2022
Sexual dimorphism in a neuronal mechanism of spinal hyperexcitability across rodent and human models of pathological pain
Dedek A, Xu J, Lorenzo LÉ, Godin AG, Kandegedara CM, Glavina G, Landrigan JA, Lombroso PJ, De Koninck Y, Tsai EC, Hildebrand ME. Sexual dimorphism in a neuronal mechanism of spinal hyperexcitability across rodent and human models of pathological pain. Brain 2022, 145: 1124-1138. PMID: 35323848, PMCID: PMC9050559, DOI: 10.1093/brain/awab408.Peer-Reviewed Original ResearchConceptsBrain-derived neurotrophic factorSuperficial dorsal horn neuronsDorsal horn neuronsFemale ratsNeurotrophic factorNeuronal mechanismsCentral neuronal mechanismsSpinal nociceptive circuitsSpinal pain processingSuperficial dorsal hornChronic pain syndromeLamina I neuronsPreclinical pain modelsHuman organ donorsSynaptic NMDAR responsesNMDAR potentiationSpinal hyperexcitabilityInflammatory painNociceptive circuitsPain syndromeTactile allodyniaDorsal hornPain modelPathological painLaminae I
2019
Loss of STEP61 couples disinhibition to N-methyl-d-aspartate receptor potentiation in rodent and human spinal pain processing
Dedek A, Xu J, Kandegedara CM, Lorenzo LÉ, Godin AG, De Koninck Y, Lombroso PJ, Tsai EC, Hildebrand ME. Loss of STEP61 couples disinhibition to N-methyl-d-aspartate receptor potentiation in rodent and human spinal pain processing. Brain 2019, 142: 1535-1546. PMID: 31135041, PMCID: PMC6536915, DOI: 10.1093/brain/awz105.Peer-Reviewed Original ResearchConceptsN-methyl-D-aspartate receptorsLaminae INMDAR responsesDorsal horn synapsesSpinal pain processingNerve injury modelSpinal dorsal hornSynaptic NMDAR responsesTyrosine phosphatase STEP61Loss of inhibitionBehavioral hypersensitivityInflammatory painNeuropathic painDorsal hornPain statesPathological painPain targetsChronic painPain processingInjury modelAssociated downregulationRodent modelsReceptor potentiationPainSTEP61 activity
2017
Synaptic NMDA Receptor Activation Induces Ubiquitination and Degradation of STEP61
Xu J, Kurup P, Nairn AC, Lombroso PJ. Synaptic NMDA Receptor Activation Induces Ubiquitination and Degradation of STEP61. Molecular Neurobiology 2017, 55: 3096-3111. PMID: 28466270, PMCID: PMC5668205, DOI: 10.1007/s12035-017-0555-x.Peer-Reviewed Original ResearchConceptsMK-801-treated miceProtein tyrosine Phosphatase 61GluN1/GluN2B receptorsNMDA receptor signalingD-serine treatmentMouse frontal cortexNMDAR signalingSynaptic NMDARsCortical samplesHuman schizophreniaTherapeutic effectFrontal cortexGluN2B receptorsSynaptic plasticityNeurological disordersCognitive deficitsReceptor signalingD-serineSTEP61SchizophreniaBicucullineMiceProteasomal degradationSurface localizationSignaling
2016
Potentiation of Synaptic GluN2B NMDAR Currents by Fyn Kinase Is Gated through BDNF-Mediated Disinhibition in Spinal Pain Processing
Hildebrand ME, Xu J, Dedek A, Li Y, Sengar AS, Beggs S, Lombroso PJ, Salter MW. Potentiation of Synaptic GluN2B NMDAR Currents by Fyn Kinase Is Gated through BDNF-Mediated Disinhibition in Spinal Pain Processing. Cell Reports 2016, 17: 2753-2765. PMID: 27926876, DOI: 10.1016/j.celrep.2016.11.024.Peer-Reviewed Original ResearchConceptsBrain-derived neurotrophic factorN-methyl-D-aspartate receptorsLaminae INeurotrophin brain-derived neurotrophic factorPeripheral nerve injury modelSynaptic N-methyl-D-aspartate receptorsBDNF-TrkB signalingSpinal pain processingNerve injury modelChronic pain statesActivation of TrkBNMDAR dysregulationNMDAR potentiationPain amplificationPain hypersensitivityNeuropathic painPain statesPain processingNeurotrophic factorSpinal neuronsSynaptic excitationSynaptic inhibitionNMDAR currentsInjury modelPotentiationSTEP activation by Gαq coupled GPCRs opposes Src regulation of NMDA receptors containing the GluN2A subunit
Tian M, Xu J, Lei G, Lombroso PJ, Jackson MF, MacDonald JF. STEP activation by Gαq coupled GPCRs opposes Src regulation of NMDA receptors containing the GluN2A subunit. Scientific Reports 2016, 6: 36684. PMID: 27857196, PMCID: PMC5114553, DOI: 10.1038/srep36684.Peer-Reviewed Original ResearchConceptsStriatal-enriched protein tyrosine phosphataseFamily of kinasesProtein tyrosine phosphataseM1R stimulationN-methyl-D-aspartate receptorsM1 muscarinic acetylcholine receptorSrc recruitmentTyrosine phosphataseSrc regulationNMDAR functionIntracellular Ca2Step activationMuscarinic acetylcholine receptorsGluN2A subunitGαqAcetylcholine receptorsHigh intracellular Ca2Function of NMDARsSynaptic plasticityPhosphataseNMDAR activationActivationReceptorsRecruitmentCa2Inhibition of STEP61 ameliorates deficits in mouse and hiPSC-based schizophrenia models
Xu J, Hartley BJ, Kurup P, Phillips A, Topol A, Xu M, Ononenyi C, Foscue E, Ho SM, Baguley TD, Carty N, Barros CS, Müller U, Gupta S, Gochman P, Rapoport J, Ellman JA, Pittenger C, Aronow B, Nairn AC, Nestor MW, Lombroso PJ, Brennand KJ. Inhibition of STEP61 ameliorates deficits in mouse and hiPSC-based schizophrenia models. Molecular Psychiatry 2016, 23: 271-281. PMID: 27752082, PMCID: PMC5395367, DOI: 10.1038/mp.2016.163.Peer-Reviewed Original ResearchConceptsBrain-specific tyrosine phosphataseDephosphorylation of GluN2BExtracellular signal-regulated kinase 1/2Signal-regulated kinase 1/2Glutamate receptor internalizationPluripotent stem cellsKnockout mouse modelTyrosine phosphataseMouse modelKinase 1/2Receptor internalizationImportant regulatorGenetic reductionLoss of NMDARsStem cellsN-methyl DPharmacological inhibitionProtein levelsSynaptic functionSTEP61Patient cohortForebrain neuronsBehavioral deficitsExcitatory neuronsSchizophrenia model
2015
Down‐regulation of BDNF in cell and animal models increases striatal‐enriched protein tyrosine phosphatase 61 (STEP61) levels
Xu J, Kurup P, Azkona G, Baguley TD, Saavedra A, Nairn AC, Ellman JA, Pérez-Navarro E, Lombroso PJ. Down‐regulation of BDNF in cell and animal models increases striatal‐enriched protein tyrosine phosphatase 61 (STEP61) levels. Journal Of Neurochemistry 2015, 136: 285-294. PMID: 26316048, PMCID: PMC4769989, DOI: 10.1111/jnc.13295.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBenzothiepinsBrainBrain-Derived Neurotrophic FactorCells, CulturedCysteine Proteinase InhibitorsDown-RegulationEmbryo, MammalianFemaleFlavonesLeupeptinsMaleMiceMice, Inbred C57BLMice, TransgenicMotor ActivityNeuronsProtein Tyrosine PhosphatasesRatsRats, Sprague-DawleyRNA, Small InterferingTime FactorsConceptsBrain-derived neurotrophic factorNormal cognitive functionSynaptic strengtheningStriatal-enriched protein tyrosine phosphataseBDNF expressionBDNF knockdownCortical culturesRegulation of BDNFN-methyl-D-aspartate receptor functionNeuropsychiatric disordersCognitive functionBetter therapeutic strategiesMouse frontal cortexNMDA receptor subunit GluN2BSTEP61 levelsHyperlocomotor activityMotor abnormalitiesNeurotrophic factorNMDA receptorsFrontal cortexKinase B signalingTherapeutic strategiesAgonists resultsAnimal modelsCultured neuronsStriatal‐enriched protein tyrosine phosphatase regulates the PTPα/Fyn signaling pathway
Xu J, Kurup P, Foscue E, Lombroso PJ. Striatal‐enriched protein tyrosine phosphatase regulates the PTPα/Fyn signaling pathway. Journal Of Neurochemistry 2015, 134: 629-641. PMID: 25951993, PMCID: PMC4516628, DOI: 10.1111/jnc.13160.Peer-Reviewed Original ResearchConceptsProtein tyrosine phosphataseProtein kinase ARegulation of FynTyrosine phosphataseReceptor-type protein tyrosine phosphatase alphaProtein tyrosine phosphatase alphaStriatal-enriched protein tyrosine phosphataseRegulatory tyrosine residuesActivation of FynTyrosine kinase FynRegulatory tyrosineProtein tyrosinePTPαKinase FynSynaptic membranesKinase ATyrosine residuesFyn activityFynNovel substratePrimary neuronal culturesSTEP61Synergistic regulationMolecular techniquesNovel mechanismSTEP61 is a substrate of the E3 ligase parkin and is upregulated in Parkinson’s disease
Kurup PK, Xu J, Videira RA, Ononenyi C, Baltazar G, Lombroso PJ, Nairn AC. STEP61 is a substrate of the E3 ligase parkin and is upregulated in Parkinson’s disease. Proceedings Of The National Academy Of Sciences Of The United States Of America 2015, 112: 1202-1207. PMID: 25583483, PMCID: PMC4313846, DOI: 10.1073/pnas.1417423112.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCorpus StriatumCyclic AMP Response Element-Binding ProteinDown-RegulationGene Expression Regulation, EnzymologicHEK293 CellsHumansMAP Kinase Signaling SystemMiceMice, KnockoutMitogen-Activated Protein Kinase 3MPTP PoisoningProtein Tyrosine Phosphatases, Non-ReceptorRatsRats, Sprague-DawleyUbiquitinationUbiquitin-Protein LigasesUp-RegulationConceptsE3 ubiquitin ligase ParkinSubstantia nigra pars compactaPathophysiology of PDProtein tyrosine phosphataseUbiquitin ligase ParkinSporadic Parkinson's diseaseE3 ligase ParkinRegulation of ParkinParkinson's diseaseTyrosine phosphataseParkin mutantsE3 ligaseProteasome systemDopaminergic neuronsDownstream targetsAutosomal recessive juvenile parkinsonismNovel substrateSTEP61ParkinCellular modelSTEP61 levelsSNc dopaminergic neuronsProtein levelsFunction contributesERK1/2
2013
Striatal-Enriched Protein Tyrosine Phosphatase—STEPs Toward Understanding Chronic Stress-Induced Activation of Corticotrophin Releasing Factor Neurons in the Rat Bed Nucleus of the Stria Terminalis
Dabrowska J, Hazra R, Guo JD, Li C, DeWitt S, Xu J, Lombroso PJ, Rainnie DG. Striatal-Enriched Protein Tyrosine Phosphatase—STEPs Toward Understanding Chronic Stress-Induced Activation of Corticotrophin Releasing Factor Neurons in the Rat Bed Nucleus of the Stria Terminalis. Biological Psychiatry 2013, 74: 817-826. PMID: 24012328, PMCID: PMC3818357, DOI: 10.1016/j.biopsych.2013.07.032.Peer-Reviewed Original ResearchConceptsStriatal-enriched protein tyrosine phosphataseLong-term potentiationProtein tyrosine phosphataseCRF neuronsReverse transcriptase-polymerase chain reactionTranscriptase-polymerase chain reactionRestraint stressTyrosine phosphatasePolymerase chain reactionBed nucleusFactor neuronsStria terminalisWhole-cell patch-clamp electrophysiologyInduction of LTPRole of STEPQuantitative reverse transcriptase-polymerase chain reactionChain reactionNovel treatment strategiesStress-induced anxiety disordersAnxiety-like behaviorSingle-cell reverse transcriptase-polymerase chain reactionPatch-clamp electrophysiologyStress-Induced ActivationRat bed nucleusTyrosine phosphatase STEP
2011
Reduced levels of the tyrosine phosphatase STEP block beta amyloid‐mediated GluA1/GluA2 receptor internalization
Zhang Y, Kurup P, Xu J, Anderson GM, Greengard P, Nairn AC, Lombroso PJ. Reduced levels of the tyrosine phosphatase STEP block beta amyloid‐mediated GluA1/GluA2 receptor internalization. Journal Of Neurochemistry 2011, 119: 664-672. PMID: 21883219, PMCID: PMC3192910, DOI: 10.1111/j.1471-4159.2011.07450.x.Peer-Reviewed Original ResearchConceptsAD mouse modelMouse modelTriple transgenic AD mouse modelAlzheimer's diseaseTransgenic AD mouse modelGluA2 receptorsAD prefrontal cortexElevated levelsGluA1/GluA2Cortical culturesBeta amyloidRegulate surface expressionCognitive deficitsStriatal-enriched protein tyrosine phosphatasePrefrontal cortexΑ-aminoReceptorsReceptor internalizationSurface expressionReduced levelsReceptor complexCortexDiseaseMiceAβ
2010
Aβ-Mediated NMDA Receptor Endocytosis in Alzheimer's Disease Involves Ubiquitination of the Tyrosine Phosphatase STEP61
Kurup P, Zhang Y, Xu J, Venkitaramani DV, Haroutunian V, Greengard P, Nairn AC, Lombroso PJ. Aβ-Mediated NMDA Receptor Endocytosis in Alzheimer's Disease Involves Ubiquitination of the Tyrosine Phosphatase STEP61. Journal Of Neuroscience 2010, 30: 5948-5957. PMID: 20427654, PMCID: PMC2868326, DOI: 10.1523/jneurosci.0157-10.2010.Peer-Reviewed Original ResearchMeSH KeywordsAgedAged, 80 and overAlzheimer DiseaseAmyloid beta-PeptidesAnimalsCell LineCells, CulturedCerebral CortexEndocytosisHumansIn Vitro TechniquesMiceMice, KnockoutMice, TransgenicMiddle AgedNeuronsProtein Tyrosine Phosphatases, Non-ReceptorRatsRats, Sprague-DawleyReceptors, N-Methyl-D-AspartateUbiquitinated ProteinsUbiquitinationConceptsAlzheimer's diseaseAbeta treatmentNR2B subunitProtein tyrosine Phosphatase 61Cognitive deficitsNMDA receptor internalizationHuman AD brainsMouse cortical culturesNR1/NR2B receptorsNMDA receptor endocytosisIonotropic glutamate receptorsTyrosine phosphatase STEP61AD brainCortical slicesCortical culturesGlutamate receptorsNR2B receptorsPostsynaptic terminalsPrefrontal cortexNeuronal membranesElevated levelsCortexReceptor internalizationUbiquitin-proteasome systemStep activity
2009
Extrasynaptic NMDA Receptors Couple Preferentially to Excitotoxicity via Calpain-Mediated Cleavage of STEP
Xu J, Kurup P, Zhang Y, Goebel-Goody SM, Wu PH, Hawasli AH, Baum ML, Bibb JA, Lombroso PJ. Extrasynaptic NMDA Receptors Couple Preferentially to Excitotoxicity via Calpain-Mediated Cleavage of STEP. Journal Of Neuroscience 2009, 29: 9330-9343. PMID: 19625523, PMCID: PMC2737362, DOI: 10.1523/jneurosci.2212-09.2009.Peer-Reviewed Original ResearchMeSH KeywordsAlternative SplicingAnimalsBrainCalpainCell DeathCells, CulturedCyclin-Dependent Kinase 5EndocytosisGlutamic AcidIn Vitro TechniquesMiceMice, KnockoutMitogen-Activated Protein Kinase 1Mitogen-Activated Protein Kinase 3NeuronsP38 Mitogen-Activated Protein KinasesProtein Tyrosine Phosphatases, Non-ReceptorRatsRats, Sprague-DawleyReceptors, N-Methyl-D-AspartateSynapsesConceptsStriatal-enriched protein tyrosine phosphataseCalpain cleavage sitesP38 activationCell deathCleavage siteExtracellular signal-regulated kinase 1/2Protein tyrosine phosphataseSignal-regulated kinase 1/2Promotes cell survivalActivation of p38Tyrosine phosphataseSubstrate bindingKinase 1/2ERK1/2 activationCalpain cleavageCell survivalNovel mechanismCalpain-mediated proteolysisReceptors coupleP38NMDAR stimulationPostsynaptic terminalsValid targetCleavage productsSTEP substrates
2008
Expression and function of striatal enriched protein tyrosine phosphatase is profoundly altered in cerebral ischemia
Braithwaite SP, Xu J, Leung J, Urfer R, Nikolich K, Oksenberg D, Lombroso PJ, Shamloo M. Expression and function of striatal enriched protein tyrosine phosphatase is profoundly altered in cerebral ischemia. European Journal Of Neuroscience 2008, 27: 2444-2452. PMID: 18445231, PMCID: PMC2738830, DOI: 10.1111/j.1460-9568.2008.06209.x.Peer-Reviewed Original ResearchConceptsStriatal enriched protein tyrosine phosphataseProtein tyrosine phosphataseTyrosine phosphatasePost-transcriptional levelNovel speciesPhosphorylation stateImportant proteinsMature formKey substrateNMDA receptor subunitsReceptor subunitsActive formSynaptic functionComplex cascadeCritical roleERKMRNA levelsProteinMRNAPERKPhosphataseCleavageCentral nervous systemNervous systemSubunits