INVESTIGADORES
MATTIAZZI Ramona Alicia
artículos
Título:
The role ofCaMKII regulation of phospholamban activity in heart disease
Autor/es:
MATTIAZZI A.; KRANIAS EG.
Revista:
fRONTIERS IN pHARMACOLOGY
Editorial:
Frontiers
Referencias:
Lugar: LAUSANNE; Año: 2014 vol. 5 p. 1 - 5
Resumen:
Phospholamban(PLN)isaphosphoproteinincardiacsarcoplasmicreticulum(SR)thatisareversibleregulatoroftheCa2+-ATPase(SERCA2a)activityandcardiaccontractility.DephosphorylatedPLNinhibitsSERCA2aandPLNphosphorylation,ateitherSer16byPKAorThr17byCa2+-calmodulin-dependentproteinkinase(CaMKII),reversesthisinhibition.Throughthismechanism,PLNisakeymodulatorofSRCa2+uptake,Ca2+load,contractility,andrelaxation.PLNphosphorylationisalsothemaindeterminantofβ1-adrenergicresponsesintheheart.AlthoughphosphorylationofThr17byCaMKIIcontributestothiseffect,itsroleissubordinatetothePKA-dependentincreaseincytosolicCa2+,necessarytoactivateCaMKII.Furthermore,theeffectsofPLNanditsphosphorylationoncardiacfunctionaresubjecttoadditionalregulationbyitsinteractingpartners,theanti-apoptoticHAX-1proteinandGmortheanchoringunitofproteinphosphatase1.RegulationofPLNactivitybythismultimericcomplexbecomesevenmoreimportantinpathologicalconditions,characterizedbyaberrantCa2+-cycling.Inthisscenario,CaMKII-dependentPLNphosphorylationhasbeenassociatedwithprotectiveeffectsinbothacidosisandischemia/reperfusion.However,thebeneficialeffectsofincreasingSRCa2+uptakethroughPLNphosphorylationmaybelostorevenbecomedeleterious,whentheseoccurinassociationwithalterationsinSRCa2+leak.Moreover,amajorcharacteristicinhumanandexperimentalheartfailure(HF)isdepressedSRCa2+uptake,associatedwithdecreasedSERCA2alevelsanddephosphorylationofPLN,leadingtodecreasedSRCa2+loadandimpairedcontractility.Thus,thestrategyofalteringSERCA2aand/orPLNlevelsoractivitytorestoreperturbedSRCa2+uptakeisapotentialtherapeutictoolforHFtreatment.WewillreviewheretheroleofCaMKII-dependentphosphorylationofPLNatThr17oncardiacfunctionunderphysiologicalandpathologicalconditions.
