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

Science. 2019 Apr 26;364(6438):395-399. doi: 10.1126/science.aav9739. Epub 2019 Apr 25.


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 PAC (TMEM206) as being essential for the widely observed proton-activated Cl- (PAC) currents (I Cl,H). Overexpression of human PAC in PAC knockout cells generated I Cl,H with the same characteristics as the endogenous ones. Zebrafish PAC encodes a PAC channel with distinct properties. Knockout of mouse Pac abolished I Cl,H 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcium / metabolism
  • Cell Death
  • Chloride Channels / classification
  • Chloride Channels / genetics
  • Chloride Channels / metabolism*
  • Chlorides / metabolism
  • Conserved Sequence
  • Evolution, Molecular
  • HEK293 Cells
  • Humans
  • Hydrogen-Ion Concentration
  • Hypoxia-Ischemia, Brain / metabolism
  • Hypoxia-Ischemia, Brain / pathology
  • Membrane Proteins / classification
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Mice
  • Mice, Knockout
  • Neurons / metabolism
  • Neurons / pathology
  • Phylogeny
  • RNA Interference
  • Stroke / metabolism
  • Stroke / pathology
  • Zebrafish
  • Zebrafish Proteins / classification
  • Zebrafish Proteins / genetics
  • Zebrafish Proteins / metabolism*


  • Chloride Channels
  • Chlorides
  • Membrane Proteins
  • PACC1 protein, human
  • Pacc1 protein, mouse
  • Zebrafish Proteins
  • pacc1 protein, zebrafish
  • Calcium