ArticleThe Journal of biological chemistry2010
Mutations in the carboxyl-terminal SEC24 binding motif of the serotonin transporter impair folding of the transporter.
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 44 papers.
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Who cites it
44 citing papers in PubMed, 77 citations in OpenAlex.
- Optogenetic Regulation of Localization and Function of Serotonin Transporter by Modulating Its Interaction with Soluble Guanylate Cyclase.International journal of molecular sciences · 2026Article
- Alpha-methyl-para-tyrosine and amphetamine ameliorate hyperactivity in a novel mouse model of dopamine transporter deficiency syndrome.EMBO molecular medicine · 2026Article
- Deciphering Ibogaine's Matrix Pharmacology: Multiple Transporter Modulation at Serotonin Synapses.Journal of the American Chemical Society · 2026Article
- Pharmacological Evaluation of Tropane Analogues at the Serotonin Transporter.ACS chemical neuroscience · 2025Article
- Fluorescent non-canonical amino acid provides insight into the human serotonin transporter.Nature communications · 2024Article
- Serotonin Signaling through Lipid Membranes.ACS chemical neuroscience · 2024Review
- A transporter's doom or destiny:Frontiers in molecular neuroscience · 2024Review
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- Article
- Functional and Biochemical Consequences of Disease Variants in Neurotransmitter Transporters: A Special Emphasis on Folding and Trafficking Deficits.Pharmacology & therapeutics · 2021Review
- SLC6 transporter oligomerization.Journal of neurochemistry · 2021Review
- Tropane-Based Ibogaine Analog Rescues Folding-Deficient Serotonin and Dopamine Transporters.ACS pharmacology & translational science · 2021Article
- The Creatine Transporter Unfolded: A Knotty Premise in the Cerebral Creatine Deficiency Syndrome.Frontiers in synaptic neuroscience · 2020Review
- How to rescue misfolded SERT, DAT and NET: targeting conformational intermediates with atypical inhibitors and partial releasers.Biochemical Society transactions · 2019Review
- Tales of tails in transporters.Open biology · 2019Review
- Folding and Misfolding of Human Membrane Proteins in Health and Disease: From Single Molecules to Cellular Proteostasis.Chemical reviews · 2019Article
- Trafficking of the amino acid transporter BBiochimica et biophysica acta. Molecular cell research · 2019Article
- Multifaceted Regulations of the Serotonin Transporter: Impact on Antidepressant Response.Frontiers in neuroscience · 2019Review
- Big Lessons from Tiny Flies:International journal of molecular sciences · 2018Review
- Dopamine transporter oligomerization involves the scaffold domain, but spares the bundle domain.PLoS computational biology · 2018Article
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Authors and funding
7 authors at 2 institutions in 1 country.
Funding
Abstract
The serotonin transporter (SERT) is a member of the SLC6 family of solute carriers. SERT plays a crucial role in synaptic neurotransmission by retrieving released serotonin. The intracellular carboxyl terminus of various neurotransmitter transporters has been shown to be important for the correct delivery of SLC6 family members to the cell surface. Here we studied the importance of the C terminus in trafficking and folding of human SERT. Serial truncations followed by mutagenesis identified sequence spots (PG(601,602), RII(607-609)) within the C terminus relevant for export of SERT from the endoplasmic reticulum (ER). RI(607,608) is homologous to the RL-motif that in other SLC6 family members provides a docking site for the COPII component Sec24D. The primary defect resulting from mutation at PG(601,602) and RI(607,608) was impaired folding, because mutated transporters failed to bind the inhibitor [(3)H]imipramine. In contrast, when retained in the ER (e.g. by dominant negative Sar1) the wild type transporter bound [(3)H]imipramine with an affinity comparable to that of the surface-expressed transporter. SERT-RI(607,608)AA and SERT-RII(607-609)AAA were partially rescued by treatment of cells with the nonspecific chemical chaperone DMSO or the specific pharmacochaperone ibogaine (which binds to the inward facing conformation of SERT) but not by other classes of ligands (inhibitors, substrates, amphetamines). These observations (i) demonstrate an hitherto unappreciated role of the C terminus in the folding of SERT, (ii) indicates that the folding trajectory proceeds via an inward facing intermediate, and (iii) suggest a model where the RI-motif plays a crucial role in preventing premature Sec24-recruitment and export of incorrectly folded transporters.
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Registered trials
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