Mechanisms of intracellular pH gating and local anesthetic inhibition of the two-pore domain K(+) channel TASK-2.

Intracellular protonation triggers a unique Z-gate mechanism that closes TASK-2 channels, involving inner helix unwinding and domain swapping to seal the cytoplasmic entrance.

• Why it matters: Understanding the molecular basis of TASK-2 gating and inhibition is crucial because of its role in respiration regulation and systemic pH homeostasis, with implications for disease treatment.
• What they did: Researchers used cryo-EM and single-channel electrophysiology to investigate TASK-2, revealing how intracellular lysine protonation induces conformational changes and how bupivacaine inhibits the channel.
• The result: Findings show protonation causes a Z-gate to block the pore and lipids invade to reinforce closure, while bupivacaine competes with lipids at the cavity, informing future drug design.