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 neuronsGlutamate
2001
Protein phosphatase 1 regulation by inhibitors and targeting subunits
Watanabe T, Huang H, Horiuchi A, da Cruze Silva E, Hsieh-Wilson L, Allen P, Shenolikar S, Greengard P, Nairn A. Protein phosphatase 1 regulation by inhibitors and targeting subunits. Proceedings Of The National Academy Of Sciences Of The United States Of America 2001, 98: 3080-3085. PMID: 11248035, PMCID: PMC30610, DOI: 10.1073/pnas.051003898.Peer-Reviewed Original ResearchMeSH KeywordsAmino Acid SequenceAnimalsCell LineChromosomal Proteins, Non-HistoneDNA-Binding ProteinsDopamine and cAMP-Regulated Phosphoprotein 32Enzyme InhibitorsGene ExpressionHistone ChaperonesMicrofilament ProteinsMolecular Sequence DataMyelin Basic ProteinNerve Tissue ProteinsPhosphoprotein PhosphatasesPhosphoproteinsProtein Phosphatase 1ProteinsRabbitsRecombinant Fusion ProteinsSpodopteraSubstrate SpecificityTranscription FactorsConceptsProtein phosphatase 1Native protein phosphatase-1PP1 nuclear targeting subunitPhosphotyrosine-containing substratesInhibitor 2Protein phosphatase 1 regulationRecombinant protein phosphatase 1Sf9 insect cellsC-terminal sequencesLoss of interactionTargeting subunitPP1/Phosphatase 1Insect cellsResidues 274Inhibitor proteinRecombinant proteinsProtein inhibitorSubunitsEscherichia coliY272Corresponding regionPhosphorylase a.MutationsRegulationPhosphorylation of Protein Phosphatase Inhibitor-1 by Cdk5*
Bibb J, Nishi A, O'Callaghan J, Ule J, Lan M, Snyder G, Horiuchi A, Saito T, Hisanaga S, Czernik A, Nairn A, Greengard P. Phosphorylation of Protein Phosphatase Inhibitor-1 by Cdk5*. Journal Of Biological Chemistry 2001, 276: 14490-14497. PMID: 11278334, DOI: 10.1074/jbc.m007197200.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBinding SitesBrainCalcineurinCarrier ProteinsCDC2 Protein KinaseCyclic AMPCyclic AMP-Dependent Protein KinasesCyclin-Dependent Kinase 5Cyclin-Dependent KinasesGlutamic AcidIntracellular Signaling Peptides and ProteinsKineticsMiceMice, Inbred C57BLMutagenesis, Site-DirectedN-MethylaspartatePhosphoprotein PhosphatasesPhosphorylationProlineProtein Phosphatase 1RabbitsRatsRecombinant ProteinsRNA-Binding ProteinsSerineTime FactorsConceptsProtein phosphatase inhibitor-1Protein phosphatase 1Phosphatase inhibitor-1Ser-67Protein kinasePhosphatase 1CAMP-dependent protein kinase resultsSelective protein kinase inhibitorsCAMP-dependent protein kinaseProtein phosphatase 2AProline-directed kinasesMitogen-activated protein kinaseInhibitor-1Protein kinase resultsSignal transduction eventsPhosphorylation state-specific antibodiesCAMP-dependent protein kinase activationState of phosphorylationProtein kinase inhibitorsProtein kinase activationPhosphatase 2AThr-35Protein phosphatasePhosphorylation sitesGlutamate-dependent regulation
2000
Drugs of abuse modulate the phosphorylation of ARPP-21, a cyclic AMP-regulated phosphoprotein enriched in the basal ganglia
Caporaso G, Bibb J, Snyder G, Valle C, Rakhilin S, Fienberg A, Hemmings H, Nairn A, Greengard P. Drugs of abuse modulate the phosphorylation of ARPP-21, a cyclic AMP-regulated phosphoprotein enriched in the basal ganglia. Neuropharmacology 2000, 39: 1637-1644. PMID: 10854908, DOI: 10.1016/s0028-3908(99)00230-0.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAntibodies, MonoclonalBasal GangliaCattleCocaineCorpus StriatumCyclosporineDopamine and cAMP-Regulated Phosphoprotein 32Dopamine Uptake InhibitorsEnzyme InhibitorsIllicit DrugsMarine ToxinsMethamphetamineMiceMice, Inbred C57BLMice, TransgenicNerve Tissue ProteinsOkadaic AcidOxazolesPhosphoproteinsPhosphorylationRatsLetter to the Editor: Backbone 1H, 15N, and 13C resonance assignments of inhibitor-2 – a protein inhibitor of protein phosphatase-1
Huang H, Chen Y, Tsai L, Wang H, Lin F, Horiuchi A, Greengard P, Nairn A, Shiao M, Lin T. Letter to the Editor: Backbone 1H, 15N, and 13C resonance assignments of inhibitor-2 – a protein inhibitor of protein phosphatase-1. Journal Of Biomolecular NMR 2000, 17: 359-360. PMID: 11014604, DOI: 10.1023/a:1008355428294.Peer-Reviewed Original ResearchConceptsProtein phosphatase 1Phosphatase 1Backbone 1HResonance assignmentsInhibitor 2Protein inhibitorInhibitorsCellular Mechanisms Regulating Protein Phosphatase-1 A KEY FUNCTIONAL INTERACTION BETWEEN INHIBITOR-2 AND THE TYPE 1 PROTEIN PHOSPHATASE CATALYTIC SUBUNIT*
Frederick D, Huang H, Yang J, Helps N, Cohen P, Nairn A, DePaoli-Roach A, Tatchell K, Connor J, Shenolikar S. Cellular Mechanisms Regulating Protein Phosphatase-1 A KEY FUNCTIONAL INTERACTION BETWEEN INHIBITOR-2 AND THE TYPE 1 PROTEIN PHOSPHATASE CATALYTIC SUBUNIT*. Journal Of Biological Chemistry 2000, 275: 18670-18675. PMID: 10748125, DOI: 10.1074/jbc.m909312199.Peer-Reviewed Original ResearchConceptsPP1 catalytic subunitCatalytic subunitType 1 protein phosphatase catalytic subunitAmino acidsProtein phosphatase catalytic subunitN-terminusProtein serine/threonineN-terminal 35 amino acidsInhibitor 2Phosphatase catalytic subunitTwo-hybrid analysisNovel regulatory interactionsProtein phosphatase 1Serine/threoninePull-down assaysSite-directed mutagenesisN-terminal sequencePP1 mutantsKey functional interactionsPP1 inhibitorPP1 enzymesPP1 inhibitionPhosphatase 1Regulatory interactionsSaccharomyces cerevisiaeRegulation of protein phosphatase-1
Aggen J, Nairn A, Chamberlin R. Regulation of protein phosphatase-1. Cell Chemical Biology 2000, 7: r13-r23. PMID: 10662690, DOI: 10.1016/s1074-5521(00)00069-7.Peer-Reviewed Original Research
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 mechanismsKinaseRegulation of Neurabin I Interaction with Protein Phosphatase 1 by Phosphorylation †
McAvoy T, Allen P, Obaishi H, Nakanishi H, Takai Y, Greengard P, Nairn A, Hemmings H. Regulation of Neurabin I Interaction with Protein Phosphatase 1 by Phosphorylation †. Biochemistry 1999, 38: 12943-12949. PMID: 10504266, DOI: 10.1021/bi991227d.Peer-Reviewed Original ResearchConceptsProtein phosphatase 1Neurabin IPP1 activityPhosphatase 1Two-hybrid interaction analysisActin-binding proteinsCo-immunoprecipitation experimentsMimic phosphorylationSerine 461Phosphorylated residuesGlutathione S-transferaseOverlay assaysFusion proteinSignaling mechanismGamma isoformsCAMP pathwayPhosphorylationS-transferaseProteinTryptic digestPKARegulationHPLC-MS analysisInteraction analysisS461Role 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 assaysMolecular identification of human G-substrate, a possible downstream component of the cGMP-dependent protein kinase cascade in cerebellar Purkinje cells
Endo S, Suzuki M, Sumi M, Nairn A, Morita R, Yamakawa K, Greengard P, Ito M. Molecular identification of human G-substrate, a possible downstream component of the cGMP-dependent protein kinase cascade in cerebellar Purkinje cells. Proceedings Of The National Academy Of Sciences Of The United States Of America 1999, 96: 2467-2472. PMID: 10051666, PMCID: PMC26808, DOI: 10.1073/pnas.96.5.2467.Peer-Reviewed Original ResearchMeSH KeywordsAmino Acid SequenceAnimalsBase SequenceBrainCerebellumCloning, MolecularCyclic GMP-Dependent Protein KinasesDatabases as TopicExpressed Sequence TagsHumansMolecular Sequence DataNerve Tissue ProteinsPurkinje CellsRabbitsRecombinant ProteinsRNA, MessengerSequence AlignmentSequence Homology, Amino AcidTranscription, GeneticConceptsAmino acid sequenceProtein phosphatase 1G-substrateAcid sequencePhosphatase 1Deduced amino acid sequenceRadiation hybrid panel analysisProtein phosphatase 2APutative phosphorylation sitesCGMP-dependent protein kinaseProtein kinase cascadeProtein phosphatase inhibitorSequence tag databaseSites of phosphorylationVitro translation productsHuman brain libraryCGMP-dependent proteinAcid-soluble proteinsApparent molecular massSDS/PAGEPhosphatase 2AThr-35Kinase cascadePhosphorylation sitesTag databaseCharacterization of the Inhibition of Protein Phosphatase-1 by DARPP-32 and Inhibitor-2*
Huang H, Horiuchi A, Watanabe T, Shih S, Tsay H, Li H, Greengard P, Nairn A. Characterization of the Inhibition of Protein Phosphatase-1 by DARPP-32 and Inhibitor-2*. Journal Of Biological Chemistry 1999, 274: 7870-7878. PMID: 10075680, DOI: 10.1074/jbc.274.12.7870.Peer-Reviewed Original ResearchMeSH KeywordsAmino Acid SequenceAmino Acid SubstitutionAnimalsCatalytic DomainDopamine and cAMP-Regulated Phosphoprotein 32Enzyme InhibitorsHumansMolecular Sequence DataMolecular WeightMuscle ProteinsMutagenesis, Site-DirectedNerve Tissue ProteinsPhosphoprotein PhosphatasesPhosphoproteinsPhosphorylationProtein Phosphatase 1ProteinsRabbitsSerineThreonineConceptsProtein phosphatase 1Inhibition of PP1Phospho-DARPP-32Inhibitor 2Phosphatase 1Distinct amino acid motifsThe design, synthesis, and biological evaluation of analogues of the serine-threonine protein phosphatase 1 and 2A selective inhibitor microcystin LA: rational modifications imparting PP1 selectivity
Aggen J, Humphrey J, Gauss C, Huang H, Nairn A, Chamberlin A. The design, synthesis, and biological evaluation of analogues of the serine-threonine protein phosphatase 1 and 2A selective inhibitor microcystin LA: rational modifications imparting PP1 selectivity. Bioorganic & Medicinal Chemistry 1999, 7: 543-564. PMID: 10220039, DOI: 10.1016/s0968-0896(98)00254-5.Peer-Reviewed Original ResearchConceptsPP1 selectivityProtein phosphatase 1Serine-threonine proteinMicrocystin-LAFirst-generation analogsSmall molecule inhibitorsPhosphatase 1Observed selectivityBiological evaluationMolecular modeling analysisMolecule inhibitorsRational modificationSelectivityStructural modificationsSynthesisAnaloguesInhibition assaysPP1MicrocystinsProteinLaModificationAssaysInhibitorsProtein 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
1998
Isolation and Characterization of PNUTS, a Putative Protein Phosphatase 1 Nuclear Targeting Subunit*
Allen P, Kwon Y, Nairn A, Greengard P. Isolation and Characterization of PNUTS, a Putative Protein Phosphatase 1 Nuclear Targeting Subunit*. Journal Of Biological Chemistry 1998, 273: 4089-4095. PMID: 9461602, DOI: 10.1074/jbc.273.7.4089.Peer-Reviewed Original ResearchConceptsPhosphatase 1 nuclear targeting subunitProtein phosphatase 1Targeting subunitPP1 catalytic activityMammalian cell lysatesTwo-hybrid assayPP1 functionsNuclear functionsNuclear compartmentalizationNovel proteinPhosphatase 1Subcellular localizationCell physiologyCell lysatesCell nucleiSubunitsExogenous substratesInitial characterizationProteinStable complexesPotent modulationChromatinCloningMitosisCompartmentalization
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 pretreatmentSite-directed mutagenesis of amino acid residues of protein phosphatase 1 involved in catalysis and inhibitor binding
Huang H, Horiuchi A, Goldberg J, Greengard P, Nairn A. Site-directed mutagenesis of amino acid residues of protein phosphatase 1 involved in catalysis and inhibitor binding. Proceedings Of The National Academy Of Sciences Of The United States Of America 1997, 94: 3530-3535. PMID: 9108010, PMCID: PMC20473, DOI: 10.1073/pnas.94.8.3530.Peer-Reviewed Original ResearchConceptsProtein phosphatase 1Site-directed mutagenesisActive site residuesOkadaic acidPhosphatase 1Calyculin AMammalian protein phosphatase 1PP-1Site residuesEnzyme activityMutation of residuesAmino acid residuesMechanism of catalysisActive siteInhibitor bindingAcid residuesInhibitory proteinMutationsResiduesMutagenesisDivalent cationsToxinY272Large lossesR221Characterization 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