An alternate pathway of cAMP-stimulated Cl− secretion across the NKCC1-null murine duodenum

• Published in: Gastroenterology (New York, N.Y. 1943) Vol. 123; no. 2; pp. 531 - 541
• Main Authors: Walker, Nancy M., Flagella, Michael, Gawenis, Lara R., Shull, Gary E., Clarke, Lane L.
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier Inc 01-08-2002; Elsevier
• Subjects: Animals; Biological and medical sciences; Chlorides - metabolism; Colforsin - pharmacology; Cyclic AMP - physiology; Cystic Fibrosis Transmembrane Conductance Regulator - physiology; Duodenum - metabolism; Fundamental and applied biological sciences. Psychology; Hydrogen-Ion Concentration; Intestine. Mesentery; Mice; Mice, Knockout; Sodium-Hydrogen Exchangers - physiology; Sodium-Potassium-Chloride Symporters - genetics; Sodium-Potassium-Chloride Symporters - physiology; Vertebrates: digestive system; Jms; SITS; DIDS; EIPA; Jsm; Isc; cAMPi; Gt; CFTR; Duodenum; Digestive system; Secretion; Cell biology; Cyclic AMP; Transgenic animal; Chlorine ion; Stimulation; Experimental study; Conveyor; Hydrogencarbonates; Electrolyte; Sodium ion; Cystic fibrosis transmembrane conductance regulator
• ISSN: 0016-5085; 1528-0012
• DOI: 10.1053/gast.2002.34757

Background & Aims: Adenosine 3',5'-cyclic monophosphate (cAMP)-stimulated anion secretion across the duodenal epithelium requires the cystic fibrosis transmembrane conductance regulator (CFTR) in the apical membrane and anion uptake proteins in the basolateral membrane. NKCC1, the epithelial Na+/K+/2Cl− cotransporter, is the major protein responsible for Cl− uptake. In this study, we evaluate the role of NKCC1 in determining the relative rates of transepithelial Cl− and HCO3− secretion during cAMP stimulation of the duodenum. Methods: Bicarbonate and chloride secretion across duodenal mucosa was measured in Ussing chambers by pH stat and 36Cl flux methods using mice with either gene-targeted deletion of NKCC1 (NKCC1−/−) or bumetanide blockade of NKCC1. Results: Total anion secretion stimulated by forskolin treatment of NKCC1-null duodenum resulted from approximately equivalent rates of electrogenic chloride, electrogenic bicarbonate, and electroneutral bicarbonate secretion. Evaluation of the alternate chloride secretory pathway indicated chloride uptake by a basolateral membrane anion exchange process with characteristics consistent with the anion exchanger isoform AE2. Conclusions: Chloride uptake by basolateral anion exchanger activity (AE2) supports intracellular cAMP–stimulated chloride secretion in the NKCC1-null duodenum. A model for the alternate chloride secretion pathway is proposed whereby chloride uptake via AE2 is coupled to basolateral NaHCO3 cotransport to support CFTR-mediated chloride and bicarbonate secretion.
GASTROENTEROLOGY 2002;123:531-541