The TWK-26/KCNK3 potassium channel and FLR-4 protein kinase coordinate nutrient absorption in the intestine.

Ion channels are necessary for proper water and nutrient absorption in the intestine, thereby supporting cellular metabolism and organismal growth. While a role for Na co-transporters and pumps in intestinal nutrient absorption is well defined, how individual K uniporters function in this process is poorly understood. Using , we show that a gain-of-function mutation in , which encodes a two-pore domain K ion channel orthologous to human KCNK3, facilitates nutrient absorption and suppresses the metabolic and developmental defects caused by loss of DRL-1/FLR-4 signaling. Mutations in and which encode two unique kinases that are components of a mitogen-activated protein kinase (MAPK) pathway, and the downstream Na ion channel, cause severe growth defects, reduced lipid storage, and a dramatic increase in autophagic lysosomes, which mirror dietary restriction phenotypes. We reveal that this dietary restriction phenotype is likely the result of impaired intestinal amino acid absorption, which is restored upon activation of TWK-26. Furthermore, we show that loss of disrupts intracellular and extracellular pH gradients, suggesting that the FLR-4 pathway may be necessary to maintain intestinal ion homeostasis and facilitate nutrient absorption. The altered pH gradients in the mutant are partially restored by activation of TWK-26, demonstrating a novel role for this K ion channel in governing intestinal physiology and metabolism.