Dopamine Transporter Activity Is Modulated by alpha-synuclein. Butler B, Goodwin S, Saha K, Becker J, Sambo D, Davari P, Khoshbouei H. J Biol Chem 2015.
The duration and strength of the dopaminergic signal is regulated by the dopamine transporter (DAT). Drug addiction, 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 (AMPH) induced DAT-meditated DA 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 AMPH-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 DA efflux and enhances DAT localization in cholesterol rich membrane microdomains.
Copyright © 2015, The American Society for Biochemistry and Molecular Biology.
KEYWORDS: addiction; amphetamine; dopamine; dopamine efflux; dopamine transporter; drug addiction; neurobiology; neurochemistry; synuclein