J Biol Chem. 2015 Dec 4;290(49):29542-54.

Dopamine Transporter Activity Is Modulated by α-Synuclein.

Butler B1, Saha K1, Rana T2, Becker JP1, Sambo D1, Davari P1, Goodwin JS3, Khoshbouei H4.
  • 1From the Departments of Neuroscience and Psychiatry University of Florida, Gainesville, Florida 32611 and.
  • 2the Department of Biochemistry and Cancer Biology, Meharry Medical College, Nashville, Tennessee 37208.
  • 3the Department of Biochemistry and Cancer Biology, Meharry Medical College, Nashville, Tennessee 37208 jgoodwin@mmc.edu.
  • 4From the Departments of Neuroscience and Psychiatry University of Florida, Gainesville, Florida 32611 and Habibeh@ufl.edu.

 

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.

KEYWORDS: addiction; amphetamine; dopamine; dopamine efflux; dopamine transporter; neurochemistry; synuclein

PMID: 26442590

 

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