2022
DARPP-32/protein phosphatase 1 regulates Rasgrp2 as a novel component of dopamine D1 receptor signaling in striatum
Kuroiwa M, Shuto T, Nagai T, Amano M, Kaibuchi K, Nairn A, Nishi A. DARPP-32/protein phosphatase 1 regulates Rasgrp2 as a novel component of dopamine D1 receptor signaling in striatum. Neurochemistry International 2022, 162: 105438. PMID: 36351540, DOI: 10.1016/j.neuint.2022.105438.Peer-Reviewed Original ResearchConceptsProtein phosphatase 1Phosphatase 1DARPP-32Receptor-induced phosphorylationPKA-dependent phosphorylationPKA/DARPPPP1 inhibitorPP1 substratesPP1 inhibitionPKA sitesRap1 activationOkadaic acidRASGRP2Novel componentRap1GAPPhosphorylationDARPP-32 knockout micePhospho-Thr34 DARPP-32Receptor activationPKAKnockout miceReceptor stimulationPP2A.Ser499Rap1
2016
Glutamate Counteracts Dopamine/PKA Signaling via Dephosphorylation of DARPP-32 Ser-97 and Alteration of Its Cytonuclear Distribution
Nishi A, Matamales M, Musante V, Valjent E, Kuroiwa M, Kitahara Y, Rebholz H, Greengard P, Girault JA, Nairn AC. Glutamate Counteracts Dopamine/PKA Signaling via Dephosphorylation of DARPP-32 Ser-97 and Alteration of Its Cytonuclear Distribution. Journal Of Biological Chemistry 2016, 292: 1462-1476. PMID: 27998980, PMCID: PMC5270488, DOI: 10.1074/jbc.m116.752402.Peer-Reviewed Original ResearchConceptsProtein phosphatase 1Ser-97PKA signalingDARPP-32Thr-34Activation of PP2A.Multiple cellular levelsProtein DARPP-32Phosphatase 1Heterotrimer complexPKA actionPhosphorylation stateNuclear localizationThr-75Phosphatase assaysDephosphorylationDARPP-32 phosphorylationCultured striatal neuronsSer-130Cellular levelSignalingPhosphorylationMajor siteStriatal neuronsGlutamateChapter 29 Regulation of Striatal Signaling by Protein Phosphatases
Girault J, Greengard P, Nairn A. Chapter 29 Regulation of Striatal Signaling by Protein Phosphatases. Techniques In The Behavioral And Neural Sciences 2016, 24: 583-607. DOI: 10.1016/b978-0-12-802206-1.00029-5.Peer-Reviewed Original ResearchSerine/threonine proteinProtein phosphatase regulationRegulation of proteinsPhosphatase regulationProtein phosphataseARPP-16Regulatory phosphoproteinsIntracellular signalingIntercellular communicationMedium spiny projection neuronsKey roleDARPP-32Major classesGenesRegulationSignalingProteinStriatal medium spiny projection neuronsSpecific setStriatal signalingPhosphoproteinRoleModulatory rolePhosphataseNeurons
2011
Beyond the Dopamine Receptor: Regulation and Roles of Serine/Threonine Protein Phosphatases
Walaas SI, Hemmings HC, Greengard P, Nairn AC. Beyond the Dopamine Receptor: Regulation and Roles of Serine/Threonine Protein Phosphatases. Frontiers In Neuroanatomy 2011, 5: 50. PMID: 21904525, PMCID: PMC3162284, DOI: 10.3389/fnana.2011.00050.Peer-Reviewed Original ResearchSerine/threonine proteinARPP-16Signaling pathwaysDARPP-32Striatal signaling pathwaysRegulator of calmodulinMultiple neurological diseasesNovel roleMolecular actionsProteinPP1Monophosphate-regulated phosphoproteinPhosphoproteinMolecular integratorPleiotropic actionsMultiple stepsMajor subclassesDopamine receptorsPathwayHuntington's diseaseRecent studiesStriatal signalingPP2ACentral nervous systemPP2B
2008
DARPP-32 Mediates the Actions of Multiple Drugs of Abuse
Svenningsson P, Nairn A, Greengard P. DARPP-32 Mediates the Actions of Multiple Drugs of Abuse. 2008, 3-16. DOI: 10.1007/978-0-387-76678-2_1.Peer-Reviewed Original ResearchPhosphorylation stateSerine/threonine protein phosphatasePP-1DARPP-32Threonine protein phosphataseState of phosphorylationProtein kinase A.Protein kinase AProtein phosphatasePhosphorylation sitesVirtue of regulationKinase AKey rolePhosphorylationThr34Potent inhibitorAdditional neurotransmittersCK2Ser97Behavioral responsesPhosphoproteinInhibitorsCK1Thr75Protein
2001
Regulation of cyclin-dependent kinase 5 and casein kinase 1 by metabotropic glutamate receptors
Liu F, Ma X, Ule J, Bibb J, Nishi A, DeMaggio A, Yan Z, Nairn A, Greengard P. Regulation of cyclin-dependent kinase 5 and casein kinase 1 by metabotropic glutamate receptors. Proceedings Of The National Academy Of Sciences Of The United States Of America 2001, 98: 11062-11068. PMID: 11572969, PMCID: PMC58683, DOI: 10.1073/pnas.191353898.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCalcium ChannelsCasein KinasesCyclin-Dependent Kinase 5Cyclin-Dependent KinasesDopamine and cAMP-Regulated Phosphoprotein 32Enzyme InhibitorsIn Vitro TechniquesKineticsMaleMembrane PotentialsMethoxyhydroxyphenylglycolMiceMice, Inbred C57BLNeostriatumNerve Tissue ProteinsNeuronsPatch-Clamp TechniquesPhosphoproteinsPhosphorylationPhosphoserinePhosphothreonineProtein KinasesReceptors, Metabotropic GlutamateConceptsCasein kinase 1Cyclin-dependent kinase 5Ser-137Thr-75CK1 activityKinase 1Kinase 5DARPP-32Regulation of Cdk5Neuronal protein kinaseActivation of Cdk5Cellular functionsProtein kinaseDNA repairEnhanced phosphorylationFirst messengersCdk5 activitySpecific inhibitorCdk5Effects of DHPGMetabotropic glutamate receptorsNeurite outgrowthIC261Glutamate receptorsDHPG-induced increase
2000
Amplification of dopaminergic signaling by a positive feedback loop
Nishi A, Bibb J, Snyder G, Higashi H, Nairn A, Greengard P. Amplification of dopaminergic signaling by a positive feedback loop. Proceedings Of The National Academy Of Sciences Of The United States Of America 2000, 97: 12840-12845. PMID: 11050161, PMCID: PMC18851, DOI: 10.1073/pnas.220410397.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCalcineurinCocaineCyclic AMP-Dependent Protein KinasesCyclin-Dependent Kinase 5Cyclin-Dependent KinasesDopamineDopamine and cAMP-Regulated Phosphoprotein 32FeedbackIn Vitro TechniquesMiceMice, Inbred C57BLNeostriatumNerve Tissue ProteinsPhosphoprotein PhosphatasesPhosphoproteinsPhosphorylationProtein Phosphatase 2Receptors, Dopamine D1Receptors, Dopamine D2Signal TransductionConceptsState of phosphorylationProtein kinaseThr-75Protein phosphatase 2A activityCAMP-dependent protein kinasePhosphatase 2A activityCyclin-dependent kinase 5DARPP-32Dopamine D1 receptor-mediated activationDopamine D2 receptor stimulationStriatal DARPP-32Receptor-mediated activationD2 receptor stimulationAction of dopamineEffects of dopaminePositive feedback loopPKA signalingKinase 5Inhibitory constraintPhosphorylationAcute cocaineWhole animalNeostriatal slicesReceptor stimulationDopaminergic signalingRegulation of Phosphorylation of the GluR1 AMPA Receptor in the Neostriatum by Dopamine and Psychostimulants In Vivo
Snyder G, Allen P, Fienberg A, Valle C, Huganir R, Nairn A, Greengard P. Regulation of Phosphorylation of the GluR1 AMPA Receptor in the Neostriatum by Dopamine and Psychostimulants In Vivo. Journal Of Neuroscience 2000, 20: 4480-4488. PMID: 10844017, PMCID: PMC6772453, DOI: 10.1523/jneurosci.20-12-04480.2000.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBenzazepinesCentral Nervous System StimulantsDopamineDopamine and cAMP-Regulated Phosphoprotein 32In Vitro TechniquesMaleMethamphetamineMiceMice, Inbred C57BLMice, KnockoutMicrowavesNeostriatumNerve Tissue ProteinsOkadaic AcidPhosphoprotein PhosphatasesPhosphoproteinsPhosphorylationProtein Phosphatase 1Protein Phosphatase 2Receptors, AMPAReceptors, Dopamine D1Receptors, Dopamine D2Recombinant Fusion ProteinsSerineConceptsCAMP-dependent protein kinaseProtein phosphatase 2A.AMPA-type glutamate receptorsCalmodulin-dependent kinase IICalcium/calmodulin-dependent kinase IIRegulation of phosphorylationProtein kinase CPhosphatase 2A.Protein kinaseKinase IIPhosphorylation of GluR1Kinase CGluR1 AMPA receptorsPhosphorylationCellular effectorsGlutamate receptorsDARPP-32Physiological activityAMPA receptorsPsychostimulant cocaineChannel conductanceReceptorsD1-type dopamine receptorsActivationVivoSevere deficiencies in dopamine signaling in presymptomatic Huntington's disease mice
Bibb J, Yan Z, Svenningsson P, Snyder G, Pieribone V, Horiuchi A, Nairn A, Messer A, Greengard P. Severe deficiencies in dopamine signaling in presymptomatic Huntington's disease mice. Proceedings Of The National Academy Of Sciences Of The United States Of America 2000, 97: 6809-6814. PMID: 10829080, PMCID: PMC18747, DOI: 10.1073/pnas.120166397.Peer-Reviewed Original ResearchConceptsMedium spiny neuronsDisease miceSpiny neuronsStriatal medium spiny neuronsHuntington's diseaseSevere deficiencyHuntington's disease miceHD model miceModel miceDopaminergic neurotransmissionHD miceSelective neurodegenerationHD pathologyMiceDARPP-32DopamineHuman huntingtinBehavioral phenotypesDiseaseNeuronsIon channelsTotal levelsDisease-causing formHuntingtinDeficiency
1999
Phosphorylation of DARPP-32 by Cdk5 modulates dopamine signalling in neurons
Bibb J, Snyder G, Nishi A, Yan Z, Meijer L, Fienberg A, Tsai L, Kwon Y, Girault J, Czernik A, Huganir R, Hemmings H, Nairn A, Greengard P. Phosphorylation of DARPP-32 by Cdk5 modulates dopamine signalling in neurons. Nature 1999, 402: 669-671. PMID: 10604473, DOI: 10.1038/45251.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCDC2 Protein KinaseCyclic AMP-Dependent Protein KinasesCyclin-Dependent Kinase 5Cyclin-Dependent KinasesDopamineDopamine and cAMP-Regulated Phosphoprotein 32Enzyme InhibitorsIn Vitro TechniquesMiceNerve Tissue ProteinsNeuronsPhosphoproteinsPhosphorylationRecombinant ProteinsSignal TransductionThreonineConceptsProtein kinase APhospho-ThrDARPP-32Serine/threonine phosphataseSerine/threonine kinaseInhibitor of PKAProtein phosphatase 1Signal transduction moleculesParticular amino acid residuesSignal transduction mechanismsAmino acid residuesCyclin-dependent kinase 5Threonine phosphataseThreonine 75PKA substratesThreonine kinasePhosphatase 1Phosphatase inhibitorProtein kinaseTransduction moleculesKinase ASingle proteinKinase 5Transduction mechanismsKinaseRequirement for DARPP‐32 in mediating effect of dopamine D2 receptor activation
Nishi A, Snyder G, Fienberg A, Fisone G, Aperia A, Nairn A, Greengard P. Requirement for DARPP‐32 in mediating effect of dopamine D2 receptor activation. European Journal Of Neuroscience 1999, 11: 2589-2592. PMID: 10383649, DOI: 10.1046/j.1460-9568.1999.00724.x.Peer-Reviewed Original ResearchConceptsDopamine D2 agonistD1 agonistDopamine D1 agonistDARPP-32D2 agonistDopamine D2 receptor activationDopamine D2 receptor agonistD2 receptor activationD2 receptor agonistBiological effectsReceptor agonistD1 receptorsD2 receptorsMouse neostriatumProtein phosphatase-1 inhibitorReceptor activationAgonistsPhosphatase-1 inhibitorDopamine signalingObligatory roleRole of Calcineurin and Protein Phosphatase‐2A in the Regulation of DARPP‐32 Dephosphorylation in Neostriatal Neurons
Nishi A, Snyder G, Nairn A, Greengard P. Role of Calcineurin and Protein Phosphatase‐2A in the Regulation of DARPP‐32 Dephosphorylation in Neostriatal Neurons. Journal Of Neurochemistry 1999, 72: 2015-2021. PMID: 10217279, DOI: 10.1046/j.1471-4159.1999.0722015.x.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCalcineurinCalcineurin InhibitorsCyclosporineDopamine and cAMP-Regulated Phosphoprotein 32Drug CombinationsDrug SynergismEnzyme InhibitorsIn Vitro TechniquesMaleMarine ToxinsMiceMice, Inbred C57BLNeostriatumNerve Tissue ProteinsNeuronsOkadaic AcidOxazolesPhosphoprotein PhosphatasesPhosphoproteinsPhosphorylationProtein Phosphatase 1Protein Phosphatase 2ConceptsProtein phosphatase 1Protein phosphatase 2AOkadaic acidPhosphorylated DARPP-32DARPP-32 phosphorylationPhosphatase 2APP-2ADARPP-32Cyclic AMP-dependent protein kinaseAMP-dependent protein kinasePP-2A activityRole of calcineurinPhosphatase 1Calyculin AMouse neostriatal slicesProtein kinaseAction of cyclosporinDependent activationCalcineurinPresence of cyclosporinPhosphorylationDephosphorylationSynergistic increaseThr34Potent inhibitorCharacterization of the Neuronal Targeting Protein Spinophilin and Its Interactions with Protein Phosphatase-1 †
Hsieh-Wilson L, Allen P, Watanabe T, Nairn A, Greengard P. Characterization of the Neuronal Targeting Protein Spinophilin and Its Interactions with Protein Phosphatase-1 †. Biochemistry 1999, 38: 4365-4373. PMID: 10194355, DOI: 10.1021/bi982900m.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBinding SitesCell LineDopamine and cAMP-Regulated Phosphoprotein 32HumansMicrofilament ProteinsNerve Tissue ProteinsNeuronsPeptide FragmentsPeptidesPhosphoprotein PhosphatasesPhosphoproteinsProtein Phosphatase 1Protein Structure, TertiaryProteinsRabbitsSequence Homology, Amino AcidConceptsProtein phosphatase 1Ability of spinophilinPhosphatase 1PP1 regulatory subunitClass of proteinsAmino acids 447Cell cycle progressionPP1 activityPentapeptide motifRegulatory subunitCellular processesDeletion analysisDistinct subdomainsSubstrate specificityBinding domainsPhysiological substratesMutational analysisNeuronal proteinsProtein spinophilinCompetition binding assaysHigh-affinity binding domainsDARPP-32SpinophilinPostsynaptic densityBinding assaysProtein phosphatase 1 modulation of neostriatal AMPA channels: regulation by DARPP–32 and spinophilin
Yan Z, Hsieh–Wilson L, Feng J, Tomizawa K, Allen P, Fienberg A, Nairn A, Greengard P. Protein phosphatase 1 modulation of neostriatal AMPA channels: regulation by DARPP–32 and spinophilin. Nature Neuroscience 1999, 2: 13-17. PMID: 10195174, DOI: 10.1038/4516.Peer-Reviewed Original ResearchConceptsPP-1Protein phosphatase 1DARPP-32Distinct molecular mechanismsPhosphatase 1Molecular mechanismsAMPA receptor-mediated synaptic transmissionPostsynaptic densityAMPA channelsRegulationSynaptic plasticitySpinophilinNeostriatal neuronsPlasticityPhysiological evidenceGlutamate channelsSynaptic transmissionAMPA receptorsPhosphoproteinProteinMechanismBindingActivityModulationCatalytic activity
1997
The Regulation of Glycogen Synthase by Protein Phosphatase 1 in 3T3-L1 Adipocytes EVIDENCE FOR A POTENTIAL ROLE FOR DARPP-32 IN INSULIN ACTION*
Brady M, Nairn A, Saltiel A. The Regulation of Glycogen Synthase by Protein Phosphatase 1 in 3T3-L1 Adipocytes EVIDENCE FOR A POTENTIAL ROLE FOR DARPP-32 IN INSULIN ACTION*. Journal Of Biological Chemistry 1997, 272: 29698-29703. PMID: 9368038, DOI: 10.1074/jbc.272.47.29698.Peer-Reviewed Original ResearchConceptsProtein phosphatase 1PP1 activityGlycogen synthasePhosphatase 1DARPP-32Glycogen synthesisPrimary rat adipocytesPP1 proteinProtein DARPP-32Glycogen synthase activityKinetic lagSynthase activityGlycogen accumulationDifferentiationRat adipocytesAdipocytesFibroblast extractsAdipocyte cellsTotal glycogen synthase activitySynthaseInsulin actionPotential roleSpecific activityParticulate fractionInsulin pretreatmentCharacterization of the interaction between DARPP-32 and protein phosphatase 1 (PP-1): DARPP-32 peptides antagonize the interaction of PP-1 with binding proteins
Kwon Y, Huang H, Desdouits F, Girault J, Greengard P, Nairn A. Characterization of the interaction between DARPP-32 and protein phosphatase 1 (PP-1): DARPP-32 peptides antagonize the interaction of PP-1 with binding proteins. Proceedings Of The National Academy Of Sciences Of The United States Of America 1997, 94: 3536-3541. PMID: 9108011, PMCID: PMC20474, DOI: 10.1073/pnas.94.8.3536.Peer-Reviewed Original ResearchConceptsPP-1cPP-1C.PP-1DARPP-32Inhibitor 2Protein phosphatase 1Amino acid sequence analysisAmino acid residuesNH2-terminal regionAcid sequence analysisPhosphoinhibitor-1Threonine residuesPhosphatase 1Inhibitor-1Catalytic subunitCalyculin AOkadaic acidInhibitor proteinActive siteAcid residuesSequence analysisProteinEnzyme activityMotifResidues
1995
Phosphorylation of DARPP-32, a Dopamine- and cAMP-regulated Phosphoprotein, by Casein Kinase I in Vitro and in Vivo *
Desdouits F, Cohen D, Nairn A, Greengard P, Girault J. Phosphorylation of DARPP-32, a Dopamine- and cAMP-regulated Phosphoprotein, by Casein Kinase I in Vitro and in Vivo *. Journal Of Biological Chemistry 1995, 270: 8772-8778. PMID: 7721783, DOI: 10.1074/jbc.270.15.8772.Peer-Reviewed Original ResearchMeSH KeywordsAmino Acid SequenceAnimalsBase SequenceCasein KinasesCattleCorpus StriatumCyclic AMPDNA PrimersDopamineDopamine and cAMP-Regulated Phosphoprotein 32Electrophoresis, Polyacrylamide GelHumansMolecular Sequence DataMutagenesis, Site-DirectedNerve Tissue ProteinsNeuronsPeptide MappingPhosphoproteinsPhosphorylationProtein KinasesRabbitsRatsSubstantia NigraConceptsCasein kinase IProtein phosphatase 1Kinase ISer-137Phosphatase 1Ser-189DARPP-32CAMP-dependent protein kinasePhosphatase-1 inhibitorStoichiometry of phosphorylationSite-directed mutagenesisSpecific cell populationsProtein kinaseProtein sequencingSeryl residuesAcidic residuesThr-34PhosphorylationPhosphate/Presence of SDSChoroid plexus epithelial cellsResiduesCell populationsElectrophoretic mobilityEpithelial cells
1992
Distribution of Protein Phosphatase Inhibitor‐1 in Brain and Peripheral Tissues of Various Species: Comparison with DARPP‐32
Hemmings H, Girault J, Nairn A, Bertuzzi G, Greengard P. Distribution of Protein Phosphatase Inhibitor‐1 in Brain and Peripheral Tissues of Various Species: Comparison with DARPP‐32. Journal Of Neurochemistry 1992, 59: 1053-1061. PMID: 1353788, DOI: 10.1111/j.1471-4159.1992.tb08347.x.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBrainCarrier ProteinsCentral Nervous SystemDopamine and cAMP-Regulated Phosphoprotein 32Enzyme InhibitorsFemaleIntracellular Signaling Peptides and ProteinsMaleNerve Tissue ProteinsPhosphoproteinsProteinsRatsRats, Inbred StrainsSubcellular FractionsTissue DistributionTyrosine 3-MonooxygenaseVertebrates
1989
Role of protein phosphorylation in neuronal signal transduction1
Hemmings H, Nairn A, McGuinness T, Huganir R, Greengard P. Role of protein phosphorylation in neuronal signal transduction1. The FASEB Journal 1989, 3: 1583-1592. PMID: 2493406, DOI: 10.1096/fasebj.3.5.2493406.Peer-Reviewed Original ResearchConceptsProtein phosphorylationSubstrate proteinsSignal transductionProtein kinaseMolecular mechanismsProtein phosphatase inhibitorSignal transduction processesPrecise molecular mechanismsAdditional molecular mechanismsSignal transduction1Extracellular signalsPhosphatase inhibitorAdditional phosphoproteinsPhysiological processesTransduction processesNicotinic acetylcholine receptorsPhosphorylationSynaptic transmissionNervous systemSynapsin IExcitable cellsDARPP-32TransductionKinaseNeurotransmitter release
1988
DARPP‐32 and Phosphatase Inhibitor‐1, Two Structurally Related Inhibitors of Protein Phosphatase‐1, Are Both Present in Striatonigral Neurons
Nairn A, Hemmings H, Walaas S, Greengard P. DARPP‐32 and Phosphatase Inhibitor‐1, Two Structurally Related Inhibitors of Protein Phosphatase‐1, Are Both Present in Striatonigral Neurons. Journal Of Neurochemistry 1988, 50: 257-262. PMID: 3335843, DOI: 10.1111/j.1471-4159.1988.tb13258.x.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBasal GangliaCarrier ProteinsCorpus StriatumDopamine and cAMP-Regulated Phosphoprotein 32Electrophoresis, Polyacrylamide GelIntracellular Signaling Peptides and ProteinsKainic AcidMaleMusclesNerve Tissue ProteinsNeuronsPhosphoproteinsPhosphorylationProteinsRatsRats, Inbred StrainsSubstantia NigraConceptsPhosphatase inhibitor-1Protein phosphatase 1Phosphatase 1DARPP-32Inhibitor-1Striatonigral neuronsSubstantia nigraKainic acidStriatonigral fibersBiochemical propertiesRelated inhibitorsSpecific neuronal subpopulationsIpsilateral substantia nigraBovine caudate nucleusSpecific activityStriatal neuronsNeuronal localizationRat neostriatumNeuronal subpopulationsRat brainCaudate nucleusLesioned neostriatumNeostriatumNeuronsInhibitors