Cdk5isacyclindependentproteinkinaseinvolvedindopaminergicsignalingintheneostriatalregionofthebrain.Theroleofcdk5indopamineresponsesoccursthroughphosphorylationofDARPP-32.Caseinekinase1(CK1)alsoregulatesDARPP-32phosphorylationanddopaminesignaling.ThephosphorylationofDARPP-32bycdk5reduceddopaminesignaling.Dependingonitsphosphorylationstate,DARPP-32inhibitseitherproteinphosphatase1(PP1)orPKA.TheroleofmGLUR1inthisprocessissupportedbytheinductionofcdk5andCK1activitybythemGLUR1agoNISTDHPGandthesubsequentphosphorylationofDARPP-32associatedwithDHPGtreatmentofnigrostriatalneurons.CK-1andCkd5inhibitorsblocktheDHPGinducedDARPP-32phosphorylation.DopamineexertsapositivesignalthatincreasesdopamineresponsebyreversingphosphorylationofDARPP-32atthreonine-75.DopamineinitiatesthispathwaythroughactivationoftheD1dopaminereceptor,aGscoupledGPCR,elevatingcAMPandactivatingPKA.PKAactivatesproteinphosphatase2A(PP2A)whichdephosphorylatesDARPP-32andincreasesdopamineresponsiveness.ThisalsoremovestheinhibitionofPKAbyDARPP-32,formingapositivefeedbackloopforfurtherDARPP-32inactivationbyPKA.ActivationoftheD2dopaminereceptorhastheoppositeeffect,shiftingtheDARPP-32populationtowardthethreonine-75phosphorylatedform.

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