PAC, an evolutionarily conserved membrane protein, is a proton-activated chloride channel

• Published in: Science (American Association for the Advancement of Science) Vol. 364; no. 6438; pp. 395 - 399
• Main Authors: Yang, Junhua, Chen, Jianan, Del Carmen Vitery, Maria, Osei-Owusu, James, Chu, Jiachen, Yu, Haiyang, Sun, Shuying, Qiu, Zhaozhu
• Format: Journal Article
• Language: English
• Published: United States The American Association for the Advancement of Science 26.04.2019
• Subjects: Acidosis; Animals; Brain damage; Brain injury; Calcium - metabolism; Cancer; Cell Death; Chloride channels; Chloride Channels - classification; Chloride Channels - genetics; Chloride Channels - metabolism; Chloride ions; Chlorides - metabolism; Conductance; Conserved Sequence; Domains; Evolution, Molecular; HEK293 Cells; High altitude; High altitude environments; Humans; Hydrogen-Ion Concentration; Hypoxia-Ischemia, Brain - metabolism; Hypoxia-Ischemia, Brain - pathology; Interference; Ion channels; Ischemia; Membrane proteins; Membrane Proteins - classification; Membrane Proteins - genetics; Membrane Proteins - metabolism; Mice; Mice, Knockout; Molecular modelling; Neurological Impairments; Neurons - metabolism; Neurons - pathology; Pain; Phylogeny; Physiology; Proteins; Protons; Ribonucleic acid; RNA; RNA Interference; RNA-mediated interference; Stroke; Stroke - metabolism; Stroke - pathology; Tissues; Transmembrane domains; Zebrafish; Zebrafish Proteins - classification; Zebrafish Proteins - genetics; Zebrafish Proteins - metabolism
• ISSN: 0036-8075; 1095-9203
• DOI: 10.1126/science.aav9739

Severe local acidosis causes tissue damage and pain, and is one of the hallmarks of many diseases including ischemia, cancer, and inflammation. However, the molecular mechanisms of the cellular response to acid are not fully understood. We performed an unbiased RNA interference screen and identified as being essential for the widely observed proton-activated Cl (PAC) currents ( ). Overexpression of human PAC in knockout cells generated with the same characteristics as the endogenous ones. Zebrafish PAC encodes a PAC channel with distinct properties. Knockout of mouse abolished in neurons and attenuated brain damage after ischemic stroke. The wide expression of PAC suggests a broad role for this conserved Cl channel family in physiological and pathological processes associated with acidic pH.