ArticleThe Journal of biological chemistry2010
The N terminus of monoamine transporters is a lever required for the action of amphetamines.
Article in The Journal of biological chemistry, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 93 papers.
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Who cites it
93 citing papers in PubMed, 134 citations in OpenAlex.
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- Structural and functional basis of antinociceptive action of χ-conotoxin AoIA at the noradrenaline transporter.Nature structural & molecular biology · 2026Article
- An N-terminal amphipathic helix governs activity and conformational dynamics of Nramp metal transporters.bioRxiv : the preprint server for biology · 2026Article
- Multicolor Quantum Dot Tracking Uncovers Phenotypic Rescue of DAT A559V Aberrant Diffusion Upon D2R Antagonism.ACS chemical neuroscience · 2026Article
- Cell membrane cholesterol affects serotonin transporter efflux due to altered transporter oligomerization.Molecular psychiatry · 2026Article
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- Absence of TAAR1 function increases methamphetamine-induced excitability of dorsal raphe serotonin neurons and drives binge-level methamphetamine intake.Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology · 2025Article
- Pathogenic variants at the N-terminal arginine residue 44 disrupt human GABA transporter 1 function: insights fromFrontiers in pharmacology · 2025Article
- Structure-activity relationships of serotonergic 5-MeO-DMT derivatives: insights into psychoactive and thermoregulatory properties.Molecular psychiatry · 2024Article
- MDMA for treatment of PTSD and neurorehabilitation in military populations.NeuroRehabilitation · 2024Review
- Illuminating the monoamine transporters: Fluorescently labelled ligands to study dopamine, serotonin and norepinephrine transporters.Basic & clinical pharmacology & toxicology · 2023Review
- Long QT syndrome-associated calmodulin variants disrupt the activity of the slowly activating delayed rectifier potassium channel.The Journal of physiology · 2023Article
- Structure-Activity Relationship ofACS chemical neuroscience · 2023Article
- Neuropsychopharmacology of Emerging Drugs of Abuse:International journal of molecular sciences · 2022Article
- Serotonin Transporter Ala276 Mouse: Novel Model to Assess the Neurochemical and Behavioral Impact of Thr276 Phosphorylation In Vivo.Neurochemical research · 2022Review
- Illuminating the norepinephrine transporter: fluorescent probes based on nisoxetine and talopram.RSC medicinal chemistry · 2021Article
- Tropane-Based Ibogaine Analog Rescues Folding-Deficient Serotonin and Dopamine Transporters.ACS pharmacology & translational science · 2021Article
- A Novel Biotinylated Homotryptamine Derivative for Quantum Dot Imaging of Serotonin Transporter in Live Cells.Frontiers in cellular neuroscience · 2021Article
- Neurokinin-1 Antagonism Distinguishes the Role of Norepinephrine Transporter from Dopamine Transporter in Mediating Amphetamine Behaviors.Pharmacology · 2021Article
- Heteromeric Solute Carriers: Function, Structure, Pathology and Pharmacology.Advances in experimental medicine and biology · 2021Review
33 more citing papers are in PubMed but not listed here.
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Authors and funding
14 authors at 4 institutions in 3 countries.
Funding
Abstract
The serotonin transporter (SERT) terminates neurotransmission by removing serotonin from the synaptic cleft. In addition, it is the site of action of antidepressants (which block the transporter) and of amphetamines (which induce substrate efflux). We explored the functional importance of the N terminus in mediating the action of amphetamines by focusing initially on the highly conserved threonine residue at position 81, a candidate site for phosphorylation by protein kinase C. Molecular dynamics simulations of the wild type SERT, compared with its mutations SERT(T81A) and SERT(T81D), suggested structural changes in the inner vestibule indicative of an opening of the inner vestibule. Predictions from this model (e.g. the preferential accumulation of SERT(T81A) in the inward conformation, its reduced turnover number, and a larger distance between its N and C termini) were verified. Most importantly, SERT(T81A) (and the homologous mutations in noradrenaline and dopamine) failed to support amphetamine-induced efflux, and this was not remedied by aspartate at this position. Amphetamine-induced currents through SERT(T81A) were comparable with those through the wild type transporter. Both abundant Na(+) entry and accumulation of SERT(T81A) in the inward facing conformation ought to favor amphetamine-induced efflux. Thus, we surmised that the N terminus must play a direct role in driving the transporter into a state that supports amphetamine-induced efflux. This hypothesis was verified by truncating the first 64 amino acids and by tethering the N terminus to an additional transmembrane helix. Either modification abolished amphetamine-induced efflux. We therefore conclude that the N terminus of monoamine transporters acts as a lever that sustains reverse transport.
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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.