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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REFERENCES:Bibb,J.A.etal.(1999)PhosphorylationofDARPP-32byCdk5modulatesdopaminesignalinginneurons.Nature402(6762),669-71Liu,F.etal.(2001)Regulationofcyclin-dependentkinase5andcaseinkinase1bymetabotropicglutamatereceptors.Proc.Natl.Acad.Sci.USA98(20),11062-8Nishi,A.etal.(2000)Amplificationofdopaminergicsignalingbyapositivefeedbackloop.ProcNatlAcadSciUSA97(23),12840-5

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