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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK077162-07
Application #
8597417
Study Section
Special Emphasis Panel (KMBD)
Program Officer
Ketchum, Christian J
Project Start
2006-12-01
Project End
2016-11-30
Budget Start
2013-12-01
Budget End
2014-11-30
Support Year
7
Fiscal Year
2014
Total Cost
$301,455
Indirect Cost
$105,705
Name
University of California Los Angeles
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
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Kao, Liyo; Azimov, Rustam; Abuladze, Natalia et al. (2015) Human SLC4A11-C functions as a DIDS-stimulatable H⁺(OH⁻) permeation pathway: partial correction of R109H mutant transport. Am J Physiol Cell Physiol 308:C176-88
Shcheynikov, Nikolay; Son, Aran; Hong, Jeong Hee et al. (2015) Intracellular Cl- as a signaling ion that potently regulates Na+/HCO3- transporters. Proc Natl Acad Sci U S A 112:E329-37
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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
Kurtz, Ira (2014) Molecular mechanisms and regulation of urinary acidification. Compr Physiol 4:1737-74
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Zhu, Quansheng; Shao, Xuesi M; Kao, Liyo et al. (2013) Missense mutation T485S alters NBCe1-A electrogenicity causing proximal renal tubular acidosis. Am J Physiol Cell Physiol 305:C392-405

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