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Annual Review of Physiology

Volume 87, 2025

Chloride-Dependent Cation Transport via Carriers at Atomic Resolution

  • Eric Delpire1
  • Department of Anesthesiology and Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee, USA; email: [email protected]
  • Vol. 87:397-419 (Volume publication date February 2025)
  • Copyright © 2025 by the author(s).
    This work is licensed under a Creative Commons Attribution 4.0 International License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. See credit lines of images or other third-party material in this article for license information.

Abstract

The family of genes encodes electroneutral Cl−-dependent cation transporters (i.e., Na-Cl, K-Cl, Na-K-2Cl cotransporters), which play significant roles in maintaining cell and body homeostasis. Recent resolution of their structures at the atomic level provides a new understanding how these transporters operate in health and disease and how they are targeted for therapeutic intervention. Overall, the SLC12 transporter cryo-EM structures confirm some key features established by traditional biochemical and molecular methods, such as the presence of 12 transmembrane domains and the formation of a functional dimer. Study of these structures also uncovers previously unknown features, such as the presence of strategic salt bridges that explain why transporters are stabilized in specific conformations. The cryo-EM structures show similarities with other transport protein structures, especially regarding the position of the cations. The structures also pose challenging questions regarding the number of ions bound and the strict electroneutrality that is conventional understanding.

Keyword(s): K-Cl cotransporter, loop diuretics, Na-Cl cotransporter, Na-K-2Cl cotransporter, thiazide diuretics
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2025-02-10
2025-06-22
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Chloride-Dependent Cation Transport via SLC12 Carriers at Atomic Resolution
Annual Review of Physiology 87, 397 (2025); https://doi.org/10.1146/annurev-physiol-022624-020130
/content/journals/10.1146/annurev-physiol-022624-020130
/content/journals/10.1146/annurev-physiol-022624-020130
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