Role of cholinergic-activated KCa1.1 (BK), KCa3.1 (SK4) and KV7.1 (KCNQ1) channels in mouse colonic Cl- secretion.
OBJECTIVE
Colonic crypts are the site of Cl- secretion. Basolateral K+ channels provide the driving force for luminal cystic fibrosis transmembrane regulator-mediated Cl- exit. Relevant colonic epithelial K+ channels are the intermediate conductance Ca2+-activated K(Ca)3.1 (SK4) channel and the cAMP-activated K(V)7.1 (KCNQ1) channel. In addition, big conductance Ca2+-activated K(Ca)1.1 (BK) channels may play a role in Ca2+-activated Cl- secretion. Here we use K(Ca)1.1 and K(Ca)3.1 knock-out mice, and the K(V)7.1 channel inhibitor 293B (10 microm) to investigate the role of K(Ca)1.1, K(Ca)3.1 and K(V)7.1 channels in cholinergic-stimulated Cl- secretion.


METHODS
A Ussing chamber was used to quantify agonist-stimulated increases in short circuit current (Isc) in distal colon. Chloride secretion was activated by bl. forskolin (FSK, 2 microm) followed by bl. carbachol (CCH, 100 microm). Luminal Ba2+ (5 mm) was used to inhibit K(Ca)1.1 channels.


RESULTS
K(Ca)1.1 WT and KO mice displayed identical FSK and CCH-stimulated Isc changes, indicating that K(Ca)1.1 channels are not involved in FSK- and cholinergic-stimulated Cl- secretion. CCH-stimulated DeltaIsc was significantly reduced in K(Ca)3.1 KO mice, underscoring the known relevance of this channel in the activation of Cl- secretion by an intracellular Ca2+ increasing agonist. The residual CCH effect observed in K(Ca)3.1 KO mice suggests that yet another K+ channel is driving the CCH-stimulated Cl- secretion. In the presence of the specific K(V)7.1 channel blocker 293B, the residual CCH effect was abolished.


CONCLUSIONS
This demonstrates that both K(Ca)3.1 and K(V)7.1 channels are activated by cholinergic agonists and drive Cl- secretion. In contrast, K(Ca)1.1 channels are not involved in stimulated electrogenic Cl- secretion.
Matos
J E
JE
Institute of Physiology and Biophysics, The Water and Salt Research Center, University of Aarhus, Aarhus C, Denmark.
Sausbier
M
M
Beranek
G
G
Sausbier
U
U
Ruth
P
P
Leipziger
J
J
D000818:Animals; D002217:Carbachol / Q000494:pharmacology; D002712:Chlorides / Q000502:physiology*; D018679:Cholinergic Agonists / Q000494:pharmacology; D002839:Chromans / Q000494:pharmacology; D005576:Colforsin / Q000494:pharmacology; D003106:Colon; D005260:Female; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels / Q000037:antagonists & inhibitors / Q000502:physiology; D007413:Intestinal Mucosa / Q000378:metabolism*; D051657:KCNQ1 Potassium Channel / Q000037:antagonists & inhibitors / Q000502:physiology; D051036:Large-Conductance Calcium-Activated Potassium Channels / Q000037:antagonists & inhibitors / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D026902:Potassium Channel Blockers / Q000494:pharmacology; D015221:Potassium Channels / Q000502:physiology*; D011897:Random Allocation; D013449:Sulfonamides / Q000494:pharmacology
D002712:Chlorides; D018679:Cholinergic Agonists; D002839:Chromans; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels; D051657:KCNQ1 Potassium Channel; C496925:Kcnn4 protein, mouse; D051036:Large-Conductance Calcium-Activated Potassium Channels; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D013449:Sulfonamides; C103474:6-cyano-4-(N-ethylsulfonyl-N-methylamino)-3-hydroxy-2,2-dimethylchromane; D005576:Colforsin; D002217:Carbachol