Presynaptic Gq-coupled receptors drive biphasic dopamine transporter trafficking that modulates dopamine clearance and motor function.

Autor:	Kearney PJ; Brudnick Neuropsychiatric Research Institute, Department of Neurobiology, UMASS Chan Medical School, Worcester, Massachusetts, USA; Morningside Graduate School of Biomedical Sciences, UMASS Chan Medical School, Worcester, Massachusetts, USA., Bolden NC; Brudnick Neuropsychiatric Research Institute, Department of Neurobiology, UMASS Chan Medical School, Worcester, Massachusetts, USA; Morningside Graduate School of Biomedical Sciences, UMASS Chan Medical School, Worcester, Massachusetts, USA., Kahuno E; Brudnick Neuropsychiatric Research Institute, Department of Neurobiology, UMASS Chan Medical School, Worcester, Massachusetts, USA., Conklin TL; Brudnick Neuropsychiatric Research Institute, Department of Neurobiology, UMASS Chan Medical School, Worcester, Massachusetts, USA., Martin GE; Brudnick Neuropsychiatric Research Institute, Department of Neurobiology, UMASS Chan Medical School, Worcester, Massachusetts, USA., Lubec G; Department of Neuroproteomics, Paracelsus Private Medical University, Salzburg, Austria., Melikian HE; Brudnick Neuropsychiatric Research Institute, Department of Neurobiology, UMASS Chan Medical School, Worcester, Massachusetts, USA. Electronic address: haley.melikian@umassmed.edu.
Jazyk:	angličtina
Zdroj:	The Journal of biological chemistry [J Biol Chem] 2023 Feb; Vol. 299 (2), pp. 102900. Date of Electronic Publication: 2023 Jan 12.
DOI:	10.1016/j.jbc.2023.102900
Abstrakt:	Extracellular 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. Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article. (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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