Local acidosis causes tissue damage, and pain and is one of the hallmarks of ischemia, cancer and inflammation. However, the molecular mechanisms of the cellular response to acid are not fully understood. Besides the cation-conducting, acid-sensing ion channels (ASICs), the acid also activates a chloride (Cl−) conductance in a wide range of mammalian cells. Although the electrophysiological properties of the proton-activated Cl− channel have been described in detail, its molecular identity has remained elusive. This gap makes it impossible to elucidate its precise biological function and potential contributions to the pathogenesis of acidosis-related diseases.
Taking advantage of the powerful functional genomics screen established in our lab, we identified a novel membrane protein, named PAC (also known as TMEM206), as the proton-activated Cl− channel. PAC mRNA is expressed in diverse tissues, with the highest level detected in the brain. Knockout of mouse PAC abolishes the channel activity in neurons and protects them from acid-induced cell death. Importantly, PAC KO mice exhibited significantly smaller brain infarct volume when subjected to a middle cerebral artery occlusion (MCAO) stroke model. Therefore, PAC may represent a potential drug target for stroke and other acidosis-associated diseases.
This work has been done in the laboratory of Zhaozhu Qiu, Ph.D., in the Department of Physiology.