ClC-2 regulation of intestinal barrier function: Translation of basic science to therapeutic target

Abstract

The ClC-2 chloride channel is a member of the voltage-gated chloride channel family. ClC-2 is involved in various physiological processes, including fluid transport and secretion, regulation of cell volume and pH, maintaining the membrane potential of the cell, cell-to-cell communication, and tissue homeostasis. Recently, our laboratory has accumulated evidence indicating a critical role of ClC-2 in the regulation of intestinal barrier function by altering inter-epithelial tight junction composition. This review will detail the role of ClC-2 in intestinal barrier function during intestinal disorders, including experimental ischemia/reperfusion injury and dextran sodium sulfate (DSS)-induced inflammatory bowel disease. Details of pharmacological manipulation of ClC-2 via prostone agonists will also be provided in an effort to show the potential therapeutic relevance of ClC-2 regulation, particularly during intestinal barrier disruption.

Keywords: ClC-2 chloride channel; gastrointestinal diseases; intestinal barrier function; lubiprostone; tight junctions.

Figure 1.

The role of tight junction proteins in signaling mechanisms affecting the intestinal mucosal barrier. Tight junctions consist of transmembrane proteins (e.g., claudins and occludin), cytoplasmic plaque proteins (e.g. ZO-1, -2, and -3), and signaling proteins (e.g., actin and myosin II). These proteins are dynamically regulated to maintain tight junction integrity. In intestinal disorders, proinflammatory cytokines (TNFα, INFγ, LIGHT, and IL-1β) stimulate MLCK expression and activity and induce caveolae-dependent endocytosis of tight junction proteins via contraction of perijunctional actinomyosin ring. Alternatively, IL-13 increases paracellular permeability via increased expression of pore forming claudin-2.

Figure 2.

ClC-2 has a key role in re-formation of the tight junction. ClC-2 regulates endocytosis and recycling of tight junction proteins associated with caveolin-1 and the small GTPase Rab5, both crucial molecules in caveolar transport.

Figure 3.

Model summary for the role of ClC-2 in repair of the intestinal epithelial barrier. In normal intestinal mucosa, ClC-2 is associated with dynamic trafficking of tight junction proteins to maintain tight junction integrity. In the absence of ClC-2, intestinal epithelial cells show altered tight junction morphology and dilated lateral paracellular spaces. In injured intestinal mucosa, ClC-2 has a critical role in reconstitution of tight junction proteins. Intestinal mucosa without ClC-2 has greater loss of barrier functions than epithelia with ClC-2 and resulting in development of digestive disease.