The cystic fibrosis transmembrane conductance regulator and acid-base transporters of the murine duodenum

The alkaline mucus barrier of the duodenum plays an important role in protecting the epithelium from acidic chyme entering from the stomach. Active HCO₃⁻ secretion involves the apical membrane activities of the cystic fibrosis transmembrane conductance regulator (CFTR) Cl⁻ channel, the protein that is defective in cystic fibrosis (CF), and Cl⁻/HCO₃⁻ exchangers. Under basal conditions, studies of CF patients and mouse models indicate that HCO₃⁻ secretion by anion exchange predominates. In addition, basal HCO₃⁻ secretion is reduced in the CF duodenum, but the specific pathophysiology for this deficiency has yet to be elucidated. Our studies reveal that Cl⁻ channel activity by CFTR facilitates apical membrane Cl⁻in/HCO₃⁻out exchange by providing a Cl⁻ 'leak' and is responsible for the reduced rate of Cl⁻/HCO₃⁻ exchange in the murine CF intestine. Using mice with gene-targeted deletions of the apical membrane Cl⁻/HCO₃⁻ exchangers PAT-1, DRA, and AE4, PAT-1 was found to be the major Cl⁻/HCO₃⁻ exchanger of the upper villus of the duodenum. Interestingly, these studies also revealed a novel role for PAT-1 as a base-importer (i.e., Cl⁻out/HCO₃⁻in) whereby it interacts with carbonic anhydrase II (CAII), the most widely expressed isozyme of the small intestine, during H⁺/peptide transport to minimize intracellular acidification and sustain nutrient absorption.

Name thesis:degree_name

Ph. D.

Level thesis:degree_level

Doctoral

Discipline thesis:degree_discipline

Veterinary biomedical sciences (MU)

Grantor dc:publisher

University of Missouri--Columbia

Year dc:date.issued

2006

Author dc:creator

• Simpson, Janet Elizabeth, 1976-

Advisor dc:contributor.advisor

• Clarke, Lane L. (Lane Leroy)

Statement dc:rights

• OpenAccess.

Language dc:language.iso

eng, English

DOI

https://doi.org/10.32469/10355/4391

OAI identifier oai:identifier

oai:mospace.umsystem.edu:10355/4391