ArticleThe Journal of biological chemistry2015
Dual Action of Zn2+ on the Transport Cycle of the Dopamine Transporter.
Article in The Journal of biological chemistry, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.
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Who cites it
27 citing papers in PubMed, 37 citations in OpenAlex.
- (N)-Methanocarba-adenosines as monoamine transporter allosteric inhibitors: Extended NEuropean journal of medicinal chemistry · 2026Article
- Zinc-Dependent Modulation of Dopamine Release and Uptake Is Altered in Parkinson's Disease Model Zebrafish.ACS chemical neuroscience · 2025Article
- Tissue zinc restoration alleviates the levodopa-induced dyskinesia via impeding ERK phosphorylation.European journal of nutrition · 2025Article
- Electrophysiological Methods to Explore the Function of Monoamine Transporters.Advances in neurobiology · 2025Review
- Association of Magnesium, Iron, Copper, and Zinc Levels with the Prevalence of Behavior Problems in Children and Adolescents.Biological trace element research · 2024Article
- Caged ZnACS chemical neuroscience · 2024Article
- Allosteric modulation of serotonin and dopamine transporters: New insights from computations and experiments.Current research in physiology · 2024Article
- Allosteric modulators of solute carrier function: a theoretical framework.Frontiers in physiology · 2023Article
- The schizophrenia-associated missense variant rs13107325 regulates dendritic spine density.Translational psychiatry · 2022Article
- Assessment of Urinary Lead (Pb) and Essential Trace Elements in Autism Spectrum Disorder: a Case-Control Study Among Preschool Children in Malaysia.Biological trace element research · 2022Article
- Cooperative Binding of Substrate and Ions Drives Forward Cycling of the Human Creatine Transporter-1.Frontiers in physiology · 2022Article
- Association of Prenatal Maternal Anemia with Tics and Tourette's Syndrome in Offspring.Journal of personalized medicine · 2021Article
- Handling of intracellular KeLife · 2021Article
- Descriptors of Secondary Active Transporter Function and How They Relate to Partial Reactions in the Transport Cycle.Membranes · 2021Article
- The high-energy transition state of the glutamate transporter homologue GltPh.The EMBO journal · 2021Article
- Zinc and Copper Brain Levels and Expression of Neurotransmitter Receptors in Two Rat ASD Models.Frontiers in molecular neuroscience · 2021Article
- Allosteric Modulation of Neurotransmitter Transporters as a Therapeutic Strategy.Trends in pharmacological sciences · 2020Review
- Kinetic Models of Secondary Active Transporters.International journal of molecular sciences · 2019Article
- A comparison of the transport kinetics of glycine transporter 1 and glycine transporter 2.The Journal of general physiology · 2019Article
- How to rescue misfolded SERT, DAT and NET: targeting conformational intermediates with atypical inhibitors and partial releasers.Biochemical Society transactions · 2019Review
Corrections and comments
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Authors and funding
6 authors at 1 institution in 1 country.
Funding
Abstract
The dopamine transporter shapes dopaminergic neurotransmission by clearing extracellular dopamine and by replenishing vesicular stores. The dopamine transporter carries an endogenous binding site for Zn(2+), but the nature of the Zn(2+)-dependent modulation has remained elusive: both, inhibition and stimulation of DAT have been reported. Here, we exploited the high time resolution of patch-clamp recordings to examine the effects of Zn(2+) on the transport cycle of DAT: we recorded peak currents associated with substrate translocation and steady-state currents reflecting the forward transport mode of DAT. Zn(2+) depressed the peak current but enhanced the steady-state current through DAT. The parsimonious explanation is preferential binding of Zn(2+) to the outward facing conformation of DAT, which allows for an allosteric activation of DAT, in both, the forward transport mode and substrate exchange mode. We directly confirmed that Zn(2+) dissociated more rapidly from the inward- than from the outward-facing state of DAT. Finally, we formulated a kinetic model for the action of Zn(2+) on DAT that emulated all current experimental observations and accounted for all previous (in part contradictory) findings. Importantly, the model predicts that the intracellular Na(+) concentration determines whether substrate uptake by DAT is stimulated or inhibited by Zn(2+). This prediction was directly verified. The mechanistic framework provided by the current model is of relevance for the rational design of allosteric activators of DAT. These are of interest for treating de novo loss-of-function mutations of DAT associated with neuropsychiatric disorders such as attention deficit hyperactivity disorder (ADHD).
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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.