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The role of Na+-coupled bicarbonate transporters (NCBT) in health and disease

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Abstract

Cellular and organism survival depends upon the regulation of pH, which is regulated by highly specialized cell membrane transporters, the solute carriers (SLC) (For a comprehensive list of the solute carrier family members, see: https://www.bioparadigms.org/slc/). The SLC4 family of bicarbonate (HCO3−) transporters consists of ten members, sorted by their coupling to either sodium (NBCe1, NBCe2, NBCn1, NBCn2, NDCBE), chloride (AE1, AE2, AE3), or borate (BTR1). The ionic coupling of SLC4A9 (AE4) remains controversial. These SLC4 bicarbonate transporters may be controlled by cellular ionic gradients, cellular membrane voltage, and signaling molecules to maintain critical cellular and systemic pH (acid–base) balance. There are profound consequences when blood pH deviates even a small amount outside the normal range (7.35–7.45). Chiefly, Na+-coupled bicarbonate transporters (NCBT) control intracellular pH in nearly every living cell, maintaining the biological pH required for life. Additionally, NCBTs have important roles to regulate cell volume and maintain salt balance as well as absorption and secretion of acid–base equivalents. Due to their varied tissue expression, NCBTs have roles in pathophysiology, which become apparent in physiologic responses when their expression is reduced or genetically deleted. Variations in physiological pH are seen in a wide variety of conditions, from canonically acid–base related conditions to pathologies not necessarily associated with acid–base dysfunction such as cancer, glaucoma, or various neurological diseases. The membranous location of the SLC4 transporters as well as recent advances in discovering their structural biology makes them accessible and attractive as a druggable target in a disease context. The role of sodium-coupled bicarbonate transporters in such a large array of conditions illustrates the potential of treating a wide range of disease states by modifying function of these transporters, whether that be through inhibition or enhancement.

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Notes

  1. For further information on NBCe1’s role in cancer, see below section on cancer.

  2. As multiple NBCTs are implicated in various cancers, these are discussed together in the Cancer section.

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Acknowledgements

This review in part helped fulfill degree requirements (SRH) for Mayo Clinic Graduate School of Biomedical Sciences, Biochemistry and Molecular Biology Track, Mayo Clinic, Rochester, MN. We thank Drs. Peter C. Harris, Aleksey Matveyenko, and Lisa Schimmenti for guidance and comments on the manuscript.

Funding

This work was supported by DK057061, DK101405, DK128844, DK129897, and the Mayo Foundation. The Kato laboratory work was supported by Japan Society for the Promotion of Science (grant number 21H02281) and Laboratory for Design of Social Innovation in Global Networks (DLab), Tokyo Institute of Technology, Japan.

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Authors and Affiliations

  1. Physiology & Biomedical Engineering, Mayo Clinic College of Medicine & Science, 200 1st Street SW, Rochester, MN 55905, USA

    Shannon R. Holmberg & Michael F. Romero

  2. Biochemistry & Molecular Biology, Mayo Clinic College of Medicine & Science, 200 1st Street SW, Rochester, MN, USA

    Shannon R. Holmberg

  3. School of Life Science and Technology, Tokyo Institute of Technology, Midori-Ku, Yokohama, 226-8501, Japan

    Yohei Sakamoto & Akira Kato

  4. Nephrology & Hypertension, Mayo Clinic College of Medicine & Science, 200 1st Street SW, Rochester, MN, USA

    Michael F. Romero

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S.H. and M.R wrote the main manuscript text and A.K. and Y.S. provided the details of the evolutionary components. All authors reviewed the final manuscript.

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Holmberg, S.R., Sakamoto, Y., Kato, A. et al. The role of Na+-coupled bicarbonate transporters (NCBT) in health and disease. Pflugers Arch - Eur J Physiol 476, 479–503 (2024). https://doi.org/10.1007/s00424-024-02937-w

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