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NBCe1 as a model carrier for understanding the structure–function properties of Na+-coupled SLC4 transporters in health and disease

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Abstract

SLC4 transporters are membrane proteins that in general mediate the coupled transport of bicarbonate (carbonate) and share amino acid sequence homology. These proteins differ as to whether they also transport Na+ and/or Cl−, in addition to their charge transport stoichiometry, membrane targeting, substrate affinities, developmental expression, regulatory motifs, and protein–protein interactions. These differences account in part for the fact that functionally, SLC4 transporters have various physiological roles in mammals including transepithelial bicarbonate transport, intracellular pH regulation, transport of Na+ and/or Cl−, and possibly water. Bicarbonate transport is not unique to the SLC4 family since the structurally unrelated SLC26 family has at least three proteins that mediate anion exchange. The present review focuses on the first of the sodium-dependent SLC4 transporters that was identified whose structure has been most extensively studied: the electrogenic Na+-base cotransporter NBCe1. Mutations in NBCe1 cause proximal renal tubular acidosis (pRTA) with neurologic and ophthalmologic extrarenal manifestations. Recent studies have characterized the important structure–function properties of the transporter and how they are perturbed as a result of mutations that cause pRTA. It has become increasingly apparent that the structure of NBCe1 differs in several key features from the SLC4 Cl−–HCO3 − exchanger AE1 whose structural properties have been well-studied. In this review, the structure–function properties and regulation of NBCe1 will be highlighted, and its role in health and disease will be reviewed in detail.

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Acknowledgments

This work was supported in part by the NIH grants DK077162 and DK058563. The author thanks Quansheng Zhu for several insightful discussions and Liyo Kao for technical help in preparation of the manuscript.

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  1. Division of Nephrology, David Geffen School of Medicine, and Brain Research Institute, UCLA, Los Angeles, CA, USA

    Ira Kurtz

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Kurtz, I. NBCe1 as a model carrier for understanding the structure–function properties of Na+-coupled SLC4 transporters in health and disease. Pflugers Arch - Eur J Physiol 466, 1501–1516 (2014). https://doi.org/10.1007/s00424-014-1448-8

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