K_2P TASK-2 and KCNQ1-KCNE3 K⁺ channels are major players contributing to intestinal anion and fluid secretion.

KEY POINTS:K⁺ channels are important in intestinal epithelium as they ensure the ionic homeostasis and electrical potential of epithelial cells during anion and fluid secretion. Intestinal epithelium cAMP-activated anion secretion depends on the activity of the (also cAMP dependent) KCNQ1-KCNE3 K⁺ channel, but the secretory process survives after genetic inactivation of the K⁺ channel in the mouse. Here we use double mutant mice to investigate which alternative K⁺ channels come into action to compensate for the absence of KCNQ1-KCNE3 K⁺ channels. Our data establish that whilst Ca²⁺ -activated K_Ca 3.1 channels are not involved, K_2P two-pore domain TASK-2 K⁺ channels are major players providing an alternative conductance to sustain the intestinal secretory process. Work with double mutant mice lacking both TASK-2 and KCNQ1-KCNE3 channels nevertheless points to yet-unidentified K⁺ channels that contribute to the robustness of the cAMP-activated anion secretion process. ABSTRACT:Anion and fluid secretion across the intestinal epithelium, a process altered in cystic fibrosis and secretory diarrhoea, is mediated by cAMP-activated CFTR Cl^- channels and requires the simultaneous activity of basolateral K⁺ channels to maintain cellular ionic homeostasis and membrane potential. This function is fulfilled by the cAMP-activated K⁺ channel formed by the association of pore-forming KCNQ1 with its obligatory KCNE3 β-subunit. Studies using mice show sizeable cAMP-activated intestinal anion secretion in the absence of either KCNQ1 or KCNE3 suggesting that an alternative K⁺ conductance must compensate for the loss of KCNQ1-KCNE3 activity. We used double mutant mouse and pharmacological approaches to identify such a conductance. Ca²⁺ -dependent anion secretion can also be supported by Ca²⁺ -dependent K_Ca 3.1 channels after independent CFTR activation, but cAMP-dependent anion secretion is not further decreased in the combined absence of K_Ca 3.1 and KCNQ1-KCNE3 K⁺ channel activity. We show that the K_2P K⁺ channel TASK-2 is expressed in the epithelium of the small and large intestine. Tetrapentylammonium, a TASK-2 inhibitor, abolishes anion secretory current remaining in the absence of KCNQ1-KCNE3 activity. A double mutant mouse lacking both KCNQ1-KCNE3 and TASK-2 showed a much reduced cAMP-mediated anion secretion compared to that observed in the single KCNQ1-KCNE3 deficient mouse. We conclude that KCNQ1-KCNE3 and TASK-2 play major roles in the intestinal anion and fluid secretory phenotype. The persistence of an, admittedly reduced, secretory activity in the absence of these two conductances suggests that further additional K⁺ channel(s) as yet unidentified contribute to the robustness of the intestinal anion secretory process.

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