ArticleMolecular pharmacology2009
A juxtamembrane mutation in the N terminus of the dopamine transporter induces preference for an inward-facing conformation.
Article in Molecular pharmacology, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 49 papers.
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Who cites it
49 citing papers in PubMed, 63 citations in OpenAlex.
- Effects of SRI-32743, a Novel Quinazoline Structure-Based Compound, on HIV-1 Tat and Cocaine Interaction with Norepinephrine Transporter.International journal of molecular sciences · 2024Article
- Atorvastatin differentially regulates the interactions of cocaine and amphetamine with dopamine transporters.Neuropharmacology · 2023Article
- Modeling dopamine dysfunction in autism spectrum disorder: From invertebrates to vertebrates.Neuroscience and biobehavioral reviews · 2022Review
- Molecular mechanisms of action of stimulant novel psychoactive substances that target the high-affinity transporter for dopamine.Neuronal signaling · 2021Review
- Heteromeric Solute Carriers: Function, Structure, Pathology and Pharmacology.Advances in experimental medicine and biology · 2021Review
- Dopamine D2 autoreceptor interactome: Targeting the receptor complex as a strategy for treatment of substance use disorder.Pharmacology & therapeutics · 2020Review
- Human Serotonin Transporter Coding Variation Establishes Conformational Bias with Functional Consequences.ACS chemical neuroscience · 2019Article
- Tales of tails in transporters.Open biology · 2019Review
- Mutational effects of human dopamine transporter at tyrosine88, lysine92, and histidine547 on basal and HIV-1 Tat-inhibited dopamine transport.Scientific reports · 2019Article
- Quantitative Assessment of the Energetics of Dopamine Translocation by Human Dopamine Transporter.The journal of physical chemistry. B · 2018Article
- The dopamine transporter: An unrecognized nexus for dysfunctional peripheral immunity and signaling in Parkinson's Disease.Brain, behavior, and immunity · 2018Review
- The role of human dopamine transporter in NeuroAIDS.Pharmacology & therapeutics · 2018Review
- Molecular Mechanism and Dynamics ofACS omega · 2017Article
- Dopamine transporter phosphorylation site threonine 53 is stimulated by amphetamines and regulates dopamine transport, efflux, and cocaine analog binding.The Journal of biological chemistry · 2017Article
- HIV, Tat and dopamine transmission.Neurobiology of disease · 2017Review
- Dopamine Transporter Amino and Carboxyl Termini Synergistically Contribute to Substrate and Inhibitor Affinities.The Journal of biological chemistry · 2017Article
- A Markov State-based Quantitative Kinetic Model of Sodium Release from the Dopamine Transporter.Scientific reports · 2017Article
- Computational modeling of human dopamine transporter structures, mechanism and its interaction with HIV-1 transactivator of transcription.Future medicinal chemistry · 2016Article
- Conformational Dynamics on the Extracellular Side of LeuT Controlled by Na+ and K+ Ions and the Protonation State of Glu290.The Journal of biological chemistry · 2016Article
- Structure and Dynamics Study of LeuT Using the Markov State Model and Perturbation Response Scanning Reveals Distinct Ion Induced Conformational States.The journal of physical chemistry. B · 2016Article
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Authors and funding
10 authors at 4 institutions in 1 country.
Funding
Abstract
The human dopamine transporter (hDAT) regulates synaptic dopamine (DA) levels and is the site of action of abused and therapeutic drugs. Here we study the effect of a threonine residue (Thr62 in hDAT) that is highly conserved within a canonical phosphorylation site (RETW) in the juxtamembrane N-terminal region of monoamine transporters. In stably transfected human embryonic kidney 293T cells, expression of T62D-hDAT was reduced compared with hDAT or T62A-hDAT. T62D-hDAT displayed dramatically reduced [(3)H]dopamine up-take but exhibited a higher basal dopamine efflux compared with hDAT or T62A-hDAT, as determined by measurements of [(3)H]dopamine efflux and amperometry. The high constitutive efflux in T62D-hDAT precluded the measurement of amphetamine-stimulated [(3)H]dopamine efflux, but when dopamine was added internally into voltage-clamped T62D-hDAT cells, amphetamine-induced efflux comparable with hDAT was detected by amperometry. In accordance with findings that Zn(2+) can rescue reduced DA uptake in mutant transporters that are predominantly inward-facing, micromolar concentrations of Zn(2+) markedly potentiated [(3)H]dopamine uptake in T62D-hDAT and permitted the measurement of amphetamine-stimulated dopamine efflux. These results suggest that T62D-hDAT prefers an inward-facing conformation in the transition between inward- and outward-facing conformations. For T62A-hDAT, however, the measured 50% reduction in both [(3)H]dopamine uptake and [(3)H]dopamine efflux was consistent with a slowed transition between inward- and outward-facing conformations. The mechanism underlying the important functional role of Thr62 in hDAT activity suggested by these findings is examined in a structural context using dynamic simulations of a three-dimensional molecular model of DAT.
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