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  • Title: Abolition of Ca2+-mediated intestinal anion secretion and increased stool dehydration in mice lacking the intermediate conductance Ca2+-dependent K+ channel Kcnn4.
    Author: Flores CA, Melvin JE, Figueroa CD, Sepúlveda FV.
    Journal: J Physiol; 2007 Sep 01; 583(Pt 2):705-17. PubMed ID: 17584847.
    Abstract:
    Intestinal fluid secretion is driven by apical membrane, cystic fibrosis transmembrane conductance regulator (CFTR)-mediated efflux of Cl- that is concentrated in cells by basolateral Na(+)-K(+)-2Cl- cotransporters (NKCC1). An absolute requirement for Cl- efflux is the parallel activation of K(+) channels which maintain a membrane potential that sustains apical anion secretion. Both cAMP and Ca(2+) are intracellular signals for intestinal Cl- secretion. The K(+) channel involved in cAMP-dependent secretion has been identified as the KCNQ1-KCNE3 complex, but the identity of the K(+) channel driving Ca(2+)-activated Cl- secretion is controversial. We have now used a Kcnn4 null mouse to show that the intermediate conductance IK1 K(+) channel is necessary and sufficient to support Ca(2+)-dependent Cl- secretion in large and small intestine. Ussing chambers were used to monitor transepithelial potential, resistance and equivalent short-circuit current in colon and jejunum from control and Kcnn4 null mice. Na(+), K(+) and water content of stools was also measured. Distal colon and small intestinal epithelia from Kcnn4 null mice had normal cAMP-dependent Cl- secretory responses. In contrast, they completely lacked Cl- secretion in response to Ca(2+)-mobilizing agonists. Ca(2+)-activated electrogenic K(+) secretion was increased in colon epithelium of mice deficient in the IK1 channel. Na(+) and water content of stools was diminished in IK1-null animals. The use of Kcnn4 null mice has allowed us to demonstrate that IK1 K(+) channels are solely responsible for driving intestinal Ca(2+)-activated Cl- secretion. The absence of this channel leads to a marked reduction in water content in the stools, probably as a consequence of decreased electrolyte and water secretion.
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