PAC, an evolutionarily conserved membrane protein, is a proton-activated chloride channel
Junhua Yang1, Jianan Chen1, Maria Del Carmen Vitery1
1Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Science (New York, N.Y.)
|April 27, 2019
Summary
Researchers identified PAC (TMEM206) as crucial for proton-activated chloride currents (ICl,H). This discovery sheds light on cellular responses to acidosis and its role in diseases like stroke.
Area of Science:
- Molecular biology
- Cellular physiology
- Neuroscience
Background:
- Severe local acidosis is a key factor in tissue damage and pain, common in diseases like ischemia, cancer, and inflammation.
- The precise molecular mechanisms governing cellular responses to acidic environments remain incompletely understood.
Purpose of the Study:
- To identify molecular players involved in cellular responses to acidosis.
- To elucidate the function of proton-activated chloride currents (ICl,H) in physiological and pathological conditions.
Main Methods:
- Conducted an unbiased RNA interference screen to identify genes critical for proton-activated chloride currents.
- Utilized gene knockout and overexpression techniques in cell lines and animal models (zebrafish, mice).
- Measured proton-activated chloride currents (ICl,H) and assessed brain damage in a mouse model of ischemic stroke.
Main Results:
- Identified PAC (TMEM206) as essential for proton-activated chloride currents (ICl,H).
- Demonstrated that overexpressed human PAC can restore ICl,H in knockout cells.
- Showed that mouse Pac knockout eliminates ICl,H in neurons and reduces brain damage post-ischemic stroke.
- Zebrafish PAC exhibits distinct channel properties.
Conclusions:
- PAC (TMEM206) is a critical component of the proton-activated chloride channel.
- The PAC channel family plays a significant role in cellular responses to acidic pH.
- Targeting PAC may offer therapeutic strategies for conditions involving acidosis, such as ischemic stroke.
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