The SLC4 family of membrane transporters mediate Cl--HCO3- and Na+-driven Cl--HCO3- exchange, and Na+- HCO3- cotransport (electrogenic, electroneutral). The importance of these transporters in mammalian cell biology is highlighted by the phenotypic abnormalities resulting from spontaneous SLC4 mutations in humans and targeted deletions in mice. Abnormalities in either the function and/or plasma membrane expression of certain members of the SLC4 family are the cause of various genetic diseases in man. Of the known SLC4 genes, SLC4A4 (NBCe1) and SLC4A1 (AE1) play key roles in mediating renal bicarbonate absorption, and the maintenance of systemic and intracellular acid-base balance. Mutations in NBCe1 impair both proximal tubule and extrarenal acid-base transport. In preliminary experiments, we have begun to examine the structural basis for the functional properties of NBCe1 and have made several novel discoveries that form the background for this proposal. Preliminary studies of the anion binding machinery of NBCe1 have led to the novel finding that it functions as both an electrogenic Na+-CO32- cotransporter and an electroneutral Na+-NO3- cotransporter. Mutations in NBCe1 that cause renal tubular acidosis also inhibit NO3- transport. Based on these new findings, NBCe1 must now be considered to be a bi-functional transporter that mediates carbonate and nitrate transport in the proximal tubule, and potentially in extrarenal tissues where it is expressed. Given our findings that NBCe1 transports Na+-CO32- and Na+-NO3-, the role of the kidney and the proximal tubule in inter-organ NO3- cycling and whole body NO3- balance becomes particularly relevant both from a physiologic and clinical standpoint. The proposal will characterize the architectural basis for the function of NBCe1 as both an electrogenic Na+-CO32- cotransporter and an electroneutral Na+-NO3- cotransporter, the perturbation of these functional properties in disease, and the role of NBCe1 and the proximal tubule in NO3- transport.

Public Health Relevance

Diseases involving NBCe1 (renal tubular acidosis) affect the ability of the kidney and extrarenal organs from maintaining the normal chemistry of the cells in the body that results in organ damage. The results of this grant will greatly increase our understanding of how NBCe1 functions in health and disease.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (KMBD)
Program Officer
Ketchum, Christian J
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California Los Angeles
Internal Medicine/Medicine
Schools of Medicine
Los Angeles
United States
Zip Code
Wen, Xin; Kurtz, Ira; Paine, Michael L (2014) Prevention of the disrupted enamel phenotype in Slc4a4-null mice using explant organ culture maintained in a living host kidney capsule. PLoS One 9:e97318
Kurtz, Ira (2014) NBCe1 as a model carrier for understanding the structure-function properties of Na? -coupled SLC4 transporters in health and disease. Pflugers Arch 466:1501-16
Lacruz, R S; Smith, C E; Kurtz, I et al. (2013) New paradigms on the transport functions of maturation-stage ameloblasts. J Dent Res 92:122-9
Jiang, Jiansen; Magilnick, Nathaniel; Tsirulnikov, Kirill et al. (2013) Single particle electron microscopy analysis of the bovine anion exchanger 1 reveals a flexible linker connecting the cytoplasmic and membrane domains. PLoS One 8:e55408
Kurtz, Ira; Zhu, Quansheng (2013) Structure, function, and regulation of the SLC4 NBCe1 transporter and its role in causing proximal renal tubular acidosis. Curr Opin Nephrol Hypertens 22:572-83
Zhu, Quansheng; Liu, Weixin; Kao, Liyo et al. (2013) Topology of NBCe1 protein transmembrane segment 1 and structural effect of proximal renal tubular acidosis (pRTA) S427L mutation. J Biol Chem 288:7894-906
Lacruz, Rodrigo S; Smith, Charles E; Moffatt, Pierre et al. (2012) Requirements for ion and solute transport, and pH regulation during enamel maturation. J Cell Physiol 227:1776-85
Burette, Alain C; Weinberg, Richard J; Sassani, Patrick et al. (2012) The sodium-driven chloride/bicarbonate exchanger in presynaptic terminals. J Comp Neurol 520:1481-92
Lacruz, Rodrigo S; Smith, Charles E; Bringas Jr, Pablo et al. (2012) Identification of novel candidate genes involved in mineralization of dental enamel by genome-wide transcript profiling. J Cell Physiol 227:2264-75
Kao, Liyo; Kurtz, Lisa M; Shao, Xuesi et al. (2011) Severe neurologic impairment in mice with targeted disruption of the electrogenic sodium bicarbonate cotransporter NBCe2 (Slc4a5 gene). J Biol Chem 286:32563-74

Showing the most recent 10 out of 25 publications