Pharmacological Chaperones of the Dopamine Transporter Rescue Dopamine Transporter Deficiency Syndrome Mutations in Heterologous Cells.
The Journal of biological chemistry October 14, 2016 Pieter Beerepoot, Vincent M Lam, Ali Salahpour 59 citations
Mutations in the dopamine transporter (DAT) gene cause hereditary dopamine transporter deficiency syndrome (DTDS), a rare condition often involving defective transporter trafficking and folding. Screening known DAT ligands revealed that bupropion and ibogaine increase DAT surface expression, while cocaine and methylphenidate do not. These drugs raise wild-type DAT protein levels and promote maturation of the ER-retained mutant K590A, an effect blocked by inhibiting ER-to-Golgi transport or by knocking down the COPII component SEC24D. Both drugs also rescue maturation and functional activity of DTDS-associated mutations A314V and R445C. This is the first demonstration of pharmacological chaperoning of DAT, suggesting a potential therapeutic approach for DTDS and related conditions.