ArticleMolecular pharmacology2011
Site-directed mutations near transmembrane domain 1 alter conformation and function of norepinephrine and dopamine transporters.
Article in Molecular pharmacology, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Who cites it
17 citing papers in PubMed, 22 citations in OpenAlex.
- The Impact of Neurotransmitters on the Neurobiology of Neurodegenerative Diseases.International journal of molecular sciences · 2023Review
- Atorvastatin differentially regulates the interactions of cocaine and amphetamine with dopamine transporters.Neuropharmacology · 2023Article
- Amphetamine Stimulates Endocytosis of the Norepinephrine and Neuronal Glutamate Transporters in Cultured Locus Coeruleus Neurons.Neurochemical research · 2020Article
- Insights into the mechanism and pharmacology of neurotransmitter sodium symporters.Current opinion in structural biology · 2019Review
- Model systems for analysis of dopamine transporter function and regulation.Neurochemistry international · 2019Review
- The dopamine transporter: An unrecognized nexus for dysfunctional peripheral immunity and signaling in Parkinson's Disease.Brain, behavior, and immunity · 2018Review
- Targeting of dopamine transporter to filopodia requires an outward-facing conformation of the transporter.Scientific reports · 2017Article
- Dopamine Transporter Amino and Carboxyl Termini Synergistically Contribute to Substrate and Inhibitor Affinities.The Journal of biological chemistry · 2017Article
- Reciprocal Phosphorylation and Palmitoylation Control Dopamine Transporter Kinetics.The Journal of biological chemistry · 2015Article
- Molecular basis for the interaction of the mammalian amino acid transporters B0AT1 and B0AT3 with their ancillary protein collectrin.The Journal of biological chemistry · 2015Article
- An N-terminal threonine mutation produces an efflux-favorable, sodium-primed conformation of the human dopamine transporter.Molecular pharmacology · 2014Article
- Mechanisms of dopamine transporter regulation in normal and disease states.Trends in pharmacological sciences · 2013Review
- Mutation of tyrosine 470 of human dopamine transporter is critical for HIV-1 Tat-induced inhibition of dopamine transport and transporter conformational transitions.Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology · 2013Article
- Bath salts components mephedrone and methylenedioxypyrovalerone (MDPV) act synergistically at the human dopamine transporter.British journal of pharmacology · 2013Article
- Phosphorylation of dopamine transporter serine 7 modulates cocaine analog binding.The Journal of biological chemistry · 2013Article
- Dopamine transporter phosphorylation site threonine 53 regulates substrate reuptake and amphetamine-stimulated efflux.The Journal of biological chemistry · 2012Article
- SLC6 transporters: structure, function, regulation, disease association and therapeutics.Molecular aspects of medicineReview
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Authors and funding
5 authors at 1 institution in 1 country.
Funding
Abstract
The human dopamine and norepinephrine transporters (hDAT and hNET, respectively) control neurotransmitter levels within the synaptic cleft and are the site of action for amphetamine (AMPH) and cocaine. We investigated the role of a threonine residue within the highly conserved and putative phosphorylation sequence RETW, located just before transmembrane domain 1, in regulating hNET and hDAT function. The Thr residue was mutated to either alanine or aspartate. Similar to the inward facing T62D-hDAT, T58D-hNET demonstrated reduced [(3)H]DA uptake but enhanced basal DA efflux compared with hNET with no further effect of AMPH. The mutations had profound effects on substrate function and binding. The potency of substrates to inhibit [(3)H]DA uptake and compete with radioligand binding was increased in T→A and/or T→D mutants. Substrates, but not inhibitors, demonstrated temperature-sensitive effects of binding. Neither the functional nor the binding potency for hNET blockers was altered from wild type in hNET mutants. There was, however, a significant reduction in potency for cocaine and benztropine to inhibit [(3)H]DA uptake in T62D-hDAT compared with hDAT. The potency of these drugs to inhibit [(3)H](-)-2-β-carbomethoxy-3-β-(4-fluorophenyl)tropane-1,5-napthalenedisulfonate (WIN35,428) binding was not increased, demonstrating a discordance between functional and binding site effects. Taken together, these results concur with the notion that the T→D mutation in RETW alters the preferred conformation of both hNET and hDAT to favor one that is more inward facing. Although substrate activity and binding are primarily altered in this conformation, the function of inhibitors with distinct structural characteristics may also be affected.
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