Activation of Ca(2+)- and cAMP-sensitive K(+) channels in murine colonic epithelia by 1-ethyl-2-benzimidazolone.
1-Ethyl-2-benzimidazolone (EBIO) caused a sustained increase in electrogenic Cl(-) secretion in isolated mouse colon mucosae, an effect reduced by blocking basolateral K(+) channels. The Ca(2+)-sensitive K(+) channel blocker charybdotoxin (ChTX) and the cAMP-sensitive K(+) channel blocker 293B were more effective when the other had been added first, suggesting that both types of K(+) channel were activated. EBIO did not cause Cl(-) secretion in cystic fibrosis (CF) colonic epithelia. In apically permeabilized colonic mucosae, EBIO increased the K(+) current when a concentration gradient was imposed, an effect that was completely sensitive to ChTX. No current sensitive to trans-6-cyano-4-(N-ethylsulfonyl-N-methylamino)-3-hydroxy-2, 2-dimethylchromane (293B) was found in this condition. However, the presence of basolateral cAMP-sensitive K(+) channels was demonstrated by the development of a 293B-sensitive K(+) current after cAMP application in permeabilized mucosae. In isolated colonic crypts EBIO increased cAMP content but had no effect on intracellular Ca(2+). It is concluded that EBIO stimulates Cl(-) secretion by activating Ca(2+)-sensitive and cAMP-sensitive K(+) channels, thereby hyperpolarizing the apical membrane, which increases the electrical gradient for Cl(-) efflux through the CF transmembrane conductance regulator (CFTR). CFTR is also activated by the accumulation of cAMP as well as by direct activation.
Cuthbert
A W
AW
Department of Pharmacology, University of Cambridge, Cambridge CB2 1QJ, United Kingdom. awc1000@cam.ac.uk
Hickman
M E
ME
Thorn
P
P
MacVinish
L J
LJ
D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology*; D002118:Calcium / Q000502:physiology*; D002120:Calcium Channel Agonists / Q000494:pharmacology*; D018999:Charybdotoxin / Q000494:pharmacology; D002712:Chlorides / Q000378:metabolism; D002839:Chromans / Q000494:pharmacology; D003106:Colon / Q000187:drug effects / Q000378:metabolism*; D000242:Cyclic AMP / Q000502:physiology*; D003550:Cystic Fibrosis / Q000378:metabolism; D004357:Drug Synergism; D004553:Electric Conductivity; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D026902:Potassium Channel Blockers; D015221:Potassium Channels / Q000378:metabolism* / Q000502:physiology; D013449:Sulfonamides / Q000494:pharmacology
D001562:Benzimidazoles; D002120:Calcium Channel Agonists; D002712:Chlorides; D002839:Chromans; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D013449:Sulfonamides; D018999:Charybdotoxin; C103474:6-cyano-4-(N-ethylsulfonyl-N-methylamino)-3-hydroxy-2,2-dimethylchromane; D000242:Cyclic AMP; C102635:1-ethyl-2-benzimidazolinone; D002118:Calcium