KCa3.1 Transgene Induction in Murine Intestinal Epithelium Causes Duodenal Chyme Accumulation and Impairs Duodenal Contractility

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.

Conditional KCa3.1-transgene induction in murine skin produces pruritic eczematous dermatitis with severe epidermal hyperplasia and hyperkeratosis

“…It is also worth mentioning that sub-chronic conditional gene deletion of KCa3.1 in the epidermis as well as life-long KCa3.1-deficiency [16] complete did not produce any skin alterations, indicating that basal KCa3.1 expression is apparently not crucial for epidermal homeostasis. In keeping with the induction of KCa3.1 in the small intestine, we also demonstrate a mild intestinal phenotype characterized by moderate chyme accumulation and lower propulsive spontaneous motility, which is the content of a separate report [46].…”

Ion channels and transporters regulate nutrient absorption in health and disease

“…(Figure 1), and have been proved to regulate ion secretion, migration of epithelial cells and other functions. [30][31][32] Volker Vallon et al used Ussing Chamber to study nutrient transport in mouse jejunum. I sc generated by glucose and phenylalanine represent absorption processes, and jejunal currents were significantly attenuated after gene knockout or drug inhibition of K v 7.1 (KCNQ1), suggesting that basolateral K v 7.1 is required for membrane…”

“…K + channels are involved in the repolarization of cell membranes, which is essential for stabilizing the driving force of electrogenic nutrient transport. Several subtypes of K + channels have been described in IEC, including K v 1.1 (KCNA1), K v 1.3 (KCNA3), K Ca 3.1 (KCNN4) and K v 7.1 (KCNQ1) (Figure 1), and have been proved to regulate ion secretion, migration of epithelial cells and other functions 30–32 …”

Colonoscopic Examination Profile at the Uki Hospital, East Jakarta From January 2014 - July 2015

“…Adventist covers part of the rectum, and serosa covers the rest. Many vessels are found in the submucosa and adventitia Valero et al (2019).…”