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

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Science  26 Apr 2019:
Vol. 364, Issue 6438, pp. 395-399
DOI: 10.1126/science.aav9739

A new protein channel family

Exposure of cells to acidic conditions outside the cell activates chloride-conducting channels that influence physiological and pathological processes. Yang et al. used an unbiased RNA interference screen to identify the channel protein that allows such proton-activated ion conductance. The protein, called PAC for proton-activated channel, has two predicted transmembrane domains and is unlike any previously identified channel. Identification of the channel should advance studies of its physiological roles, which range from tissue injury after stroke to adaptation of Tibetan natives to a high-altitude environment.

Science, this issue p. 395


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 (ICl,H). Overexpression of human PAC in PAC knockout cells generated ICl,H with the same characteristics as the endogenous ones. Zebrafish PAC encodes a PAC channel with distinct properties. Knockout of mouse Pac abolished ICl,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.

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