ArticleThe Journal of biological chemistry2010
Transmembrane domain 6 of the human serotonin transporter contributes to an aqueously accessible binding pocket for serotonin and the psychostimulant 3,4-methylene dioxymethamphetamine.
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 22 papers.
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Who cites it
22 citing papers in PubMed, 30 citations in OpenAlex.
- Duloxetine inhibits effects of MDMA ("ecstasy") in vitro and in humans in a randomized placebo-controlled laboratory study.PloS one · 2012Trial
- SLC6A1 variant pathogenicity, molecular function and phenotype: a genetic and clinical analysis.Brain : a journal of neurology · 2023Article
- Serotonin Transporter Ala276 Mouse: Novel Model to Assess the Neurochemical and Behavioral Impact of Thr276 Phosphorylation In Vivo.Neurochemical research · 2022Review
- Structure-Function of the High Affinity Substrate Binding Site (S1) of Human Norepinephrine Transporter.Frontiers in pharmacology · 2020Article
- Article
- Aromatic Bromination Abolishes the Psychomotor Features and Pro-social Responses of MDMA ("Ecstasy") in Rats and Preserves Affinity for the Serotonin Transporter (SERT).Frontiers in pharmacology · 2019Article
- Article
- A Conserved Role for Serotonergic Neurotransmission in Mediating Social Behavior in Octopus.Current biology : CB · 2018Article
- Inhibition of the Serotonin Transporter Is Altered by Metabolites of Selective Serotonin and Norepinephrine Reuptake Inhibitors and Represents a Caution to Acute or Chronic Treatment Paradigms.ACS chemical neuroscience · 2017Article
- Antagonist-induced conformational changes in dopamine transporter extracellular loop two involve residues in a potential salt bridge.Neurochemistry international · 2014Article
- Extracellular loop 3 of the noradrenaline transporter contributes to substrate and inhibitor selectivity.Naunyn-Schmiedeberg's archives of pharmacology · 2014Article
- Synthesis, antidepressant evaluation and docking studies of long-chain alkylnitroquipazines as serotonin transporter inhibitors.Chemical biology & drug design · 2013Article
- Comparative modeling of the human monoamine transporters: similarities in substrate binding.ACS chemical neuroscience · 2013Article
- 4-(4-(dimethylamino)phenyl)-1-methylpyridinium (APP+) is a fluorescent substrate for the human serotonin transporter.The Journal of biological chemistry · 2012Article
- Substrate binding and translocation of the serotonin transporter studied by docking and molecular dynamics simulations.Journal of molecular modeling · 2012Article
- Structures of LeuT in bicelles define conformation and substrate binding in a membrane-like context.Nature structural & molecular biology · 2012Article
- Molecular mechanism of serotonin transporter inhibition elucidated by a new flexible docking protocol.European journal of medicinal chemistry · 2012Article
- A conserved asparagine residue in transmembrane segment 1 (TM1) of serotonin transporter dictates chloride-coupled neurotransmitter transport.The Journal of biological chemistry · 2011Article
- Transgenic elimination of high-affinity antidepressant and cocaine sensitivity in the presynaptic serotonin transporter.Proceedings of the National Academy of Sciences of the United States of America · 2011Article
- Monoamine transporters: vulnerable and vital doorkeepers.Progress in molecular biology and translational science · 2011Review
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Authors and funding
3 authors at 2 institutions in 1 country.
Funding
Abstract
The plasma membrane serotonin (5-HT) transporter (SERT, SLC6A4) clears 5-HT after release at nerve termini and is targeted by both antidepressant medications and psychostimulants (e.g. MDMA, cocaine). Homology modeling of human SERT (hSERT), based on high resolution structures of the microbial SLC6 family member LeuT(Aa), along with biochemical studies of wild type and mutant transporters, predicts transmembrane (TM) domains 1, 3, 6, and 8 comprise the 5-HT-binding pocket. We utilized the substituted cysteine accessibility method along with surface and site-specific biotinylation to probe TM6 for aqueous accessibility and differential interactions with 5-HT and psychostimulants. Our results are consistent with TM6 being composed of an aqueous-accessible, alpha-helical extracellular domain (TM6a) that is separated by a central, unwound section from a cytoplasmically localized domain (TM6b) with limited aqueous accessibility. The substitution G338C appears to lock hSERT in an outward-facing conformation that, although accessible to aminoethylmethanethiosulfonate-biotin, 5-HT, and citalopram, is incapable of inward 5-HT transport. Transport of 5-HT by G338C can be partially restored by the TM1 mutation Y95F. With regard to methanethiosulfonate (MTS) inactivation of uptake, TM6a Cys mutants demonstrate Na(+)-dependent [2-(trimethylammonium)ethyl]-MTS sensitivity. Studies with the centrally located substitution S336C reveal features of a common binding pocket for 5-HT and 3,4-methylenedioxymethamphetamine (MDMA). Interestingly, the substitution I333C reveals an MDMA-induced conformation not observed with 5-HT. In the context of prior studies on TM1, our findings document shared and unique features of TM6 contributing to hSERT aqueous accessibility, ligand recognition, and conformational dynamics.
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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.