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
2018
Striatal Signaling Regulated by the H3R Histamine Receptor in a Mouse Model of tic Pathophysiology
Rapanelli M, Frick L, Jindachomthong K, Xu J, Ohtsu H, Nairn A, Pittenger C. Striatal Signaling Regulated by the H3R Histamine Receptor in a Mouse Model of tic Pathophysiology. Neuroscience 2018, 392: 172-179. PMID: 30278251, PMCID: PMC6204318, DOI: 10.1016/j.neuroscience.2018.09.035.Peer-Reviewed Original ResearchConceptsHDC-KO miceMitogen-activated protein kinaseHistamine receptorsWT animalsDorsal striatumH3R activationTic-like movementsStriatonigral medium spiny neuronsAkt phosphorylationMedium spiny neuronsWild-type miceRare genetic causeHistamine dysregulationAgonist treatmentKO miceSpiny neuronsTic disordersTic pathophysiologyStriatal signalingMouse modelNeuropsychiatric diseasesKO modelRepetitive movementsStriatumMice
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 modelPotentiationInhibition 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
Inhibition of the tyrosine phosphatase STEP61 restores BDNF expression and reverses motor and cognitive deficits in phencyclidine-treated mice
Xu J, Kurup P, Baguley TD, Foscue E, Ellman JA, Nairn AC, Lombroso PJ. Inhibition of the tyrosine phosphatase STEP61 restores BDNF expression and reverses motor and cognitive deficits in phencyclidine-treated mice. Cellular And Molecular Life Sciences 2015, 73: 1503-1514. PMID: 26450419, PMCID: PMC4801664, DOI: 10.1007/s00018-015-2057-1.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBenzothiepinsBrain-Derived Neurotrophic FactorCells, CulturedCognition DisordersCREB-Binding ProteinDown-RegulationMaleMiceMice, Inbred C57BLMitogen-Activated Protein Kinase 1Mitogen-Activated Protein Kinase 3Motor ActivityNeuronsPhencyclidinePhosphorylationProtein Tyrosine PhosphatasesReceptors, N-Methyl-D-AspartateRNA InterferenceUbiquitinationConceptsBrain-derived neurotrophic factorBDNF expressionProtein tyrosine Phosphatase 61Cognitive deficitsPCP-induced reductionPCP-treated micePhencyclidine-treated micePCP-induced increasePCP-induced hyperlocomotionTyrosine phosphatase STEP61STEP61 levelsBDNF transcriptionNeurotrophic factorNMDAR antagonistsCortical culturesCortical neuronsCNS disordersSynaptic strengtheningPsychotic episodeRodent modelsBrain disordersPharmacologic inhibitionSTEP61SchizophreniaCognitive functioningDown‐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 neuronsBDNF Induces Striatal-Enriched Protein Tyrosine Phosphatase 61 Degradation Through the Proteasome
Saavedra A, Puigdellívol M, Tyebji S, Kurup P, Xu J, Ginés S, Alberch J, Lombroso PJ, Pérez-Navarro E. BDNF Induces Striatal-Enriched Protein Tyrosine Phosphatase 61 Degradation Through the Proteasome. Molecular Neurobiology 2015, 53: 4261-4273. PMID: 26223799, PMCID: PMC4738169, DOI: 10.1007/s12035-015-9335-7.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBrain-Derived Neurotrophic FactorCerebral CortexExtracellular Signal-Regulated MAP KinasesHippocampusMembrane PotentialsMiceNeostriatumNerve Growth FactorNeuronsNeurotrophin 3Phospholipase C gammaPhosphorylationProteasome Endopeptidase ComplexProtein Tyrosine Phosphatases, Non-ReceptorProteolysisReceptors, N-Methyl-D-AspartateUbiquitinationConceptsBrain-derived neurotrophic factorSTEP61 levelsCortical neuronsUbiquitin-proteasome systemStriatal-enriched protein tyrosine phosphatasePrimary cortical neuronsLevels/activitiesNerve growth factorNeurotrophic factorNeurotrophin-3Cultured striatalHippocampal neuronsCell depolarizationGrowth factorERK1/2 phosphorylationNeuronsStriatalTyrosine kinasePhospholipase C-gammaC gammaDifferent mechanismsLevelsBlockadeGluN2BProtein tyrosine phosphatase
2014
Inhibitor of the Tyrosine Phosphatase STEP Reverses Cognitive Deficits in a Mouse Model of Alzheimer's Disease
Xu J, Chatterjee M, Baguley TD, Brouillette J, Kurup P, Ghosh D, Kanyo J, Zhang Y, Seyb K, Ononenyi C, Foscue E, Anderson GM, Gresack J, Cuny GD, Glicksman MA, Greengard P, Lam TT, Tautz L, Nairn AC, Ellman JA, Lombroso PJ. Inhibitor of the Tyrosine Phosphatase STEP Reverses Cognitive Deficits in a Mouse Model of Alzheimer's Disease. PLOS Biology 2014, 12: e1001923. PMID: 25093460, PMCID: PMC4122355, DOI: 10.1371/journal.pbio.1001923.Peer-Reviewed Original ResearchMeSH KeywordsAlzheimer DiseaseAmino Acid SequenceAnimalsBenzothiepinsCatalytic DomainCell DeathCerebral CortexCognition DisordersCysteineDisease Models, AnimalEnzyme InhibitorsHigh-Throughput Screening AssaysHumansMaleMice, Inbred C57BLMice, KnockoutMolecular Sequence DataNeuronsPhosphorylationPhosphotyrosineProtein Tyrosine Phosphatases, Non-ReceptorSubstrate SpecificityConceptsInhibitors of stepsSpecificity of inhibitorsIsoxazolepropionic acid receptor (AMPAR) traffickingCatalytic cysteinePTP inhibitorsTyrosine phosphataseTyrosine phosphorylationSecondary assaysSTEP KO miceReceptor traffickingFirst large-scale effortN-methyl-D-aspartate receptorsPyk2 activitySTEP inhibitorLarge-scale effortsNovel therapeutic targetSynaptic functionAlzheimer's diseaseNeurodegenerative disordersCortical cellsTherapeutic targetERK1/2Specificity experimentsPhosphataseInhibitors
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
2012
Calpain and STriatal-Enriched protein tyrosine Phosphatase (STEP) activation contribute to extrasynaptic NMDA receptor localization in a Huntington's disease mouse model
Gladding CM, Sepers MD, Xu J, Zhang LY, Milnerwood AJ, Lombroso PJ, Raymond LA. Calpain and STriatal-Enriched protein tyrosine Phosphatase (STEP) activation contribute to extrasynaptic NMDA receptor localization in a Huntington's disease mouse model. Human Molecular Genetics 2012, 21: 3739-3752. PMID: 22523092, PMCID: PMC3412376, DOI: 10.1093/hmg/dds154.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCalpainCoculture TechniquesDisease Models, AnimalEnzyme ActivationEnzyme InhibitorsHuntington DiseaseIon Channel GatingMiceModels, BiologicalNeostriatumNeuronsPhosphorylationPhosphotyrosineProtein TransportProtein Tyrosine Phosphatases, Non-ReceptorReceptors, N-Methyl-D-AspartateSynapsesConceptsYAC128 striatumProtein tyrosine phosphatase activationNMDAR localizationCalpain cleavageProtein tyrosine phosphataseTyrosine phosphatase activationEarly synaptic defectsWhole-cell NMDAR currentsDisease mouse modelGluN2B expressionNMDA receptor traffickingMutant huntingtin proteinCalpain inhibitionTyrosine phosphataseHuntington's diseaseFull-length mhttPlasma membranePhosphatase activationC-terminusReceptor traffickingNMDAR traffickingPolyglutamine repeatsMouse modelHuntingtin proteinNMDA receptor localization
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
2002
Cloning, expression and characterization of a novel human VMP gene*
Cheng C, Xu J, Ye X, Dai J, Wu Q, Zeng L, Wang L, Zhao W, Ji C, Gu S, Xie Y, Mao Y. Cloning, expression and characterization of a novel human VMP gene*. Molecular Biology Reports 2002, 29: 281-286. PMID: 12463420, DOI: 10.1023/a:1020402410522.Peer-Reviewed Original ResearchConceptsMembrane proteinsVesicular membrane proteinsNovel human genePutative molecular weightNeuron-specific membrane proteinMicrotubule-binding domainPutative membraneRT-PCR analysisHuman genesOrganelle transportVmp genesC-terminalAmino acidsCloningGenesProteinHydrophilic tailImportant roleCDNAMolecular weightMicrotubulesDomainKDaExpression