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

Abstract

Significance The potassium channel TWIK-related acid-sensitive K+ channel 2 (TASK-2) is a critical physiological sensor that regulates breathing and kidney function to maintain pH homeostasis. Despite its importance, the molecular mechanisms controlling its intracellular gating and inhibition have remained unclear. We use cryoelectron microscopy and electrophysiology to address these questions. We found TASK-2 employs a unique mechanism to gate closed in response to low intracellular pH that involves protein and lipid components. We further show that the local anesthetic bupivacaine inhibits TASK-2 by binding inside the channel at a site that overlaps with the lipid binding site. These findings define a paradigm for intracellular channel regulation and offer a structural blueprint for designing specific inhibitors of TASK-2.