The role of chloride ions in serotonin transport
- 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
2026-08-24
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.