Abolition of Ca 2+-mediated intestinal anion secretion and increased stool dehydration in mice lacking the intermediate conductance Ca 2+-dependent K + channel Kcnn4

Flores C.A.; Sepulveda, F. V.; Figueroa C.D.; Melvin, J. E.

Keywords: chemistry, water, diffusion, membrane, transport, mouse, animals, glucose, potentials, complex, culture, histamine, ion, cell, colon, conductance, chloride, channel, mutant, calcium, impedance, mice, metabolism, electrolyte, channels, secretion, transduction, fluid, potassium, male, genetics, sodium, time, composition, intestine, intermediate, agent, tissue, body, agonists, signal, formation, drug, mucosa, article, feces, anion, carbachol, regulator, mobilization, jejunum, apical, basolateral, chlorides, content, signaling, transmembrane, controlled, small, chamber, animal, knockout, secretions, factors, kcnq1, study, priority, cyclic, nonhuman, journal, AMP, effect, potential, Inbred, Electric, Mice,, C57BL, unclassified, muscarinic, Intestinal, activated, protein,, phenylalanine, Channels,, Calcium-Activated, cotransporter, IK1, KCNE3, Kcnn4, Chambers,, Intermediate-Conductance


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 KK + channels which maintain a membrane potential that sustains apical anion secretion. Both cAMP and Ca 2+ are intracellular signals for intestinal Cl - secretion. The KK + 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 +-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. © 2007 The Authors. Journal compilation © 2007 The Physiological Society.

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Título de la Revista: Journal of Physiology
Volumen: 583
Número: 2
Fecha de publicación: 2007
Página de inicio: 705
Página final: 717
URL: http://www.scopus.com/inward/record.url?eid=2-s2.0-34548317519&partnerID=q2rCbXpz