ArticleFrontiers in neurology2015
Insights into the Modulation of Dopamine Transporter Function by Amphetamine, Orphenadrine, and Cocaine Binding.
Article in Frontiers in neurology, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 46 papers.
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Who cites it
46 citing papers in PubMed, 78 citations in OpenAlex.
- Well-Known and Novel Behavioural Risk Factors for Heart Failure.Journal of cardiovascular development and disease · 2026Review
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- Monoamine transporter ubiquitination and inward-open conformation synergistically maximize transporter endocytosis.Science advances · 2024Article
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- Allosteric modulation of serotonin and dopamine transporters: New insights from computations and experiments.Current research in physiology · 2024Article
- The Alkylamine Stimulant 1,3-Dimethylamylamine Exhibits Substrate-Like Regulation of Dopamine Transporter Function and Localization.The Journal of pharmacology and experimental therapeutics · 2023Article
- Structures and membrane interactions of native serotonin transporter in complexes with psychostimulants.Proceedings of the National Academy of Sciences of the United States of America · 2023Article
- Sigma-1 Receptor Signaling: In Search of New Therapeutic Alternatives for Cardiovascular and Renal Diseases.International journal of molecular sciences · 2023Review
- Syntaxin 1 SerScience advances · 2023Article
- Overview of the structure and function of the dopamine transporter and its protein interactions.Frontiers in physiology · 2023Review
- The complex role of inflammation and gliotransmitters in Parkinson's disease.Neurobiology of disease · 2023Review
- Effects of the N-terminal dynamics on the conformational states of human dopamine transporter.Biophysical chemistry · 2022Article
- HIDTI: integration of heterogeneous information to predict drug-target interactions.Scientific reports · 2022Article
- Allosteric Modulator KM822 Attenuates Behavioral Actions of Amphetamine inMolecular pharmacology · 2022Article
- Novel Molecular Targets of Antidepressants.Molecules (Basel, Switzerland) · 2022Review
- Illumination of serotonin transporter mechanism and role of the allosteric site.Science advances · 2021Article
- Molecular mechanisms of action of stimulant novel psychoactive substances that target the high-affinity transporter for dopamine.Neuronal signaling · 2021Review
- Proteome-Informed Machine Learning Studies of Cocaine Addiction.The journal of physical chemistry letters · 2021Article
- Smartphone-integrated colorimetric sensor array-based reader system and fluorometric detection of dopamine in male and female geriatric plasma by bluish-green fluorescent carbon quantum dots.Materials today. Bio · 2021Article
- A network of phosphatidylinositol (4,5)-bisphosphate (PIPMolecular psychiatry · 2021Article
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Authors and funding
6 authors at 2 institutions in 2 countries.
Funding
Abstract
Human dopamine (DA) transporter (hDAT) regulates dopaminergic signaling in the central nervous system by maintaining the synaptic concentration of DA at physiological levels, upon reuptake of DA into presynaptic terminals. DA translocation involves the co-transport of two sodium ions and the channeling of a chloride ion, and it is achieved via alternating access between outward-facing (OF) and inward-facing states of DAT. hDAT is a target for addictive drugs, such as cocaine, amphetamine (AMPH), and therapeutic antidepressants. Our recent quantitative systems pharmacology study suggested that orphenadrine (ORPH), an anticholinergic agent and anti-Parkinson drug, might be repurposable as a DAT drug. Previous studies have shown that DAT-substrates like AMPH or -blockers like cocaine modulate the function of DAT in different ways. However, the molecular mechanisms of modulation remained elusive due to the lack of structural data on DAT. The newly resolved DAT structure from Drosophila melanogaster opens the way to a deeper understanding of the mechanism and time evolution of DAT-drug/ligand interactions. Using a combination of homology modeling, docking analysis, molecular dynamics simulations, and molecular biology experiments, we performed a comparative study of the binding properties of DA, AMPH, ORPH, and cocaine and their modulation of hDAT function. Simulations demonstrate that binding DA or AMPH drives a structural transition toward a functional form predisposed to translocate the ligand. In contrast, ORPH appears to inhibit DAT function by arresting it in the OF open conformation. The analysis shows that cocaine and ORPH competitively bind DAT, with the binding pose and affinity dependent on the conformational state of DAT. Further assays show that the effect of ORPH on DAT uptake and endocytosis is comparable to that of cocaine.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.