ArticleThe Journal of biological chemistry2014
The second sodium site in the dopamine transporter controls cation permeation and is regulated by chloride.
Article in The Journal of biological chemistry, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 31 papers.
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Who cites it
31 citing papers in PubMed, 50 citations in OpenAlex.
- Unlocking the Potential of High-Quality Dopamine Transporter Pharmacological Data: Advancing Robust Machine Learning-Based QSAR Modeling.Advances in neurobiology · 2025Review
- Substrate Binding and Conformational Dynamics of the Monoamine Transporters.Advances in neurobiology · 2025Review
- Fluorescent non-canonical amino acid provides insight into the human serotonin transporter.Nature communications · 2024Article
- Article
- The Structural Basis of the Activity Cliff in Modafinil-Based Dopamine Transporter Inhibitors.Biomolecules · 2024Article
- Review
- Structural and functional perspectives on interactions between synthetic cathinones and monoamine transporters.Advances in pharmacology (San Diego, Calif.) · 2024Article
- Functional characterization of dopamine and norepinephrine transport across the apical and basal plasma membranes of the human placental syncytiotrophoblast.Scientific reports · 2022Article
- Effects of the N-terminal dynamics on the conformational states of human dopamine transporter.Biophysical chemistry · 2022Article
- Article
- Investigating the Mechanism of Sodium Binding to SERT Using Direct Simulations.Frontiers in cellular neuroscience · 2021Article
- Bile Acids Gate Dopamine Transporter Mediated Currents.Frontiers in chemistry · 2021Article
- Increased Sodium Concentration in Substantia Nigra in Early Parkinson's Disease: A Preliminary Study With Ultra-High Field (7T) MRI.Frontiers in neurology · 2021Article
- Substrate-induced conformational dynamics of the dopamine transporter.Nature communications · 2019Article
- Using CaPsychopharmacology · 2019Review
- Insights into the mechanism and pharmacology of neurotransmitter sodium symporters.Current opinion in structural biology · 2019Review
- Neuropsychiatric disease-associated genetic variants of the dopamine transporter display heterogeneous molecular phenotypes.The Journal of biological chemistry · 2018Article
- Competition between LiChemical science · 2018Article
- Substrate-bound outward-open structure of a NaNature communications · 2018Article
- Threonine 67 is a key component in the coupling of the NSS amino acid transporter KAAT1.Biochimica et biophysica acta. Biomembranes · 2018Article
Corrections and comments
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Authors and funding
5 authors at 3 institutions in 2 countries.
Funding
Abstract
The dopamine transporter (DAT) belongs to the family of neurotransmitter:sodium symporters and controls dopamine (DA) homeostasis by mediating Na(+)- and Cl(-)-dependent reuptake of DA. Here we used two-electrode voltage clamp measurements in Xenopus oocytes together with targeted mutagenesis to investigate the mechanistic relationship between DAT ion binding sites and transporter conductances. In Li(+), DAT displayed a cocaine-sensitive cation leak current ∼10-fold larger than the substrate-induced current in Na(+). Mutation of Na(+) coordinating residues in the first (Na1) and second (Na2) binding sites suggested that the Li(+) leak depends on Li(+) interaction with Na2 rather than Na1. DA caused a marked inhibition of the Li(+) leak, consistent with the ability of the substrate to interact with the Li(+)-occupied state of the transporter. The leak current in Li(+) was also potently inhibited by low millimolar concentrations of Na(+), which according to our mutational data conceivably depended on high affinity binding to Na1. The Li(+) leak was further regulated by Cl(-) that most likely increases Li(+) permeation by allosterically lowering Na2 affinity. Interestingly, mutational lowering of Na2 affinity by substituting Asp-420 with asparagine dramatically increased cation permeability in Na(+) to a level higher than seen in Li(+). In addition to reveal a functional link between the bound Cl(-) and the cation bound in the Na2 site, the data support a key role of Na2 in determining cation permeability of the transporter and thereby possibly in regulating the opening probability of the inner gate.
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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.