K2P TASK-2 and KCNQ1/KCNE3 K+ channels are major players contributing to intestinal anion and fluid secretion

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 sizable 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 now use double mutant mouse and pharmacological approaches to identify such conductance. Ca²⁺-dependent anion secretion can also be supported by Ca²⁺-dependent K_Ca3.1 channels after independent CFTR activation, but cAMP-dependent anion secretion is not further decreased in the combined absence of K_Ca3.1 and KCNQ1/KCNE3 K⁺ channel activity. We show that 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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