusionofvesicularcompartments,alsoa Ca2+-dependentprocess,whereverithasbeenaccessibletoanaly- sis.Thismusthavebeenprerequisitetoanyfurtherdifferentiation andtrafficking.Thiscapability,togetherwithacytoskeleton,has beenascribedtothechronocyte[27].Incontrast,aLAECA-(latest archaeal-eukaryotecommonancestor)typeorganisms,endowed withhighinternalcomplexity,hasbeenpostulatedtoprecedegen- uineeukaryotes[29].Endocytosisandintracellulardigestionare thoughttohavebecomeimportantforfurthercomplexityofthe LAECA-typeancestor,and theearlyeukaryoticcell [30,31].The acquisition of endomembranes and intracellular compartments thatcouldemergeinsomeprokaryoteswascertainlyassociated withthetransitionfromprokaryotestoeukaryotesandprompted newdevelopmentsinCa2+signalling.

Regulation of intracellular trafficking become the special functionofCa2+,whichgenerallyassumesakeyroleinmembrane- membrane interactions, and hence complex [Ca2+]i dynamics, regulatedinspaceandtime,providedacanvassforubiquitousand versatileCa2+signalling.Ca2+hasoutstandingpropertiesthatmake itanalmostidealsecondmessenger[32].Sincetoohigh[Ca2+]iis toxic,strictregulationand“taming”ofCa2+movementsisrequired, whichhavemadeitamoleculesuitableforsignallingatalowaddi- tionalenergycosts.Thehumanbody containsupto1.4–2kgof Ca2+(ofwhich99%ispresentintheformofinsolublephosphates accumulatedin bones).Concentrationof Ca2+ is∼10mMinthe ocean;totalCa2+concentrationreaches25mMinplants;inmam- maliancells,totalCa2+concentrationinthecytoplasm(freeand bound)isinthemillimolarrange[32],whereasfreeconcentrations of[Ca2+]iare,asarule,below∼0.1micromolarintherestingcell [33].Theexistenceofacontinuousconcentrationgradientaimed atthecytosolallows[Ca2+]itoberapidlyandlocallyincreasedfor signallingatdefinedsites,whichriseisfollowedbyreversiblebind- ingtoCaBPs.Theselatterproteinsaregenerallycharacterisedby rapidbindingkineticsandwidelydifferentaffinity(expressedas abindingconstant,KD).Highcapacity/lowaffinitybindingmakes someCaBPssuitableforCa2+bindinginsidetheorganelles(uni- versallyknownasdynamicCa2+stores)andforsignalinactivation inthecytosol,whereasrapidactivationofdynamicprocessesis aresponsibilityoflowcapacity/highaffinitybindingwithavari- etyofmembrane-boundandcytosolicCaBPs.Localregulationof

Ca2+controlsselectiveandspatiallyrestrictedspecificprocesses [33],avoidstoxicityandkeepsenergeticcostsforre-establishing homeostasislow.Forthelatterpurpose,somehighcapacity/low affinityCaBPsarealsopresentinthecytosol[34].

3. AnevolutionarytimescaleanddiversificationofCa2+

signalling

Ancestral eukaryotes diversified into two main branches, Unikonta(thateventuallyevolvedintovertebrates)andBikonta (thatareattherootofangiosperms,orfloweringplants[35,36]).

Thefoundersofthesebranchesaretwounicellulargroupswhose currentmain representativesdateback to∼760–960 millionof years(choanoflagellates[37])and∼800millionofyears(ciliates [23]).Choanoflagellatesareconsideredasthefoundinggroupof metazoaand,therefore,deservespecialinterestwithregardtoCa2+

signalling (Caietal. [48],this special issue).Myxamoebae (Dic- tyostelium)areanotherwellanalysedunikont;theirphylogenetic ageissomewhatambiguous,althoughtheycanbeyoungerthan theothergroups[38].Mammalsaremorethan200millionofyears oldbeingthereforeolderthanfloweringplantsthatarebelievedto emerge130–190millionofyearsago[23,39].

Moleculesparticipatingin traffickinghave greatlydiversified during evolution, which could be extrapolated from compara- tivegenomicstudies.Thereareabout20SNAREs(solubleN-ethyl maleimide sensitive attachment protein receptors) in the Ur- eukaryote,whereastheyareabouttwiceasmanyinmammals[40].

ThenumberofRab-typeGTPasesincreasedfromanestimated20in ancestraleukaryote[41]to163inhuman[42].Insightsfromcells livingtodaysuggeststhatalreadyinearlytimesCa2+musthave been“hired”forsignallingpurposes.Consideringrapiddiffusion, bindinganddeactivationofCa2+,increasinglyelaborateintracel- lulartraffickingrequiredastrictlocalisatonofCa2+signals.This inturnrequiresCa2+stores,withhighcapacity/lowaffinityCaBPs intheirlumen,andmechanismsforCa2+uptakeandlocalrelease [43,44].Allthesecomponents,includingprimaryand secondary activeCa2+transportmechanismsandCa2+releasechannels(CRC) areabundantinprotozoainoneor theotherform,asfoundin Paramecium[45,46],andtosomeextentinDictyostelium[47]and inchoanoflagellates([48],thisspecial issue).Thefirst twogen- erarepresentthemajorphylogeneticlinesandarefrequentlyused forstudiesincellbiology,whereaschoanoflagellatesarecurrently onlyanalysedbymolecularbiology,althoughwithimportantpre- dictions. The increasingimportanceof Ca2+ during evolution is highlightedbyanincreaseinthenumberofCaBPs,whichrisesfrom

∼70inbacteriato3640inmammals[16,49].Substantialincrease innumbersanddiversityofCaBPin eukaryotesreflectsa rising capabilityoffinetuningCa2+signals[50].Aratherdifferentway ofdiversificationofCa2+signalling,however,isobservedinplants ([51–53]inthisspecialissue).

Itisnowgenerallyacknowledgedthatevolutionaryimprove- ment of cell energetic is associated with endocytosis and domesticationofeubacteriawithrespiratoryactivity,thatbecome mitochondria, about 1.5billion years ago [54]. Considering the highproportionofenergyinvestmentinionicbalanceinmodern eukaryotes,onemayassumethatacquisitionofmitochondrialpre- cursorswasanimportantstepinadvancementofCa2+signalling ([2], this special issue). The uptake of Ca2+ by mitochondria, achievedinmoderneukaryotesbyanuniporter[55]isswiftand it stimulates ATP production by activating dehydrogenases in themitochondrialmatrix[56].AhomologueofCa2+uniporteris presentalreadyinbacteria[57],andinchoanoflagellates([48],this specialissue),whileamitochondrialcalciumuniporter(MCU)is conservedfromprotozoatohuman,noMCUhomologues,how- ever,werefoundinvariousparasiticprotozoa[57,58].Theessential

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MCUregulator,EMRE,isabsentinsomeprotozoaanalysed,includ- ingDictyosteliumandTetrahymena[58],thusprobablyindicating lowercapabilityforadjustmentofCa2+transport.Insummary,dur- ingevolution,mitochondriaareactivelyengagedregulatingand exploitingenergeticallyCa2+signals,butwithsomevariability.

Consideringthegreatageofthemostancientformsofeukary- otes we have to concede that cells of modernity are remote descendants,withamplechancesforparallelevolution,possibly alsoincludinggenetransfer,thusdisguisingimagesofthedistant past.However,themultitudeofCa2+regulatingandCa2+regulated activitiessuggestsignificantoriginalevolutionaryinheritanceofa remarkableinventoryofmoleculesrelevantforCa2+regulation.

4. Ca2+signallingincellsofmodernera

Can modern protists (protozoa and algae) provide clues to theevolutionofCa2+signalling?Asalreadymentioned,unikonts include myxamoebae(withDictyosteliumbeingthebestknown example [59]), and choanoflagellates, whereas bikontsare rep- resented by alveolates, including ciliates like Paramecium and Tetrahymena.Experimental dataonCa2+ signallingareavailable forDictyosteliumandParamecium[46].Placingchoanoflagellates attherootsofmetazoanevolution[60]is basedonavarietyof molecularaspects,mainlyTyrphosphorylationandoccurrenceof celladhesionmolecules[61].Whetherandhowthesemolecules bindextracellularCa2+remainstobeclarified.Bothciliatesand choanoflagellates,possessseveralCa2+influxchannels,including transientreceptorpotentialchannels,cyclicnucleotidegatedchan- nelsandvoltage-gatedchannels.Remarkablyciliarylocalisationof voltage-dependentCa2+channelsisalsofoundinctenophores[62].

Ca2+isfundamentalforregulationofmultipleanddistinctpro- cessesoperatingonwidelydifferenttimescalenotonlyin“higher”

eukaryotes such as mammals [63], but alsoin protozoa. These cellularprocesses regulatedby Ca2+ include gene transcription, exocytosis,endocytosis,vesicletrafficking,amoeboidmovement andchemotaxis,ciliaryandflagellarbeatetc.Whentimedomain isconcerned,inciliatesCa2+-regulatedreactionscanoccurinsub- millisecondtimesincaseofmembranefusion,insub-secondtimes inciliarybeat[64]andmayalsolasthoursintheregulationofgene transcription[65].Insubsequentsectionsweshallnarrateaconsid- erablecongruenceofdifferentcellbiologicalphenomenainlowand higheukaryotes,respectively,withconsiderabledeviations,how- ever,inhigherplants.Asummaryofcertainimportantaspectsis presentedinFig.1.

5. Ca2+signallingtoolkitsinprotozoa

InthemodernworldCa2+normallyoccursinsufficientlyhigh concentrationintheenvironment;Ca2+concentrationinthebody fluids(thatisextracellular Ca2+,[Ca2+]o)isalsoatthemillimo- larrange beingthus20,000timesinexcessover resting[Ca2+]i [5].Ongoingdiffusionthroughtheplasmalemmalporesrequires counter-regulation(i.e.Ca2+efflux)inallcelltypesstudiedsofar.

ActivetransportbyCa2+-pumpsandcationexchangers,possibly inheritedfrombacterialancestors,executethistask.Inalleukary- otes, a variety of plasmalemmal channels make Ca2+ available locally, but not distantly. Therefore, eukaryotic cells are addi- tionallyendowedwithintracellularCa2+release channels,CRCs, pumpsandantiporterslocalisedtothemembranesofCa2+-storing organelles in animal [33,44,66] and plant cells [51,52]. Ca2+ is containednotonlyindedicatedCa2+stores,suchastheEndoplas- micandSarcoplasmicReticulum(ER/SR),butalsoinorganellesof thedifferenttraffickingpathways.Inessence,thisarrangementis maintainedthroughouteukaryoticcellevolution.

5.1. Ca2+influx

ThespectrumofplasmalemmalCa2+influxchannels,aswellas ofCa2+activatedcation(Na+,K+etc.)channelsoperatinginthecell membranesteadilyincreasesinevolution,frombacteriaonwards [10].ThereareconsiderabledifferencesinCa2+channelsbetween myxamoebae(Dictyostelium)andciliates (Paramecium)[10].The mechanosensitive cationic channelswith Ca2+ permeability are presentfrombacteriatohuman,asareligand-gatedandvoltage- dependentCa2+channels.Specificsubtypesofmechanosensitive channelsareabundantinmanyofpathogenicprotozoa,although Piezo subunits are not found in Apicomplexa [67], and yet they occur in the genome of related ciliates [68]. In many protozoa,includingciliatesandparasites(ApicomplexaandTry- panosomatids),there is a diversified interactionbetweencyclic nucleotidesandCa2+[69].EvidenceforpurinergicCa2+-permeable channelsisavailablefromprotozoa–inchoanoflagellatesandin Dictyostelium[3,70].InDictyosteliumCa2+releasebytheP2XAchan- nelmediatesvesiclefusionatthelevelofthecontractilevacuole [71].Higherplantshavemechanosensitiveandnucleotide-gated channels[9] as wellasionotropic purinoceptors[72],but miss voltage-dependentCa2+channels([73,53]thisspecialissue).The higherupintheanimalkingdom,themoredifferentiatedbecome ligand-gated Ca2+ influx channels [74]. In summary, there is a variabilityofplasmalemmalCa2+channelsdependingonthesys- tematicpositionofaspecies(forinstance,significantdifferences arefoundbetweenalgaeandfloweringplants[73]),butsomechan- nelsarepreservedmoreorlessthroughoutevolution.

5.2. Ca2+pumps

TheplasmamembraneCa2+-ATPase(PMCA)alsoknownasplas- malemmal Ca2+ pump contributes to keep [Ca2+]i low despite permanentinflux fromtheoutsidemedium, asdoestheSERCA pump; both are P-type ATPases. Faster Ca2+ removal can be achievedbysecondaryactivetransporters,suchasantiportersys- tems. Both primary and secondary active mechanisms of Ca2+

regulation are already known from bacteria, including SERCA- relatedpumps.ThePMCAandSERCAarealsopresentinprotozoa beingthustheoldregulatorymechanismsmaintainedduringevo- lution(Fig.1).In Dictyostelium,according tosequencingdata,a putativePMCA(pat1),∼120kDalarge,isreportedtolackthetypi- calcalmodulin-bindingdomain[75].Latersequencedatasuggested thepresenceofsuchadomaininthreeparalogues,includingpatA, althoughforallthreeisoformslocalisationtotheERand/orthe plasmamembranehasbeenleftopen[47].Theplasmalemmalpres- ence,however,issupportedbythecolocalisationwithcalmodulin [75].InParameciumthePMCAis∼130kDainsizeandshowsacon- served21aminoacids-longpotentialcalmodulin-bindingdomain [76],incontrasttotheSERCAofthesamespecies[77].Thus,despite someuncertaintiesinmyxamoebae,itappearsthatCa2+extrusion andsequestrationmechanismsaregenerallypreservedoverevo- lution.ThePMCA-typepumpsareoperationalnotonlyinthecell membraneofanimalcells,butalsoinfloweringplants.Theautoin- hibitorydomainofthePMCAissituatedintheamino-terminalpart inplantsandinthecarboxy-terminalpartinmammals[78].De- inhibitionoccursbybindingcalmodulin.Inplants,autoinhibited formscalledACA(forauto-inhibitedCa2+-ATPase),areslightlydif- ferent andtheyoccurnot onlyintheplasmalemmabutalsoin thevacuolemembrane, alsowitha calmodulin-binding domain ([53,79,80]thisspecialissue).Duringevolution,theinventoryof pumpscanbecomplementedbyCa2+-pyrophosphatase(CaPPase) inacidocalcisomesandinthecontractilevacuolecomplexofsome protozoa.Thisisofparticularimportanceforprotozoanparasites (see[81,82],thisspecialissue).

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man ... , ,.. ,. flowering plants vertebrates '. \ / ,. ..

r

learning stre;s .

t

CaN 8

' lmmuno defence activated

I

de·'-nce CDPK C/PKs (kmases)

JC various

I

I

transcnption functions

1

CaM

~

regulation

i !

~

metazoa

~ :

I \ 1 1

i {

f lower plants

I 1 t I

t

I I I f

R'PfXamoebae

! ! !

i characea CaM

kinases CaN A+B CaM

I t I I

Unikonta ! ! j

1

Bikonta

coN

~

: : : : A+B ~

choanoflagella

! l ! !(

ciliates CoM CDPK

!

CaM like protein!

...._ _ _ _ _ _ _ _ _ _ _ P type (32• ATPases/pumps

Eubact eria

Fig. 1. This scheme highlights the transfer of some highly important molecules. or precursors thereof. through evolution, according to data cited in the text. It also reveals some essential differences between the two main lineages. Unikonta and Bikonta. P-type Ca~· -ATPasesjpumps and calmodulin-like proteins are found already in bacteria.

They are most elaborate already in protists of the mono- and bikont lineage. They acquire high significance on the way up to man where calmodulin regulates ion channels and the activity of the multifunctional dimeric protein phosphatase calcineurin (CaN). This in turn regulates gene transcription. immune defence and long term potentiation (learning). In higher plants. only the B subunit of calcineurin is maintained which regulates calcineurin B-activated protein kinases (CIPKs = fBL-interacting protein !_inases) in an extremely high number of combination of isoforms. The scheme also shows that ciliates and plants of different evolutionary level contain (a:!> -dependent protein kinases (CDPK. with integrated calmodulin-like EF-hand motifs). much more than- if any- Ca2•jcalmodulin-activated protein kinases (CaM kinases). Beyond that, in plants calmodulin also regulates many processes. some of which are plant specific.

5.3. Exchangers

Various Ca

2•

exchangers are present from archaebacteria onwards [83), up to higher plants [51,52) and mammals [33].

In

the absence of specific inhibitors, fictional expression of these exchangers is difficult to verify in protozoa: convincing evidence exists only for the different parasites ([81

,82]

, this special issue).

Antiporter systems for

Ca2+

are frequently supported by a V-type Ca2• -ATPase/pump. Although little is known about antiporters in free-living protozoa and although in ciliates antiporters have not been identified at a molecular level, their occurrence can be derived from functional observations. When in

Paramecium

the V-type W- ATPase, a salient feature of the contractile vacuole/osmoregulatory complex, is blocked, [Ca2•]

1

recovery after stimulated Ca

2•

increase is retarded by about

10 times (84)

(in agreement with the per- manent ea

2•

extrusion by the organelle) just as after knock-out of cortical centrin [85].

5.4. Intracellular stores: Lumenal Ca/Ws

Little is known about lumenal high capadty/low affinity CaBPs

in vesicular stores of protists. Genes encoding calreticulin and calsequestrin have not been found in the

Paramecium

database, although there are some hints for their existence [86].

Difficul-

ties in finding gene sequences (see (87), this special issue), can be explained by the abundance of acid.ic aminoacid residues, rather than of specific motifs [88]. However, the ER-resident forms, cal- reticulin and calnexin have been identified in the database of

Dityostelium,

where knockout experiments resulted in inhibition of phagocytosis [89]. In that latter study, calreticulin sequences were also detected in

Trypanosoma

and

Leishmania.

5.5. Intracellular stores: lnsP3R/RyR calcium release channels

The

inositol 1,4,5-trisphosphate (lnsP

3 )

Ca

2•

release chan- nels generally referred to as

lnsP3

receptors (lnsP

3

Rs) have been identified in genomic studies in

Dictyostelium [90)

and in the choanoflagellate,

Monosiga [61,91]. Although not studied in

detail at the molecular level, lnsP

3R

null-mutants of

Dictyostelium

are available and, thus,

lnsP3

was shown to contribute to the

motility responses to shear stress, together with Ca

2

+ influx acti- vated by trimeric G-protein [92].1n

Paramecium,

genomic analysis revealed

lnsP3Rs [93], and a second type of CRC resembling a

ryanodine receptor (RyR), defined as

RyR-LPs [94], or CRCs with

mixed features ((45,87,95) this special issue). When compared with their mammalian counterparts

[96,97) RyR-LPs of Parame-

cium were remarkably different in size

(45). Two

of

Paramecium

CRCs have been thoroughly characterised at a cellular and func- tional level, including lnsP

3

binding [93) and stimulation with RyR agonists (94). Genomic analysis of

Monosiga

supports the presence oflnsP

3

Rs, whereas sequences indicating RyRsare detected only for

Salpingoeca

((48], this special issue). Sequences with variable simi- larity can be found in the genetic databases of different organisms, even where such CRCs have not been described in any more detail

(94,98]. However, this aspect has to be considered with caution

before any proteomic and functional analyses are made.

Although it is impossible to extrapolate to the

Ur-eukaryote,

identification of both these CRC types and intermediates in ciliates, lt!d to an assumption of a common anct!stur of both, InsP3R and a

RyRs already at the level of protozoa [ 94,98]. According to genomic

analyses, also in choanoflagellates, the most important CRCs have been formed very early, similarly to ciliates. This includes not only

lnsP3R

and possibly also homologues of RyRs, but also two-pore channels, TPCs ([48). this special issue).

In evolution, plants either

have

never

acquired, or lost all these channels ([53), this special issue). A common ancestral channel for both, lnsP

3Rs

and

RyRs,

has been proposed particularly based on similar size. on the pore domain with six transmembrane domains, and the aminoacid sig- nature within its selectivity filter [94,98].

5.6. Other CRCs and additional Ca2+ stores

The

complexity ofea2• stores and Ca

2•

release channels may be

further complemented by additional organelles capable of storing

Ca2• and by additional Ca

2•

release channels, which were observed

already in unicellular organisms. Additional Ca

2•

stores, such as

acidocaldsomes, have been recently discovered in various proto-

zoa including

Dictyostelium [99)

, in flagellate parasites, as well as

in human ([81

,100], this special issue). The big vacuole of higher

plants may be similarly considered as a Ca2+ storage organelle.

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Thereisindirectevidencefrommicroinjectionstudiesthatsome metabolites,suchascADPRandNAADPknowntoreleaseCa2+from intracellularstoresinhighereukaryotesarealsoeffectiveintrigg- eringCa2+releaseinParamecium[84].ThecADPRisdiscussedas thephysiologicalactivatorofRyRs[101],whereasNAADPactivates two-pore-channels(TPCs)inacidiccompartments[102,103],such aslysosomalandendosomalcompartmentsinmammaliancells [104].AlthoughTPCshavenotbeenhithertoidentifiedinciliates atamolecularlevel,theirpresencecanbeexpectedfromthebind- ingofNAADPwithaKDof3.3nM[84]andthereactionofcellsto microinjectedNAADP[105];seealsoref.[106],thisspecialissue.

Several types of Ca2+ channels disappeared and somewere newlyformedduringevolution.Ca2+isinvolvedinseveralsteps ofchemotaxisandavarietyofCa2+-dependentkeymoleculesare conserved from Dictyosteliumtohuman [107]. In Dictyostelium, asmentioned,putativeInsP3Rsmaycontributetothemotilityin responsetoshearflow[92].Inthemyxamoebae,certainsequences suggesttheappearanceofadditionalputativeCRCs,ofmucolipin type(lateendosomes/lysosomes),orpolycystin-2type(thesebeing equivalenttopolycystincationchannelPKD2)orTRPP2andaTPC inthecontractilevacuolecomplex[47,108].ThePKD2servesfor theperceptionoffluidflow[108].InDictyostelium,Ca2+permeable purinoceptorsofP2Xtype,serveasCRCslocalisedtothecontractile vacuolecomplex[71,109]wheretheymodulateosmoregulation [110].Inplants,InsP3RsandTRPsseemtohavedisappeared([53], thisspecialissue).TRPsandTPCchannelshavenotbeenfoundincil- iatedatabases[111]althoughtherearefunctionalhintstosupport functionalexpressionofTPCs,asoutlinedabove.

Besides dedicated Ca2+ stores (ER, SR), many trafficking organelles(endosomes,lysosomes,phagosomesandsomesecre- toryorganelles)alsocontainCa2+[112].Thisorganellesarelikely tofacilitatelocalsignallingforvesicleinteractionandfusion.Not only InsP3Rs and RyRs may be involved, but also some other typesofCRCs.AcharacteristicexampleisCa2+releasebyaP2X purinoceptorscontainedinthecontractilevacuolemembraneof Dictyosteliumatthecontactsitetothecellmembranewhereboth membranefusebyexocytosisforcontentsrelease[71].Theprin- cipleofheterogeneousdistributionofCRCsbetweendifferentCa2+

storingorganellesisrealisedalsowithotherproteinsrelevantfor trafficking[87,95].Forinstance,acidificationcandeterminetarget- ingbyatrans-membranesignalthroughaconformationalchange oftheV-typeH+-ATPasecomplexandensuingattachmentofRab- GTPasemodulatingproteins[113];similarlyatargetingsequence inhumanTPC2interactswithRabGTPases[114].Escortersofdif- ferent kindscanalsoachieve selectivedepositionof membrane proteinsrelevantforCa2+signalling(see[115]fordetails).

5.7. ReleasechannelsinotherBikonta

HowisCa2+handledingreenplants,fromalgaetoangiosperms?

Inflagellatedalgae,suchasEuglenagracilis[116],andinthecom- plexalga,Chara[117],positionedattherootsofmulticellularplant evolution, aswellas inhigher plants, InsP3Reffects havebeen experimentallydetected.InEuglena,cADPRappliedtosubcellu- larfractions wasalsoeffective[116],but noRyR-typechannels have been detected so far. This is in line with electrophysio- logical recordings withreconstituted membranesisolated from theBryoniaplant(climbingonbushesincentralEurope, [118]) andwithbiochemicalstudieswithvacuolarmembranesisolated fromcauliflower[119].Nevertheless,neitherInsP3Rs,norvoltage- gatedCa2+channelsnorTRPchannelswereidentifiedinplants, incontrasttomechanosensitive,ATP-gatedP2X-like purinocep- tors,cyclic nucleotide-gatedand two-porechannels([53,72,73], thisspecialissue).

Inessence,InsP3Rsarewidelydistributedinlowereukaryotes (thoughnotinall),whereRyRsalsoappearintheformofRyR-LPs,

asdocumentedforParamecium.Incontrast,suchchannelscould notbeascertainedinhigher-levelbikonts,suchasplants.

Mostrecently,molecularandbioinformaticanalysisofrepre- sentativesofunikontsandbikontsrevealedthepresenceofCa2+/H+ exchangersandofTPCsinbothgroups([48],this specialissue).

ThisalsoincludesacomplexflagellarCa2+channel,CatSper,ini- tiallydiscovered asa sperm-specificcation channelresponsible formotileactivityofspermatozoa[120].Thesemolecules,there- fore,seemtobelongtoacommonoriginalheritage.Analysisofa primitivebikont,Aurantiochytriumlimacinumrevealed,inaddition, sequencesofvoltage-gatedCa2+influxchannels,InsP3Rs(though functionally not tested), Ca2+ exchangers, purinergic receptors, TPCs,TRPCs,MCUandregulatorMICU,inadditiontoPMCAand SERCA([48],thisspecialissue).Thesearepromisingpredictions, whichhowever,requirefurtherscrutiny.

5.8. Store-operatedCa2+entry

Release of Ca2+ from intracellular stores, with their conse- quent depletion, in many types of mammalian cells induces thestore-operatedCa2+entry,SOCE[121],initiallydefined asa capacitativeCa2+entry[122].ThecontentoftheERstoreismoni- toredbytheendomembraneprotein,stromalinteractingmolecule (Stim),which,uponstoredepletion,oligomerises,migratestoER- plasmalemmaljunctionsandopenstheCa2+-release-activatedCa2+

(CRAC)channelsassembledfromOraiproteins[123,124].Noneof thesemoleculeshavebeendetectedinParamecium[46].Onlyin somealgaesequencesindicativeofOraihavebeenfound,whereas choanoflagellatespossessOraiandStim;noneofthemoccursin ArabidopsisandinDictyosteliumortheprotozoawhosedatabase hasbeenevaluated([48,111],thisspecialissue).TheSOCEcanbe alsomediatedbyplasmalemmalTRPchannelsthatcanbe,arguably, activatedbyoligomerisedStim [125,126].TheTRPchannelsare representedbyfivemetazoan forms,whichexist alreadyinthe genomeof choanoflagellates[127]andare highlydiversified in furtherevolutiontomammals[128].

Astore-operatedCa2+entry,however,isoperationalinParame- cium[129],whereitislinkedtoaCa2+releasemediatedbyRyR-like channels[46].ConsideringthemanifoldtypesofER-cellmembrane connectionsthatbecomeincreasinglyknown[130–133],afunc- tionalequivalentofOrai/Stimmaynotberequiredforthecoupling ofcorticalstoreswiththeplasmamembraneinlowereukaryotes providingotherproteinstakeoverthisfunction.InDictyostelium thesituationseemstobedifferent.Here,aCICRwasreportedtobe coupledtocontractilevacuole(anacidiccompartment)activityas analysedinamutantdevoidoftheputativeInsP3R[134].Itwould beinterestingtoseewhetheraNAADPsignallingpathwaycouldbe involvedhere.Insummary,plasmalemmalCa2+influxcoupledto storeactivationviaSOCEorperhapsalsotoCICR(ifverified)appear evolutionaryoldmechanisms.

6. EvolutionofCa2+bindingproteins

BacteriacontainmanyCaBPsortheirelementsfoundalsoin eukaryotes(Fig.1),includingforexampleacalmodulin-likeprotein presentineubacteria.ThisandotherbacterialCaBPsallcontainEF- handmotif[16,49],thussuggestingaconservedroleforEF-hand CaBPsthroughoutevolution allthewaytofloweringplants[80]

andmammals[135].Atthesametimethedataonbacterialexpres- sionofcentrin(alsowithEF-handmotives,[136])orCaBPswithC2 domainsaremissing.Centrinispresentfromprotozoa,including ciliates[137]tohumanandfromChlamydomonastoangiosperms [138,139a].

Inanimals,thenumberofEF-typeCaBPsexceedsC2-domain CaBPsby3times,butonlybyabouttwotimesinplants[16,49].

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TheCaBPswithtwoC2domains,aspresentinsynaptotagminof metazoans,arenotknownfromprotozoa,buttheyoccurinplants [139b].In animals,synaptotagmin is themetazoan Ca2+ sensor requiredformembranefusion.Byitsfastconformationalchange synaptotagminallowsforrapidmembranefusionduringexocyto- sis[140,141],aswellasduringendocytosis[142].InParamecium, theonlycomparableproteinwitheightC2domainscanbedetected inthedatabase(R.KissmehlandH.Plattnerunpublishedobser- vations)althoughtheexocytosisinthisspeciesisveryfast[64].

Similar proteins, called extended (E-) synaptotagmins, withup tosixC2domains havebeendetectedalsoinmammaliancells where theycan substitute for synaptotagmin for rapid vesicle fusion[143,144].Asinotherprotozoa,proteinswithC2domains [145]remaintobescrutinisedalsoinDictyostelium.Inmammalian cells,exocytosiskineticsdifferssubstantially betweencelltypes [146,147],whichcanbepossiblyassociatedwithdifferentsensors [144].Insummary,scarceinformationaboutC2-typeCa2+sensors inlowereukaryotesentailsthesalientquestion:Howismembrane fusionmediatedinthesecells?

Insummary,calmodulincontributestotheassemblyofexo- cytoticmembranefusionsitesfromprotozoa[148]tomammals [149,150].Similarly,fromprotozoaonwardscalmodulinactivates the PMCA, although reportedly not in all species, as discussed above. Centrin expression is well established in protozoa; in Parameciumforinstance,bindingofCa2+tocorticalcentrinafter strongstimulationofexocytosisissufficientlyfastandefficientto provideforfast[Ca2+]irecovery[85].

Copines and annexinsrepresent additional groups of CaBPs, eitherwithC2orwithalternativeCa2+bindingmotifs.Afterdetec- tioninParamecium[151]copineswerefoundubiquitously,from Dictyostelium[152]and Arabidopsis[153]uptothemammalian brain[154].BytheirC2domainscopinesbindtomembranesin Ca2+-dependentmannerand,hence,maycontributetovesicletraf- ficking[153].AnnexinsarewidelydistributedCa2+/phospholipid bindingproteinswithtypicaldomains,ofneitheroftheEF-nor oftheC2-type[155].ForcoordinativeCa2+bindingonlysmaller stretchesareavailable.Afteralongdebateaboutthefusogenic- ityofannexins,e.g.duringexocytosis,theyarenowconsideredas membrane-to-membranelinks[155].

Insummary,thesubstantialinventoryofCaBPsinbacteriaand protozoaprovideabackgroundforconsiderableincreaseinhigher plantsandanimals.However,inprotozoa,Ca2+sensorsmediating membranefusionremaintobecharacterised.

7. AnevolutionaryselectionforCa2+sensors

AlleukaryoticcellscontainenzymesregulatedbyCa2+binding.

TheDictyosteliumkinomecontainsabatteryofCa2+/calmodulin- dependent kinases (“CaM-kinases”) [156]. The ciliates [157], theirrelatives (Apicomplexa, e.g. Plasmodium) [158]as well as plants from green algae to land plants [159,160] all express Ca2+-dependentproteinkinases (CDPK),which containaninte- grated calmodulin-like domain, rather than binding a free Ca2+/calmodulin complex, as is the case for CaM-kinases in higher animal cells. From chlorophyceae (Chlamydomonas) to angiospermstheCDPK familyisbroadlyrepresented[161]par- ticularly in the course of transition to terrestrial life where it supports developmental processes and stress resistance [160].

Modernfloweringplantsalsocontainagenuine“CaMkinase”or Ca2+/calmodulinactivatedproteinkinase([53],thisspecialissue).

OtherCa2+sensorfunctionsincludecalcineurin(proteinphos- phatase2B,PP2B)which,duringanimalevolution,hasdeveloped asignallingnetworkbasedonconservedsubstratemotifs[162].

Inmammals,calcineurinisinvolvedinimmunedefencebyacti- vatingtranscriptionfactorNFATduringT-cellactivationaswellas

inlong-termpotentiationinPurkinjeneurones[163].Calcineurin alsoappearsin myxamoebae[164]where itregulatesdevelop- mentand differentiation.DictyosteliumandParameciumcontain bothsubunitsofcalcineurin,AandB[165,166],asisthecasewith otherprotozoa[166].Infloweringplants,onlytheregulatoryCa2+- bindingsubunitBis found; it servesfor stressdefence (Fig.1;

[53,159],thisspecialissue).Thus,calcineurin/PP2isanothersys- temdevelopedatearlystagesofCa2+signallingandmaintainedup totheverytopoftheevolutionaryladder.BeingaCaBPitself,it alsoregulatesCa2+dynamics,forexampleSOCE,viaOraiandStim [167].Homerisanotherproteinmaintainedfromthechoanoflag- ellateprecursorsofmetazoanson[168].Inmammaliannervous systemHomerservesasascaffoldfortheformationofpostsynaptic densities;remarkably,inchoanoflagellatesandinmetazoanastro- cytesitresidesinthenucleusasaHomer/Flotillin(Reggie)complex [168].

8. Specialaspectsinapicomplexanparasitesandplants 8.1. Theparasites

Parasites are notorious for evolving survival strategies. It appears that apicomplexan parasites (Plasmodium and Toxo- plasma), close relatives of ciliates [36,158], have functionally transformedtheequivalentofthealveolarsacsfromaCa2+store inciliates tothe“innermembrane complex”which, incontrast toalveoloarsacsofParamecium,haveextremelylow(i.e.below detectionthreshold)Ca2+concentration[84].Theseorganellesare, arguably, dedicated to the mechanics of host cell penetration, ratherthanservingasaCa2+store[84,169];theinfectiousattack isfacilitatedbythereleaseofnearbydockeddensecore-secretory vesicles,rhoptriesandmicronemes(remotelyresemblingParame- cium’strichocysts).Consequently,theseparasitesrelyonotherCa2+

stores(LouridoandMoreno[82]thisspecialissue).ThoughInsP3

effectsrelevantforCa2+signallingandhostcellinteractionhave beenestablished[170–172],theInsP3Rshavenotyetbeenidenti- fied[45,173].Incontrast,molecularandfunctionalidentificationof InsP3Rshasbeenachievedinotherprotozoaofthebikontbranch, theparasiticflagellates,Trypanosomabrucei[174]andTrypanosoma cruzi[175].InT.brucei,InsP3Rshavebeenshowntobelocatedin theacidocalcisomemembrane([81],thisspecialissue).

8.2. Comparisonwithhigherbikonts,theplants

Handlingof,andsignallingbyCa2+intheimmobilegreenplants differsconsiderablyfromthatinanimals.Ecologicalaspects,such asselectionofnon-calciferouslocations,aswellasgrossregula- torymechanisms,for examplereleaseof anexcessofCa2+ions byguttationfromleaves,canhelptheplantcelltoavoidstress.

LimitingstressalsorequiresregulationofCa2+atacellularlevel [51].StressdefenceactivatesasystemofCBL-interactingprotein kinases(CIPKs)thatareactivatedbycalcineurinB[176,177],the regulatorysubunitcontainingaCa2+bindingsite.Inplantcellmem- braneand in themembrane of the bigvacuole,primary active andsecondaryactivetransportprocessesoccurthroughexchang- ersconnectedtotheH+-ATPase/pump.Herethemostextensive diversificationofcalcineurinB-LPs(CBL) isobserved; theCBLin conjunctionwithCIPKs,regulatemanyfunctionsofthevacuole andoftheplasmamembrane[178].NointracellularCRCsofthe InsP3R/RyRsupergrouphavebeenunambiguouslydemonstratedin plantsalthoughsomereportsadvocatedforInsP3Rs-relatedphys- iologicaleffects,asdiscussedabove.Incontrast,numerousinflux channelsandCaBPshavebeenidentifiedinplants([53],thisspecial issue).EssentiallyplantsmayhavelostInsP3Rsaswellasvoltage- gatedandTRPchannels[73]usingotherchannelsinstead.

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8.3. Ca2+signallingandtransitiontomulticellularity

Transition to multicellularity called for cell adhesion pro- teins,includingCa2+o-dependentcadherinsortheirpredecessors.

The attachment of Dictyostelium to the substrate, similarly to mammaliancells,requires Ca2+[92].Cadherinsareabsentfrom Dictyosteliumandtheircapabilitytoformamulticellularstalkhas anothermolecularbasis[179].Thechoanoflagellatesgenomicdata miningsuggestscadherin-basedcell-to-cellconnections([60],and [48]thisspecialissue).Proteinsinvolvedinintercellularcontact formationduringconjugationinciliatesarenotrelatedtometa- zoancelladhesionmolecules[180].Cadherinsweremaintained throughoutmetazoanevolution,buthavenotbeenfoundinplant databases[181].Thisindicatesaclearseparationbetweenunikont andbikontorganisms.

9. Conclusions

FundamentalelementsofcellularCa2+ homeostasisandCa2+

signalling areconservedfrombacteriatohuman. Theseinclude Ca2+-pumpsandexchangers,Ca2+influxchannelsaswellassome CaBPs,suchascalmodulin,whichallarepresentinprokaryotes.The Ca2+/calmodulin-activatedproteinphosphatasePP2B(calcineurin) is engagedinmanifoldsignallingfromdifferentprotozoaupto human whereit regulatescomplexfunctions, such asimmune- defenceandlongtermpotentiation[182].However,somegapsin knowledgeremain;for instancethereis adiscrepancy between overt InsP3 effects observedand thefailure toidentify InsP3R- typegenomicsequencesinsomeorganisms.Therecentfocuson choanoflagellatesasancestorsofmetazoanscalls fortheexten- sionofmolecularbiologydatatocellphysiology.Interpretationof sequencesinanevolutionarycontextcanalsobehamperedbyhor- izontal,andpossiblyalsobyverticalgenetransferthatiscommon amongprotozoa[183].Nevertheless,manydataonCa2+signalling throughoutevolutionyieldaquiteconsistentpicture(Fig.1).The presentissueofCellCalciumpresentsaninterimbalance.

Acknowledgements

TheworkofH.P.citedhereinhasbeensupportedbytheGerman ResearchCouncil.A.V.wassupportedbytheWellcomeTrust,by Alzheimer’sresearchfoundation(UK)andbythegrant(agreement fromAugust272013no.02.B.49.21.0003)betweenTheMinistryof EducationandScienceoftheRussianFederationandLobachevsky StateUniversityofNizhnyNovgorodandbythegrantoftheRussian ScientificFoundationno.14-15-00633.

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