Activation of KCNQ (KV7) K+ channels in enteric neurons inhibits epithelial Cl− secretion in mouse distal colon

Voltage-gated Kv7 ( KCNQ family) K + channels are expressed in many neuronal populations and play an important role in regulating membrane potential by generating a hyperpolarizing K + current and decreasing cell excitability. However, the role of K V 7 channels in the neural regulation of intestinal epithelial Cl - secretion is not known. Cl - secretion in mouse distal colon was measured as a function of short-circuit current (I SC ), and pharmacological approaches were used to test the hypothesis that activation of K V 7 channels in enteric neurons would inhibit epithelial Cl - secretion. Flupirtine, a nonselective K V 7 activator, inhibited basal Cl - secretion in mouse distal colon and abolished or attenuated the effects of drugs that target various components of enteric neurotransmission, including tetrodotoxin (Na V channel blocker), veratridine (Na V channel activator), nicotine (nicotinic acetylcholine receptor agonist), and hexamethonium (nicotinic antagonist). In contrast, flupritine did not block the response to epithelium-targeted agents VIP (endogenous VPAC receptor ligand) or carbachol (nonselective cholinergic agonist). Flupirtine inhibited Cl - secretion in both full-thickness and seromuscular-stripped distal colon (containing the submucosal, but not myenteric plexus) but generated no response in epithelial T84 cell monolayers. K V 7.2 and K V 7.3 channel proteins were detected by immunofluorescence in whole mount preparations of the submucosa from mouse distal colon. ICA 110381 (K V 7.2/7.3 specific activator) inhibited Cl - secretion comparably to flupirtine. We conclude that K V 7 channel activators inhibit neurally driven Cl - secretion in the colonic epithelium and may therefore have therapeutic benefit in treating pathologies associated with hyperexcitable enteric nervous system, such as irritable bowel syndrome with diarrhea (IBS-D).