The Proton-Activated Chloride Channel: Molecular Identification, Structure, and Role in Organelle Physiology

In 2019, a novel membrane protein, PAC (also known as TMEM206), was identified as the long-sought molecular carrier of an acid- or proton-activated chloride current observed ubiquitously in mammalian cells. This discovery has led to rapid progress in revealing its trimetric architecture and biophysical properties, including the pH-sensing mechanism, anion selectivity, and lipid regulation. In addition to the cell surface, the PAC channel predominantly localizes to intracellular organelles (endosomes, phagosomes, and macropinosomes), where it mediates pH-dependent chloride flux to regulate luminal pH and organelle volume. Here, we review these exciting findings and discuss the many aspects of the PAC channel that remain largely unexplored, including its pharmacology, physiological function, and potential role in disease.