Altered cGMP dynamics at the plasma membrane contribute to diarrhea in ulcerative colitis.
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.
Division of Pulmonary Medicine, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Department of Physiology, University of Tennessee Health Science Center, Memphis, Tennessee.
Kavisha
K
Arora
Department of Physiology, University of Tennessee Health Science Center, Memphis, Tennessee.
Chandrima
C
Sinha
Department of Physiology, University of Tennessee Health Science Center, Memphis, Tennessee; Department of Pediatrics, University of Tennessee Health Science Center, Memphis, Tennessee.
Weiqiang
W
Zhang
Division of Pulmonary Medicine, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Department of Physiology, University of Tennessee Health Science Center, Memphis, Tennessee.
Chang Suk
CS
Moon
Department of Physiology, University of Tennessee Health Science Center, Memphis, Tennessee.
Aixia
A
Ren
Division of Pulmonary Medicine, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Department of Physiology, University of Tennessee Health Science Center, Memphis, Tennessee.
Sunitha
S
Yarlagadda
Department of Pharmacology, University of Vermont, Burlington, Vermont.
Wolfgang R
WR
Dostmann
Department of Physiology, University of Tennessee Health Science Center, Memphis, Tennessee.
Adebowale
A
Adebiyi
Division of Gastroenterology, Hepatology, and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
Yael
Y
Haberman
Division of Gastroenterology, Hepatology, and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
Lee A
LA
Denson
Department of Structural Biology and Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, Tennessee.
Xusheng
X
Wang
Division of Pulmonary Medicine, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Department of Physiology, University of Tennessee Health Science Center, Memphis, Tennessee. Electronic address: anaren@cchmc.org.
Anjaparavanda P
AP
Naren
D000818:Animals; D002462:Cell Membrane / Q000378:metabolism*; D002478:Cells, Cultured; D003093:Colitis, Ulcerative / Q000235:genetics / Q000378:metabolism*; D006152:Cyclic GMP / Q000378:metabolism*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000378:metabolism; D003967:Diarrhea / Q000378:metabolism*; D004195:Disease Models, Animal; D006801:Humans; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010750:Phosphoproteins / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D017923:Sodium-Hydrogen Exchangers / Q000378:metabolism
D010750:Phosphoproteins; D017923:Sodium-Hydrogen Exchangers; C093376:sodium-hydrogen exchanger regulatory factor; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D006152:Cyclic GMP