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dc.contributor.authorKearney, Patrick J
dc.contributor.authorBolden, Nicholas C
dc.contributor.authorKahuno, Elizabeth
dc.contributor.authorConklin, Tucker L
dc.contributor.authorMartin, Gilles E
dc.contributor.authorLubec, Gert
dc.contributor.authorMelikian, Haley E
dc.date.accessioned2023-02-14T19:44:25Z
dc.date.available2023-02-14T19:44:25Z
dc.date.issued2023-01-12
dc.identifier.citationKearney PJ, Bolden NC, Kahuno E, Conklin TL, Martin GE, Lubec G, Melikian HE. Presynaptic Gq-coupled receptors drive biphasic dopamine transporter trafficking that modulates dopamine clearance and motor function. J Biol Chem. 2023 Jan 12;299(2):102900. doi: 10.1016/j.jbc.2023.102900. Epub ahead of print. PMID: 36640864.en_US
dc.identifier.eissn1083-351X
dc.identifier.doi10.1016/j.jbc.2023.102900en_US
dc.identifier.pmid36640864
dc.identifier.urihttp://hdl.handle.net/20.500.14038/51693
dc.description.abstractExtracellular dopamine (DA) levels are constrained by the presynaptic DA transporter (DAT), a major psychostimulant target. Despite its necessity for DA neurotransmission, DAT regulation in situ is poorly understood, and it is unknown whether regulated DAT trafficking impacts dopaminergic signaling and/or behaviors. Leveraging chemogenetics and conditional gene silencing, we found that activating presynaptic Gq-coupled receptors, either hM3Dq or mGlu5, drove rapid biphasic DAT membrane trafficking in ex vivo striatal slices, with region-specific differences between ventral and dorsal striata. DAT insertion required D2 DA autoreceptors and intact retromer, whereas DAT retrieval required PKC activation and Rit2. Ex vivo voltammetric studies revealed that DAT trafficking impacts DA clearance. Furthermore, dopaminergic mGlu5 silencing elevated DAT surface expression and abolished motor learning, which was rescued by inhibiting DAT with a subthreshold CE-158 dose. We discovered that presynaptic DAT trafficking is complex, multimodal, and region specific, and for the first time, we identified cell autonomous mechanisms that govern presynaptic DAT tone. Importantly, the findings are consistent with a role for regulated DAT trafficking in DA clearance and motor function.en_US
dc.language.isoenen_US
dc.relation.ispartofJournal of Biological Chemistryen_US
dc.relation.urlhttps://doi.org/10.1016/j.jbc.2023.102900en_US
dc.rights© 2023 THE AUTHORS. Published by Elsevier Inc on behalf of American Society for Biochemistry and Molecular Biology. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).en_US
dc.rightsAttribution 4.0 International*
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/*
dc.subjectdopamineen_US
dc.subjectmembrane traffickingen_US
dc.subjectmetabotropic glutamate receptoren_US
dc.subjectmotor functionen_US
dc.subjectstriatumen_US
dc.titlePresynaptic Gq-coupled receptors drive biphasic dopamine transporter trafficking that modulates dopamine clearance and motor functionen_US
dc.typeJournal Articleen_US
dc.source.journaltitleThe Journal of biological chemistry
dc.source.volume299
dc.source.issue2
dc.source.beginpage102900
dc.source.endpage
dc.source.countryUnited States
dc.source.countryUnited States
dc.source.countryUnited States
dc.identifier.journalThe Journal of biological chemistry
refterms.dateFOA2023-02-14T19:44:26Z
dc.contributor.departmentBrudnick Neuropsychiatric Research Instituteen_US
dc.contributor.departmentMorningside Graduate School of Biomedical Sciencesen_US
dc.contributor.departmentNeurobiologyen_US
dc.contributor.departmentMorningside Graduate School of Biomedical Sciences, Neuroscience Program
dc.contributor.departmentMelikian Lab
dc.contributor.departmentMartin Lab
dc.contributor.studentPatrick Kearney
dc.contributor.studentNicholas Bolden
dc.description.thesisprogramNeuroscience
dc.description.thesisprogramMD/PhD


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© 2023 THE AUTHORS. Published by Elsevier Inc on behalf of American Society for Biochemistry and Molecular Biology. This is an open access article under the CC
BY license (http://creativecommons.org/licenses/by/4.0/).
Except where otherwise noted, this item's license is described as © 2023 THE AUTHORS. Published by Elsevier Inc on behalf of American Society for Biochemistry and Molecular Biology. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).