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Molecular mechanism of regulation of villus cell Na-K-ATPase in the chronically inflamed mammalian small intestine.

Abstract
Na-K-ATPase located on the basolateral membrane (BLM) of intestinal epithelial cells provides a favorable intracellular Na+ gradient to promote all Na dependent co-transport processes across the brush border membrane (BBM). Down-regulation of Na-K-ATPase activity has been postulated to alter the absorption via Na-solute co-transporters in human inflammatory bowel disease (IBD). Further, the altered activity of a variety of Na-solute co-transporters in intact villus cells has been reported in animal models of chronic enteritis. But the molecular mechanism of down-regulation of Na-K-ATPase is not known. In the present study, using a rabbit model of chronic intestinal inflammation, which resembles human IBD, Na-K-ATPase in villus cells was shown to decrease. The relative mRNA abundance of α-1 and β-1 subunits was not altered in villus cells during chronic intestinal inflammation. Similarly, the protein levels of these subunits were also not altered in villus cells during chronic enteritis. However, the BLM concentration of α-1 and β-1 subunits was diminished in the chronically inflamed intestinal villus cells. An ankyrin-spectrin skeleton is necessary for the proper trafficking of Na-K-ATPase to the BLM of the cell. In the present study, ankyrin expression was markedly diminished in villus cells from the chronically inflamed intestine resulting in depolarization of ankyrin-G protein. The decrease of Na-K-ATPase activity was comparable to that seen in ankyrin knockdown IEC-18 cells. Therefore, altered localization of Na-K-ATPase as a result of transcriptional down-regulation of ankyrin-G mediates the down-regulation of Na-K-ATPase activity during chronic intestinal inflammation.
AuthorsProsenjit Saha, Palanikumar Manoharan, Subha Arthur, Shanmuga Sundaram, Ramesh Kekuda, Uma Sundaram
JournalBiochimica et biophysica acta (Biochim Biophys Acta) Vol. 1848 Issue 2 Pg. 702-11 (Feb 2015) ISSN: 0006-3002 [Print] Netherlands
PMID25462166 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
CopyrightCopyright © 2014 Elsevier B.V. All rights reserved.
Chemical References
  • Actins
  • Ankyrins
  • Protein Isoforms
  • Protein Subunits
  • Sodium-Potassium-Exchanging ATPase
Topics
  • Actins (genetics, metabolism)
  • Animals
  • Ankyrins (genetics, metabolism)
  • Cell Membrane (chemistry, metabolism)
  • Cell Polarity
  • Chronic Disease
  • Disease Models, Animal
  • Epithelial Cells (chemistry, metabolism, pathology)
  • Gene Expression Regulation
  • Humans
  • Inflammatory Bowel Diseases (genetics, metabolism, pathology)
  • Intestine, Small (chemistry, metabolism, pathology)
  • Male
  • Microvilli (chemistry, metabolism, pathology)
  • Protein Isoforms (genetics, metabolism)
  • Protein Subunits (genetics, metabolism)
  • Rabbits
  • Sodium-Potassium-Exchanging ATPase (genetics, metabolism)

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