Functional Role of Basolateral ClC-2 Channels in the Regulation of Duodenal Anion Secretion in Mice
Although ClC-2 channels are important in colonic Cl− secretion, it is unclear about their roles in small intestinal anion secretion. Therefore, we sought to examine whether ClC-2 channels play important roles in anion secretion, particularly duodenal bicarbonate secretion (DBS).
Duodenal mucosae from mice were stripped of seromuscular layers and mounted in Ussing chambers. Both duodenal short-circuit current (Isc) and HCO3− secretion in vitro were simultaneously recorded. DBS in vivo was measured by a CO2-sensitive electrode.
Lubiprostone, a selective ClC-2 activator, concentration-dependently increased both duodenal Isc and DBS only when applied basolaterally, but not when applied apically. Removal of extracellular Cl− abolished lubiprostone-induced duodenal Isc, but did not alter HCO3− secretion even in the presence of DIDS, a Cl−/HCO3− exchanger inhibitor. However, further addition of glibenclamide, a CFTR channel blocker, abolished lubiprostone-evoked HCO3− secretion. Moreover, lubiprostone-induced HCO3− secretion was impaired in CFTR−/− mice compared to wild-type littermates. Luminal perfusion of duodenal lumen with lubiprostone did not alter basal DBS in vivo, but lubiprostone (i.p.) was able to induce DBS, which was also significantly inhibited by Cd2+, a ClC-2 channel blocker. [Ca2+]cyt level, Ca2+-activated K+ channel- and cAMP-mediated duodenal Isc, and HCO3− secretion were unchanged by lubiprostone.
We have provided the first evidence for the novel functional role of basolateral ClC-2 channels in the regulation of duodenal anion secretion.
KeywordsClC-2 Duodenal Bicarbonate secretion CFTR
Cystic fibrosis transmembrane conductance regulator
Duodenal bicarbonate secretion
These studies were supported by research grants from the National Key Research and Development Program of China (No. 2016YFC1302200 to HD) and the National Natural Science Foundation of China (Nos. 81570477 and 81873544 to HD).
HD designed and supervised the project, wrote and finalized the manuscript. CD and JL conducted most experiments and data analysis. HXW conducted some experiments. XZ finalized the manuscript. All authors reviewed the manuscript.
Compliance with ethical standards
Conflict of interest
The authors declare no conflicts of interest.
- 1.Montrose MH, Keely S, Barrett K. Electrolyte secretion and absorption: small intestine and colon. In: Yamada T, ed. Textbook of Gastroenterology, vol. one. 4th ed. Philadephia, PA: Lippincott Williams & Wilkins; 2003:308–340.Google Scholar
- 5.Flemstrom G, Isenberg JI. Gastroduodenal mucosal alkaline secretion and mucosal protection. News Physiol Sci. 2001;16:23–28.Google Scholar
- 16.Hogan DL, Crombie DL, Isenberg JI, Svendsen P, Schaffalitzky DMO, Ainsworth MA. CFTR mediates cAMP- and Ca2+-activated duodenal epithelial HCO3 − secretion. Am J Physiol. 1997;272:G872–G878.Google Scholar
- 19.Clarke LL, Gawenis LR, Franklin CL, Harline MC. Increased survival of CFTR knockout mice with an oral osmotic laxative. Lab Anim Sci. 1996;46:612–618.Google Scholar
- 33.Devor DC, Singh AK, Bridges RJ, Frizzell RA. Modulation of Cl− secretion by benzimidazolones. II. Coordinate regulation of apical GCl and basolateral GK. Am J Physiol. 1996;271:L785–L795.Google Scholar
- 34.Devor DC, Singh AK, Frizzell RA, Bridges RJ. Modulation of Cl− secretion by benzimidazolones. I. Direct activation of a Ca(2+)-dependent K+ channel. Am J Physiol. 1996;271:L775–L784.Google Scholar
- 42.Murray CB, Chu S, Zeitlin PL. Gestational and tissue-specific regulation of C1C-2 chloride channel expression. Am J Physiol. 1996;271:L829–L837.Google Scholar
- 44.Ueno R, Osama H, Habe T, Engelke K. Oral SPI-0211 increases intestinal fluid secretion and chloride concentration without altering serum electrolyte levels (abstract). Gastroenterology. 2004;126:A-298.Google Scholar
- 46.Kim SW, Parekh D, Townsend CJ, Thompson JC. Effects of aging on duodenal bicarbonate secretion. Ann Surg. 1990;212:332–337, 337–338.Google Scholar
- 47.Valle JD, Chey W, Scheiman J. Acid peptic disorders. In: Yamada T, ed. Textbook of Gastroenterology, vol. one. 4th ed. Philadephia, PA: Lippincott Williams & Wilkins; 2003.Google Scholar
- 48.Moeser AJ, Nighot PK, Engelke KJ, Ueno R, Blikslager AT. Recovery of mucosal barrier function in ischemic porcine ileum and colon is stimulated by a novel agonist of the ClC-2 chloride channel, lubiprostone. Am J Physiol-Gastr L. 2007;292:G647–G656.Google Scholar