Severe defects in absorptive ion transport in distal colons of mice that lack ClC-2 channels.

Abstract

BACKGROUND & AIMS:

The fluid secretion model predicts that intestinal obstruction disorders can be alleviated by promoting epithelial Cl(-) secretion. The adenosine 3',5'-cyclic monophosphate (cAMP)-activated anion channel CFTR mediates Cl(-)-dependent fluid secretion in the intestine. Although the role of the ClC-2 channel has not been determined in the intestine, this voltage-gated Cl(-) channel might compensate for the secretory defects observed in patients with cystic fibrosis and other chronic constipation disorders. We investigated whether mice that lack ClC-2 channels (Clcn2(-/-)) have defects in intestinal ion transport.

METHODS:

Immunolocalization and immunoblot analyses were used to determine the cellular localization and the amount of ClC-2 expressed in mouse early distal colon (EDC) and late distal colon (LDC). Colon sheets from wild-type and Clcn2(-/-) littermates were mounted in Ussing chambers to determine transepithelial bioelectrical parameters and Na(+), K(+), and Cl(-) fluxes.

RESULTS:

Expression of ClC-2 was higher in the basolateral membrane of surface cells in the EDC compared with the LDC, with little expression in crypts. Neither cAMP nor Ca(2+)-induced secretion of Cl(-) was affected in the EDC or LDC of Clcn2(-/-) mice, whereas the amiloride-sensitive short-circuit current was increased approximately 3-fold in Clcn2(-/-) EDC compared with control littermates. Conversely, electroneutral Na(+), K(+), and Cl(-) absorption was dramatically reduced in colons of Clcn2(-/-) mice.

CONCLUSIONS:

Basolateral ClC-2 channels are required for colonic electroneutral absorption of NaCl and KCl. The increase in the amiloride-sensitive short-circuit current in Clcn2(-/-) mice revealed a compensatory mechanism that is activated in the colons of mice that lack the ClC-2 channel.

• Authors: Marcelo A Catalán, Carlos A Flores, Mireya González-Begne, Yan Zhang, Francisco V Sepúlveda, James E Melvin
• Journal: Gastroenterology (Gastroenterology) Vol. 142 Issue 2 Pg. 346-54 (Feb 2012) ISSN: 1528-0012 [Electronic] United States
• PMID: 22079595 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 AGA Institute. Published by Elsevier Inc. All rights reserved.

Chemical References

• CLC-2 Chloride Channels
• Chloride Channels
• Clcn2 protein, mouse
• Sodium Chloride
• Chlorine
• Potassium Chloride

Topics

• Animals
• Blotting, Western
• CLC-2 Chloride Channels
• Chloride Channels (metabolism)
• Chlorine (metabolism)
• Colon (metabolism)
• Constipation (metabolism)
• Female
• Intestinal Absorption
• Intestinal Mucosa (metabolism)
• Ion Transport
• Male
• Mice
• Mice, Knockout
• Polymerase Chain Reaction
• Potassium Chloride (metabolism)
• Sodium Chloride (metabolism)