Pacc1, also known as TMEM206, encodes the proton-activated chloride (PAC) channel, an evolutionarily conserved membrane protein. The PAC channel is involved in physiological and pathological processes associated with acidic pH, regulating endosomal acidification and macropinosome shrinkage by releasing chloride from organelle lumens [1,3].

Genetic knockout of the Pacc1 gene significantly reduced endplate porosity and spinal pain in a mouse chronic low-back pain (LBP) model, without affecting bone development or bone mass homeostasis in adult mice. This indicates that Pacc1-mediated PAC channel activation in osteoclasts, via a RANKL/NFATc1 signaling pathway, plays a role in LBP development [2]. In addition, genetic deletion of Pac (the mouse ortholog of Pacc1) abolished the proton-activated Cl-currents in mouse neurons and attenuated acid-induced neuronal cell death and brain damage after ischemic stroke [4].

In conclusion, Pacc1 is crucial for the function of the proton-activated chloride channel, which is involved in multiple physiological and pathological processes. Gene knockout mouse models have revealed its role in pain-related conditions such as LBP and in acid-induced neuronal cell death and brain injury following ischemic stroke, providing potential therapeutic targets for these diseases.