Structural basis for pH gating of the two-pore domain K⁺ channel TASK2

TASK2 (also known as KCNK5) channels generate pH-gated leak-type K⁺ currents to control cellular electrical excitability^1-3. TASK2 is involved in the regulation of breathing by chemosensory neurons of the retrotrapezoid nucleus in the brainstem^4-6 and pH homeostasis by kidney proximal tubule cells^7,8. These roles depend on channel activation by intracellular and extracellular alkalization^3,8,9, but the mechanistic basis for TASK2 gating by pH is unknown. Here we present cryo-electron microscopy structures of Mus musculus TASK2 in lipid nanodiscs in open and closed conformations. We identify two gates, distinct from previously observed K⁺ channel gates, controlled by stimuli on either side of the membrane. Intracellular gating involves lysine protonation on inner helices and the formation of a protein seal between the cytoplasm and the channel. Extracellular gating involves arginine protonation on the channel surface and correlated conformational changes that displace the K⁺-selectivity filter to render it nonconductive. These results explain how internal and external protons control intracellular and selectivity filter gates to modulate TASK2 activity.