Pharmacological Chaperones of the Dopamine Transporter Rescue Dopamine Transporter Deficiency Syndrome Mutations in Heterologous Cells.
Pieter Beerepoot, Vincent M Lam, Ali Salahpour
Journal of Biological Chemistry October 14, 2016 DOI: 10.1074/jbc.M116.749119 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study Peer reviewed |
|---|---|
| Interventions | bupropion ibogaine |
| Topics | Ibogaine |
| Keywords | Copii Dtds Sec24d Bupropion Dopamine transporter Membrane protein Pharmacological chaperone Protein folding |
| Citations | 59 |
| Key findings | Bupropion and ibogaine act as pharmacological chaperones to promote dopamine transporter maturation and rescue DTDS-associated mutations. |
Abstract
A number of pathological conditions have been linked to mutations in the dopamine transporter gene, including hereditary dopamine transporter deficiency syndrome (DTDS). DTDS is a rare condition that is caused by autosomal recessive loss-of-function mutations in the dopamine transporter (DAT), which often affects transporter trafficking and folding. We examined the possibility of using pharmacological chaperones of DAT to rescue DTDS mutations. After screening a set of known DAT ligands for their ability to increase DAT surface expression, we found that bupropion and ibogaine increased DAT surface expression, whereas others, including cocaine and methylphenidate, had no effect. Bupropion and ibogaine increased wild type DAT protein levels and also promoted maturation of the endoplasmic reticulum (ER)-retained DAT mutant K590A. Rescue of K590A could be blocked by inhibiting ER to Golgi transport using brefeldin A. Furthermore, knockdown of coat protein complex II (COPII) component SEC24D, which is important in the ER export of wild type DAT, also blocked the rescue effects of bupropion and ibogaine. These data suggest that bupropion and ibogaine promote maturation of DAT by acting as pharmacological chaperones in the ER. Importantly, both drugs rescue DAT maturation and functional activity of the DTDS-associated mutations A314V and R445C. Together, these results are the first demonstration of pharmacological chaperoning of DAT and suggest this may be a viable approach to increase DAT levels in DTDS and other conditions associated with reduced DAT function.
Comparable studies
Other experimental studies on ibogaine, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Ibogaine, a noncompetitive inhibitor of serotonin transport, acts by stabilizing the cytoplasm-facing state of the transporter. In vitro (SERT) | 2007 | Laboratory study | |
| Mechanisms of action of ibogaine and harmaline congeners based on radioligand binding studies. | 1992 | Laboratory study | |
| The mechanistic basis for noncompetitive ibogaine inhibition of serotonin and dopamine transporters. | 2012 | Experimental study | |
| Identification of a primary metabolite of ibogaine that targets serotonin transporters and elevates serotonin. | 1995 | Experimental study | |
| Ibogaine and its congeners are sigma 2 receptor-selective ligands with moderate affinity. | 1995 | Laboratory study |
Citations in the library
Cited by 8
- DARK Classics in Chemical Neuroscience: Ibogaine ACS Chemical Neuroscience September 14, 2018
- SLC6 Transporter Folding Diseases and Pharmacochaperoning. Handbook of experimental pharmacology 2018
- Tropane-Based Ibogaine Analog Rescues Folding-Deficient Serotonin and Dopamine Transporters. ACS Pharmacology & Translational Science April 9, 2021
- Main targets of ibogaine and noribogaine associated with its putative anti-addictive effects: A mechanistic overview. Journal of Psychopharmacology December 1, 2023
- Structure-Activity Relationships of Dopamine Transporter Pharmacological Chaperones. Frontiers in Cellular Neuroscience 2022
and 3 more in the library
Cites 2
- Ibogaine, a noncompetitive inhibitor of serotonin transport, acts by stabilizing the cytoplasm-facing state of the transporter. Journal of Biological Chemistry October 5, 2007
- The mechanistic basis for noncompetitive ibogaine inhibition of serotonin and dopamine transporters. Journal of Biological Chemistry May 25, 2012