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

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. Mutations in the Caenorhabditis elegans genes drl-1 and flr-4, which encode two unique kinases that are components of a mitogen-activated protein kinase (MAPK) pathway, or the flr-1 Na+ ion channel, cause severe growth defects, reduced lipid storage, and a dramatic increase in autophagic lysosomes. Here, we show that a gain-of-function mutation in twk-26, which encodes a 2-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, or FLR-1 signaling. We reveal that these phenotypes likely arise from impaired intestinal amino acid absorption, which is restored upon activation of TWK-26. Furthermore, we show that loss of flr-4 disrupts intracellular and extracellular pH gradients, suggesting that the FLR-4 pathway may be necessary to maintain intestinal ion homeostasis and facilitate nutrient absorption. Importantly, the altered pH gradients in the flr-4 mutant are partially restored by the twk-26 gain-of-function mutation. Thus, this study uncovers a new role for the TWK-26 ion channel in governing intestinal physiology and metabolism.