Abstract
The epithelial intermediate-conductance calcium/calmodulin-regulated KCa3.1 channel is considered to be a regulator of intestine function by controlling chloride secretion and water/salt balance. Yet, little is known about the functional importance of KCa3.1 in the intestinal epithelium in vivo. Our objective was to determine the impact of epithelial-specific inducible overexpression of a KCa3.1 transgene (KCa3.1+) and of inducible suppression (KCa3.1−) on intestinal homeostasis and function in mice. KCa3.1 overexpression in the duodenal epithelium of doxycycline (DOX)-treated KCa3.1+ mice was 40-fold above the control levels. Overexpression caused an inflated duodenum and doubling of the chyme content. Histology showed conserved architecture of crypts, villi, and smooth muscle. Unaltered proliferating cell nuclear antigen (PCNA) immune reactivity and reduced amounts of terminal deoxynucleotide transferase mediated X-dUTP nick end labeling (TUNEL)-positive apoptotic cells in villi indicated lower epithelial turnover. Myography showed a reduction in the frequency of spontaneous propulsive muscle contractions with no change in amplitude. The amount of stool in the colon was increased and the frequency of colonic contractions was reduced in KCa3.1+ animals. Senicapoc treatment prevented the phenotype. Suppression of KCa3.1 in DOX-treated KCa3.1− mice caused no overt intestinal phenotype. In conclusion, inducible KCa3.1 overexpression alters intestinal functions by increasing the chyme content and reducing spontaneous contractions and epithelial apoptosis. Induction of epithelial KCa3.1 can play a mechanistic role in the process of adaptation of the intestine.
Highlights
The intermediate-conductance calcium-activated potassium channel (KCa3.1, encoded by the KCNN4 gene) is constitutively expressed in the intestinal epithelium [1,2,3]
0.0328 0.0120 ns
Our main findings are that sub-chronic two-week overexpression of KCa3.1 in the intestinal epithelium caused duodenal chyme accumulation and reduced spontaneous contractions of duodenum
Summary
The intermediate-conductance calcium-activated potassium channel (KCa3.1, encoded by the KCNN4 gene) is constitutively expressed in the intestinal epithelium [1,2,3]. Concerning its physiological role, it is well established that KCa3.1 activation produces membrane hyperpolarization that is needed for the secretion of chloride anions and concomitantly of water into the lumen [3]. There is early evidence that KCa3.1 may be mechanistically important in inflammatory bowel disease, because a lower epithelial KCa3.1 expression has been found in patients with ulcerative colitis (UC) [5], pointing to a disturbed regulation of chloride secretion/absorption in this disease state. Alterations of KCa3.1 have been found in experimental acute and chronic inflammatory processes and autoimmune ulcerative colitis [6,7,8]
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