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Updated: Aug 26, 2026

Thermostabilization, Expression, Purification, and Crystallization of the Human Serotonin Transporter Bound to S-citalopram
Published on: November 27, 2016
The role of chloride ions in serotonin transport
Jiahui Huang1,2, Annika Backer1, Stacy Uchendu3
1Computational Structural Biology Section, National Institutes of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892.
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.
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