Nanoscopic dopamine transporter distribution and conformation are inversely regulated by excitatory drive and D2 autoreceptor activity.

Autor:	Lycas MD; Molecular Neuropharmacology and Genetics Laboratory, Department of Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen, Maersk Tower 7.5, 2200 Copenhagen, Denmark., Ejdrup AL; Molecular Neuropharmacology and Genetics Laboratory, Department of Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen, Maersk Tower 7.5, 2200 Copenhagen, Denmark., Sørensen AT; Molecular Neuropharmacology and Genetics Laboratory, Department of Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen, Maersk Tower 7.5, 2200 Copenhagen, Denmark., Haahr NO; Molecular Neuropharmacology and Genetics Laboratory, Department of Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen, Maersk Tower 7.5, 2200 Copenhagen, Denmark., Jørgensen SH; Molecular Neuropharmacology and Genetics Laboratory, Department of Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen, Maersk Tower 7.5, 2200 Copenhagen, Denmark., Guthrie DA; Medicinal Chemistry Section, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse-Intramural Research Program, National Institutes of Health, Baltimore, MD 21224, USA., Støier JF; Molecular Neuropharmacology and Genetics Laboratory, Department of Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen, Maersk Tower 7.5, 2200 Copenhagen, Denmark., Werner C; Department of Biotechnology and Biophysics, Biocenter, Julius-Maximilians-Universität Würzburg, Am Hubland, 97074 Würzburg, Germany., Newman AH; Medicinal Chemistry Section, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse-Intramural Research Program, National Institutes of Health, Baltimore, MD 21224, USA., Sauer M; Department of Biotechnology and Biophysics, Biocenter, Julius-Maximilians-Universität Würzburg, Am Hubland, 97074 Würzburg, Germany., Herborg F; Molecular Neuropharmacology and Genetics Laboratory, Department of Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen, Maersk Tower 7.5, 2200 Copenhagen, Denmark., Gether U; Molecular Neuropharmacology and Genetics Laboratory, Department of Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen, Maersk Tower 7.5, 2200 Copenhagen, Denmark. Electronic address: gether@sund.ku.dk.
Jazyk:	angličtina
Zdroj:	Cell reports [Cell Rep] 2022 Sep 27; Vol. 40 (13), pp. 111431.
DOI:	10.1016/j.celrep.2022.111431
Abstrakt:	The nanoscopic organization and regulation of individual molecular components in presynaptic varicosities of neurons releasing modulatory volume neurotransmitters like dopamine (DA) remain largely elusive. Here we show, by application of several super-resolution microscopy techniques to cultured neurons and mouse striatal slices, that the DA transporter (DAT), a key protein in varicosities of dopaminergic neurons, exists in the membrane in dynamic equilibrium between an inward-facing nanodomain-localized and outward-facing unclustered configuration. The balance between these configurations is inversely regulated by excitatory drive and DA D2 autoreceptor activation in a manner dependent on Ca 2+ influx via N-type voltage-gated Ca 2+ channels. The DAT nanodomains contain tens of transporters molecules and overlap with nanodomains of PIP2 (phosphatidylinositol-4,5-bisphosphate) but show little overlap with D2 autoreceptor, syntaxin-1, and clathrin nanodomains. The data reveal a mechanism for rapid alterations of nanoscopic DAT distribution and show a striking link of this to the conformational state of the transporter. Competing Interests: Declaration of interests The authors declare no competing interests. (Published by Elsevier Inc.)
Databáze:	MEDLINE
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