K2P 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 KCa3.1 channels are not involved, K2P 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. 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 KCa3.1 channels after independent CFTR activation, but cAMP‐dependent anion secretion is not further decreased in the combined absence of KCa3.1 and KCNQ1–KCNE3 K+ channel activity. We show that the K2P 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