Thecalcium/calmodulin-dependentkinases(CaMKs)areinvolvedinalargenumberofcellularresponsesinducedbyhormones,neurotransmittersandothersignalling.Elevationofcalciumfunctionsasamajorsecondmessenger,wheretheintracellularconcentrationofcalciumcanbemaintainedatextremelylowlevelsandsusequentlyincreasedfollowingspecificcalcium-mobilizingstimuli.Therearemanybufferstothecalciumfluxuationsincludingmembranepumpsandcalcium-bindingproteinsthatcreatediscretespatialcontrolofitseffectorsandtheirtargets.Thecurrentfamilyofmultifunctionalcalcium/calmodulin(CaM)-dependentproteinkinases(CaMKs)consistsofCaMKI,CaMKIIandCaMKIV.Thesekinasestranslateandco-ordinatethecalciumfluxuationsintotheappropriatecellularresponsesviaphosphorylation.Thesekinasesarepartiallyregulatedbytheintracellularcalciumreceptorcalmodulin(CaM),havecommonaswellasuniquefeaturesintheirstructure,regulationandactivation.CaMKII,CaMKIandCaMKIV,haveanautoregulatorydomainthatrestrictsorinhibitsenzymicactivityintheabsenceofcalcium/CaM.Calcium/CaMbindingaloneproducesmaximalactivityofCaMKII,whereasCaMKIandCaMKIVhaveanactivationloopthatrequiresphosphorylationofathreonineresiduebyCaMKkinase(CaMKK)formaximalactivity.Twogenes(alphaandbeta)forCaMKK,whichisalsoregulatedbyCaM,havebeenidentified.ThehighestexpressionoftheseisoformsoccursinthebrainbuttheactivityoftheCaMKshasbeenidentifiedinmostcelltypes.CaMKIVhasapost-calmodulinautophosphorylationstepthatisnotobservedinCaMKI.TheCaMKIImultimercanautophosphorylateeithertheautoregulatorydomainortheCaM-bindingdomain,producingdiverseeffectsinitsregulationandsensitivitytoCalcium/CaM.AutophosphorylationofCaMKIIcanproduceCalcium/CaM-independentactivity(autonomousactivity),withoutaffectingitsmaximalCalcium/CaM-stimulatedactivity.TheCaMKIIautophosphorylationinvolvesakinasecascadeofsorts,witheachsubunitofthemultimericenzymeactingasbothkinaseandkinasekinase.Autophosphorylationestablishesa1000-foldincreaseintheaffinityforitsactivatorCalcium/CaM(alsoknownasCaMtrapping);however,autophosphorylationwithintheCaM-bindingdomainfollowingCaMdissociationofactivated/autophosphorylatedenzymerestrictsorpreventsCaMfromrebinding(CaMcapping).ThemechanismsandconsequencesofautophosphorylationarecentraltotheCaMKIIenzyme"scomplexregulatorybehaviorenablingittobecomedifferentiallyactivatedatdifferentfrequenciesandlevelsofcalciumspikes.ThetargetproteinsfortheCaMKsareverysimilar.AnexampletargetoftheCaMKsisthetranscriptionalactivatingproteinCREB.ThephosphorylationstatesofCREBafterCaMKphosphorlyationdifferbytheadditionalphosphorylationofCREBatserine142thatfunctionsasanadditionalinhibitorysite.Thisdifferenceappearstobetheresultofadjacentaminoacids(SeeCorcoranreview).

Contributor:KosiGramatikoff,PhD

REFERENCES:ChinD,WinklerKE,MeansAR.Characterizationofsubstratephosphorylationanduseofcalmodulinmutantstoaddressimplicationsfromtheenzymecrystalstructureofcalmodulin-dependentproteinkinaseI.JBiolChem.1997Dec12;272(50):31235-40.CorcoranEE,MeansAR.DefiningCa2+/calmodulin-dependentproteinkinasecascadesintranscriptionalregulation.JBiolChem.2001Feb2;276(5):2975-8.Review.Noabstractavailable.EtoK,TakahashiN,KimuraY,MasuhoY,AraiK,MuramatsuMA,TokumitsuH.Ca(2+)/Calmodulin-dependentproteinkinasecascadeinCaenorhaBDitiselegans.Implicationintranscriptionalactivation.JBiolChem.1999Aug6;274(32):22556-62.HudmonA,SchulmanH.Structure-functionofthemultifunctionalCa2+/calmodulin-dependentproteinkinaseII.BiochemJ.2002Jun15;364(Pt3):593-611.Review.IkuraM.CalciumbindingandconformationalresponseinEF-handproteins.TrendsBiochemSci.1996Jan;21(1):14-7.JamesP,VorherrT,CarafoliE.Calmodulin-bindingdomains:justtwofacedormulti-faceted?TrendsBiochemSci.1995Jan;20(1):38-42.TokumitsuH,MuramatsuM,IkuraM,KobayashiR.RegulatorymechanismofCa2+/calmodulin-dependentproteinkinasekinase.JBiolChem.2000Jun30;275(26):20090-5.