title: Abolition of Ca2+-mediated intestinal anion secretion and increased stool dehydration in mice lacking the intermediate conductance Ca2+-dependent K+ channel Kcnn4.
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.
authors.affiliation: Centro de Estudios Científicos, Avenida Arturo Prat 514, Valdivia, Chile.
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Flores
authors.forename: James E
authors.initials: JE
authors.lastname: Melvin
authors.forename: Carlos D
authors.initials: CD
authors.lastname: Figueroa
authors.forename: Francisco V
authors.initials: FV
authors.lastname: Sepúlveda
mesh_terms: D000818:Animals; D001834:Body Water / Q000378:metabolism*; D020013:Calcium Signaling / Q000187:drug effects; D002217:Carbachol / Q000494:pharmacology; D002712:Chlorides / Q000378:metabolism*; D003106:Colon / Q000187:drug effects / Q000378:metabolism*; D000242:Cyclic AMP / Q000378:metabolism; D015194:Diffusion Chambers, Culture; D017097:Electric Impedance; D005243:Feces / Q000737:chemistry*; D005947:Glucose / Q000378:metabolism; D006632:Histamine / Q000378:metabolism; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000378:metabolism; D007419:Intestinal Secretions / Q000378:metabolism*; D007583:Jejunum / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008564:Membrane Potentials; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018721:Muscarinic Agonists / Q000494:pharmacology; D010649:Phenylalanine / Q000378:metabolism; D011188:Potassium / Q000378:metabolism; D024681:Potassium Channels, Calcium-Activated / Q000378:metabolism; D012964:Sodium / Q000378:metabolism; D013997:Time Factors
chemical_list: D002712:Chlorides; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels; C496925:Kcnn4 protein, mouse; D018721:Muscarinic Agonists; D024681:Potassium Channels, Calcium-Activated; D010649:Phenylalanine; D006632:Histamine; D002217:Carbachol; D012964:Sodium; D000242:Cyclic AMP; D005947:Glucose; D011188:Potassium