Inhibition of the proton-activated chloride channel PAC by PIP₂.

ABSTRACT: Proton-activated chloride (PAC) channel is a ubiquitously expressed pH-sensing ion channel, encoded by PACC1 (TMEM206). PAC regulates endosomal acidification and macropinosome shrinkage by releasing chloride from the organelle lumens. It is also found at the cell surface, where it is activated under pathological conditions related to acidosis and contributes to acid-induced cell death. However, the pharmacology of the PAC channel is poorly understood. Here, we report that phosphatidylinositol (4,5)-bisphosphate (PIP₂) potently inhibits PAC channel activity. We solved the cryo-electron microscopy structure of PAC with PIP₂ at pH 4.0 and identified its putative binding site, which, surprisingly, locates on the extracellular side of the transmembrane domain

SUBMITTER: Mihaljevic L 

PROVIDER: S-EPMC9876566 | biostudies-literature | 2023 Jan

REPOSITORIES: biostudies-literature