title: 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.
authors.affiliation: Department of Clinical and Translational Sciences, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV 25701, USA.
authors.forename: Prosenjit
authors.initials: P
authors.lastname: Saha
authors.affiliation: Department of Clinical and Translational Sciences, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV 25701, USA.
authors.forename: Palanikumar
authors.initials: P
authors.lastname: Manoharan
authors.affiliation: Department of Clinical and Translational Sciences, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV 25701, USA.
authors.forename: Subha
authors.initials: S
authors.lastname: Arthur
authors.affiliation: Department of Clinical and Translational Sciences, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV 25701, USA.
authors.forename: Shanmuga
authors.initials: S
authors.lastname: Sundaram
authors.affiliation: Department of Clinical and Translational Sciences, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV 25701, USA.
authors.forename: Ramesh
authors.initials: R
authors.lastname: Kekuda
authors.affiliation: Department of Clinical and Translational Sciences, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV 25701, USA. Electronic address: sundaramu@marshall.edu.
authors.forename: Uma
authors.initials: U
authors.lastname: Sundaram
mesh_terms: D000199:Actins / Q000235:genetics / Q000378:metabolism; D000818:Animals; D017487:Ankyrins / Q000235:genetics* / Q000378:metabolism; D002462:Cell Membrane / Q000737:chemistry / Q000378:metabolism*; D016764:Cell Polarity; D002908:Chronic Disease; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000737:chemistry / Q000378:metabolism* / Q000473:pathology; D005786:Gene Expression Regulation; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D007421:Intestine, Small / Q000737:chemistry / Q000378:metabolism / Q000473:pathology; D008297:Male; D008871:Microvilli / Q000737:chemistry / Q000378:metabolism* / Q000473:pathology; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D021122:Protein Subunits / Q000235:genetics* / Q000378:metabolism; D011817:Rabbits; D000254:Sodium-Potassium-Exchanging ATPase / Q000235:genetics* / Q000378:metabolism
chemical_list: D000199:Actins; D017487:Ankyrins; D020033:Protein Isoforms; D021122:Protein Subunits; D000254:Sodium-Potassium-Exchanging ATPase
keywords: Ankyrin; Chronic intestinal inflammation; Inflammatory bowel disease; Na-K-ATPase; Na-nutrient co-transport; Villus cell