Proceedings of the National Academy of Sciences of the United States of America · 2026
The role of chloride ions in serotonin transport.
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Huang Jiahui, Backer Annika, Uchendu Stacy, Bekele Bethlehem, Li Chan, Chen Qingyang, Orabi Esam A, Stix Robyn, Shide Jasper D, Zhang Yuan-Wei, Rudnick Gary, Hellsberg Eva, Forrest Lucy R
Аннотация
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.