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.
Department of Pharmacology, University of Cambridge, Cambridge CB2 1QJ, United Kingdom. awc1000@cam.ac.uk
A W
AW
Cuthbert
M E
ME
Hickman
P
P
Thorn
L J
LJ
MacVinish
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