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Open AccessArticle

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

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Department of Pharmacology and Physiology, Universidad de Zaragoza, 22002 Huesca, Spain
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Instituto Agroalimentario de Aragón-IA2 (Universidad de Zaragoza-CITA), 50013 Zaragoza, Spain
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Universidad San Jorge, 50830 Villanueva de Gállego, Spain
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Instituto Aragonés de Ciencias de la Salud (IACS), 50009 Zaragoza, Spain
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Unidad de Investigación Traslacional, Hospital Universitario Miguel Servet, Instituto de Investigación Sanitaria (IIS) Aragón, 50009 Zaragoza, Spain
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Department of Biology, Universidad Autónoma de Madrid (UAM), 28049 Madrid, Spain
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Clinical Biochemistry Service, Hospital Universitario Miguel Servet, 50009 Zaragoza, Spain
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BSICoS, Aragón Institute of Engineering Research (IA3), IIS-Aragón, University of Zaragoza, 50009 Zaragoza, Spain
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Biomedical Research Networking Center in Bioengineering, Biomaterials and Nanomedicina (CIBER-BBN), 50018 Zaragoza, Spain
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Valero Analítica, S.L. 50011, Zaragoza, Spain
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Department of Physiology, School of Biomedical Sciences, University of Otago, 9054 Dunedin, New Zealand
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Department of Physiology and Cell Biology, University of Nevada School of Medicine, Reno, NV 89557, USA
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Aragón Agency for Research and Development (ARAID), 50009 Zaragoza, Spain
*
Authors to whom correspondence should be addressed.
Int. J. Mol. Sci. 2019, 20(5), 1193; https://doi.org/10.3390/ijms20051193
Received: 30 January 2019 / Revised: 1 March 2019 / Accepted: 4 March 2019 / Published: 8 March 2019
(This article belongs to the Special Issue Cell Targets and Toxicity)
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. View Full-Text
Keywords: intermediate-conductance calcium-activated potassium channel; KCa3.1; epithelium; duodenum; contractility; transgenic mice intermediate-conductance calcium-activated potassium channel; KCa3.1; epithelium; duodenum; contractility; transgenic mice
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Valero, M.S.; Ramón-Gimenez, M.; Lozano-Gerona, J.; Delgado-Wicke, P.; Calmarza, P.; Oliván-Viguera, A.; López, V.; Garcia-Otín, Á.-L.; Valero, S.; Pueyo, E.; Hamilton, K.L.; Miura, H.; Köhler, R. KCa3.1 Transgene Induction in Murine Intestinal Epithelium Causes Duodenal Chyme Accumulation and Impairs Duodenal Contractility. Int. J. Mol. Sci. 2019, 20, 1193.

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