Role of cholinergic-activated KCa1.1 (BK), KCa3.1 (SK4) and KV7.1 (KCNQ1) channels in mouse colonic Cl?secretion

Aim: 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 Ca 2+ -activated K ca 3.1 (SK4) channel and the cAMP-activated K v 7.1 (KCNQ1) channel. In addition, big conductance Ca 2+ -activated K ca 1.1 (BK) channels may play a role in Ca 2+ -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 μM) 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 (I sc ) in distal colon. Chloride secretion was activated by bl. forskolin (FSK, 2 μM) followed by bl. carbachol (CCH, 100 μM). Luminal Ba 2+ (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 I sc changes, indicating that K ca 1.1 channels are not involved in FSK- and cholinergic-stimulated Cl - secretion. CCH-stimulated ∇I sc 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 Ca 2+ 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.