Abstract |
Ulcerative colitis (UC) belongs to inflammatory bowel disorders, a group of gastrointestinal disorders that can produce serious recurring diarrhea in affected patients. The mechanism for UC- and inflammatory bowel disorder-associated diarrhea is not well understood. The cystic fibrosis transmembrane-conductance regulator (CFTR) chloride channel plays an important role in fluid and water transport across the intestinal mucosa. CFTR channel function is regulated in a compartmentalized manner through the formation of CFTR-containing macromolecular complexes at the plasma membrane. In this study, we demonstrate the involvement of a novel macromolecular signaling pathway that causes diarrhea in UC. We found that a nitric oxide-producing enzyme, inducible nitric oxide synthase (iNOS), is overexpressed under the plasma membrane and generates compartmentalized cGMP in gut epithelia in UC. The scaffolding protein Na(+)/H(+) exchanger regulatory factor 2 (NHERF2) bridges iNOS with CFTR, forming CFTR-NHERF2-iNOS macromolecular complexes that potentiate CFTR channel function via the nitric oxide-cGMP pathway under inflammatory conditions both in vitro and in vivo. Potential disruption of these complexes in Nherf2(-/-) mice may render them more resistant to CFTR-mediated secretory diarrhea than Nherf2(+/+) mice in murine colitis models. Our study provides insight into the mechanism of pathophysiologic occurrence of diarrhea in UC and suggests that targeting CFTR and CFTR-containing macromolecular complexes will ameliorate diarrheal symptoms and improve conditions associated with inflammatory bowel disorders.
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Authors | Kavisha Arora, Chandrima Sinha, Weiqiang Zhang, Chang Suk Moon, Aixia Ren, Sunitha Yarlagadda, Wolfgang R Dostmann, Adebowale Adebiyi, Yael Haberman, Lee A Denson, Xusheng Wang, Anjaparavanda P Naren |
Journal | The American journal of pathology
(Am J Pathol)
Vol. 185
Issue 10
Pg. 2790-804
(Oct 2015)
ISSN: 1525-2191 [Electronic] United States |
PMID | 26261085
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Copyright | Copyright © 2015 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved. |
Chemical References |
- Phosphoproteins
- Sodium-Hydrogen Exchangers
- sodium-hydrogen exchanger regulatory factor
- Cystic Fibrosis Transmembrane Conductance Regulator
- Cyclic GMP
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Topics |
- Animals
- Cell Membrane
(metabolism)
- Cells, Cultured
- Colitis, Ulcerative
(genetics, metabolism)
- Cyclic GMP
(metabolism)
- Cystic Fibrosis Transmembrane Conductance Regulator
(metabolism)
- Diarrhea
(metabolism)
- Disease Models, Animal
- Humans
- Male
- Mice, Inbred C57BL
- Mice, Knockout
- Phosphoproteins
(metabolism)
- Signal Transduction
(physiology)
- Sodium-Hydrogen Exchangers
(metabolism)
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