title: Dopamine Transporter Activity Is Modulated by α-Synuclein.
abstract: The duration and strength of the dopaminergic signal are regulated by the dopamine transporter (DAT). Drug addiction and neurodegenerative and neuropsychiatric diseases have all been associated with altered DAT activity. The membrane localization and the activity of DAT are regulated by a number of intracellular proteins. α-Synuclein, a protein partner of DAT, is implicated in neurodegenerative disease and drug addiction. Little is known about the regulatory mechanisms of the interaction between DAT and α-synuclein, the cellular location of this interaction, and the functional consequences of this interaction on the basal, amphetamine-induced DAT-mediated dopamine efflux, and membrane microdomain distribution of the transporter. Here, we found that the majority of DAT·α-synuclein protein complexes are found at the plasma membrane of dopaminergic neurons or mammalian cells and that the amphetamine-mediated increase in DAT activity enhances the association of these proteins at the plasma membrane. Further examination of the interaction of DAT and α-synuclein revealed a transient interaction between these two proteins at the plasma membrane. Additionally, we found DAT-induced membrane depolarization enhances plasma membrane localization of α-synuclein, which in turn increases dopamine efflux and enhances DAT localization in cholesterol-rich membrane microdomains.
authors.affiliation: From the Departments of Neuroscience and Psychiatry University of Florida, Gainesville, Florida 32611 and.
authors.forename: Brittany
authors.initials: B
authors.lastname: Butler
authors.affiliation: From the Departments of Neuroscience and Psychiatry University of Florida, Gainesville, Florida 32611 and.
authors.forename: Kaustuv
authors.initials: K
authors.lastname: Saha
authors.affiliation: the Department of Biochemistry and Cancer Biology, Meharry Medical College, Nashville, Tennessee 37208.
authors.forename: Tanu
authors.initials: T
authors.lastname: Rana
authors.affiliation: From the Departments of Neuroscience and Psychiatry University of Florida, Gainesville, Florida 32611 and.
authors.forename: Jonas P
authors.initials: JP
authors.lastname: Becker
authors.affiliation: From the Departments of Neuroscience and Psychiatry University of Florida, Gainesville, Florida 32611 and.
authors.forename: Danielle
authors.initials: D
authors.lastname: Sambo
authors.affiliation: From the Departments of Neuroscience and Psychiatry University of Florida, Gainesville, Florida 32611 and.
authors.forename: Paran
authors.initials: P
authors.lastname: Davari
authors.affiliation: the Department of Biochemistry and Cancer Biology, Meharry Medical College, Nashville, Tennessee 37208 jgoodwin@mmc.edu.
authors.forename: J Shawn
authors.initials: JS
authors.lastname: Goodwin
authors.affiliation: From the Departments of Neuroscience and Psychiatry University of Florida, Gainesville, Florida 32611 and Habibeh@ufl.edu.
authors.forename: Habibeh
authors.initials: H
authors.lastname: Khoshbouei
mesh_terms: D000661:Amphetamine / Q000378:metabolism; D000818:Animals; D019921:Biotinylation; D001921:Brain / Q000378:metabolism; D016466:CHO Cells; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D006224:Cricetinae; D003412:Cricetulus; D004298:Dopamine / Q000378:metabolism*; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism*; D059290:Dopaminergic Neurons / Q000378:metabolism; D031541:Fluorescence Resonance Energy Transfer; D006801:Humans; D021962:Membrane Microdomains / Q000378:metabolism; D019636:Neurodegenerative Diseases / Q000378:metabolism; D009435:Synaptic Transmission; D051843:Synucleins / Q000378:metabolism; D051844:alpha-Synuclein / Q000378:metabolism*
chemical_list: D050483:Dopamine Plasma Membrane Transport Proteins; D051843:Synucleins; D051844:alpha-Synuclein; D000661:Amphetamine; D004298:Dopamine
keywords: addiction; amphetamine; dopamine; dopamine efflux; dopamine transporter; neurochemistry; synuclein