Acute regulation of the SLC26A3 congenital chloride diarrhoea anion exchanger (DRA) expressed in Xenopus oocytes.
Publication/Presentation Date
5-15-2003
Abstract
Mutations in the human SLC26A3 gene, also known as down-regulated in adenoma (hDRA), cause autosomal recessive congenital chloride-losing diarrhoea (CLD). hDRA expressed in Xenopus oocytes mediated bidirectional Cl--Cl- and Cl--HCO3- exchange. In contrast, transport of oxalate was low, and transport of sulfate and of butyrate was undetectable. Two CLD missense disease mutants of hDRA were nonfunctional in oocytes. Truncation of up to 44 C-terminal amino acids from the putatively cytoplasmic C-terminal hydrophilic domain left transport function unimpaired, but deletion of the adjacent STAS (sulfate transporter anti-sigma factor antagonist) domain abolished function. hDRA-mediated Cl- transport was insensitive to changing extracellular pH, but was inhibited by intracellular acidification and activated by NH4+ at acidifying concentrations. These regulatory responses did not require the presence of either hDRA's N-terminal cytoplasmic tail or its 44 C-terminal amino acids, but they did require more proximate residues of the C-terminal cytoplasmic domain. Although only weakly sensitive to inhibition by stilbenes, hDRA was inhibited with two orders of magnitude greater potency by the anti-inflammatory drugs niflumate and tenidap. cAMP-insensitive Cl--HCO3- exchange mediated by hDRA gained modest cAMP sensitivity when co-expressed with cystic fibrosis transmembrane conductance regulator (CFTR). Despite the absence of hDRA transcripts in human cell lines derived from CFTR patients, DRA mRNA was present at wild-type levels in proximal colon and nearly so in the distal ileum of CFTR(-/-) mice. Thus, pharmacological modulation of DRA might be a useful adjunct treatment of cystic fibrosis.
Volume
549
Issue
Pt 1
First Page
3
Last Page
19
ISSN
0022-3751
Published In/Presented At
Chernova, M. N., Jiang, L., Shmukler, B. E., Schweinfest, C. W., Blanco, P., Freedman, S. D., Stewart, A. K., & Alper, S. L. (2003). Acute regulation of the SLC26A3 congenital chloride diarrhoea anion exchanger (DRA) expressed in Xenopus oocytes. The Journal of physiology, 549(Pt 1), 3–19. https://doi.org/10.1113/jphysiol.2003.039818
Disciplines
Medicine and Health Sciences
PubMedID
12651923
Department(s)
Department of Medicine
Document Type
Article