LAUSR

Significance The acidic environment is critical for the proper function of many intracellular organelles. It is also associated with various diseases such as ischemia, cancer, and inflammation. In response to acidic pH, the proton-activated chloride (PAC) channel permeates chloride ions across membranes and plays an important role in endosomal acidification. It is also involved in acid-induced cell death and ischemic brain injury. However, how proton binding leads to the opening of this newly identified family of ion channels remains unknown. In this study, we identified several critical protonation sites and intersubunit interactions that work together to determine PAC pH sensitivity. Our work reveals a distinct pH-sensing mechanism and is relevant to the development of inhibitors targeting PAC in diseases associated with acidosis.