Authors
Jiahui Huang, Annika Backer, Stacy Uchendu, Bethlehem Bekele, Chan Li, Qingyang Chen, Esam A Orabi, Robyn Stix, Jasper D Shide, Yuan-Wei Zhang, Gary Rudnick, Eva Hellsberg, Lucy R Forrest
Published in
Proceedings of the National Academy of Sciences of the United States of America. Volume 123. Issue 35. Pages e2605760123. Epub Aug 24, 2026.
Abstract
The human serotonin (5-HT+) transporter SERT facilitates 5-HT+ transport into cells by coupling it to Na+ symport and K+ antiport. Although extracellular Cl- is also essential for transport, Cl- cotransport has been disputed, raising questions about the role of Cl- ions and why they are required. We show that Cl- gradients do not impact 5-HT+ accumulation, indicating that Cl- does not provide a driving force for uptake and arguing against stoichiometric Cl- symport. The presence of Cl- had only a small effect on Na+-mediated cytoplasmic pathway closure but markedly reduced the accessibility of residues in the extracellular pathway, consistent with modulation of the outward-facing states. Simulations illustrate that Cl- interacts strongly with a bound Na+ ion and stabilizes helix packing on the extracellular side. We propose that Cl- acts as an essential architectural cofactor by enhancing Na+ affinity and interactions between helices, thereby facilitating transport-related conformational transitions.
PMID:
42636362
Bibliographic data and abstract were imported from PubMed on 25 Aug 2026.
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