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.
Frontiers in cellular neuroscience
January 1, 2022
Charles Sutton, Erin Q Williams, Hoomam Homsi et al.
13 citations
Mutations in the dopamine transporter gene cause Dopamine Transporter Deficiency Syndrome (DTDS), a fatal infantile parkinsonism-dystonia with no current treatment. Pharmacological chaperones can rescue some disease-causing variants. This study examined structure-activity relationships for two known chaperones, bupropion and ibogaine. The isoquinuclidine substituent of ibogaine and its analogs is important for chaperone efficacy. For bupropion, the secondary amine group is essential. Additional analogs with varying chemical modifications showed variable chaperone efficacies, contributing to the design of improved dopamine transporter pharmacological chaperones.
Neuroscience letters
December 3, 2008
Pieter Beerepoot, Vincent Lam, Alice Luu et al.
The kappa opioid receptor agonist salvinorin A, the active compound in Salvia divinorum, can either increase or decrease locomotor sensitization caused by the dopamine agonist quinpirole, depending on dose. Rats received biweekly injections of quinpirole plus salvinorin A (0.04, 0.4, or 2.0 mg/kg) or the synthetic kappa agonist U69593 (0.3 mg/kg) for ten sessions. The highest salvinorin A dose and U69593 both potentiated sensitization; the middle dose had no effect; the lowest dose attenuated it. Structural differences between salvinorin A and U69593 do not affect potentiation, and salvinorin A can bidirectionally modulate dopamine agonist sensitization.