TY - JOUR
T1 - PAC proton-activated chloride channel contributes to acid-induced cell death in primary rat cortical neurons
AU - Osei-Owusu, James
AU - Yang, Junhua
AU - Del Carmen Vitery, Maria
AU - Tian, Mengnan
AU - Qiu, Zhaozhu
N1 - Funding Information:
This work was supported by grants from the National Institutes of Health NIGMS R35 GM124824 (Z.Q.), the Klingenstein-Simons Fellowship in Neuroscience (Z.Q.), and an American Heart Association Predoctoral Fellowship 18PRE34060025 (J.O.-O.).
Publisher Copyright:
© 2020, © 2020 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.
PY - 2020/1/1
Y1 - 2020/1/1
N2 - Severe local acidosis causes tissue damage and pain, and is associated with many diseases, including cerebral and cardiac ischemia, cancer, infection, and inflammation. However, the molecular mechanisms of the cellular response to extracellular acidic environment are not fully understood. We recently identified a novel and evolutionarily conserved membrane protein, PAC (also known as PACC1 or TMEM206), encoding the proton-activated chloride (Cl−) channel, whose activity is widely observed in human cell lines. We demonstrated that genetic deletion of Pac abolished the proton-activated Cl− currents in mouse neurons and also attenuated the acid-induced neuronal cell death and brain damage after ischemic stroke. Here, we show that the proton-activated Cl− currents are also conserved in primary rat cortical neurons, with characteristics similar to those observed in human and mouse cells. Pac gene knockdown nearly abolished the proton-activated Cl− currents in rat neurons and reduced the neuronal cell death triggered by acid treatment. These data further support the notion that activation of the PAC channel and subsequent Cl− entry into neurons during acidosis play a pathogenic role in acidotoxicity and brain injury.
AB - Severe local acidosis causes tissue damage and pain, and is associated with many diseases, including cerebral and cardiac ischemia, cancer, infection, and inflammation. However, the molecular mechanisms of the cellular response to extracellular acidic environment are not fully understood. We recently identified a novel and evolutionarily conserved membrane protein, PAC (also known as PACC1 or TMEM206), encoding the proton-activated chloride (Cl−) channel, whose activity is widely observed in human cell lines. We demonstrated that genetic deletion of Pac abolished the proton-activated Cl− currents in mouse neurons and also attenuated the acid-induced neuronal cell death and brain damage after ischemic stroke. Here, we show that the proton-activated Cl− currents are also conserved in primary rat cortical neurons, with characteristics similar to those observed in human and mouse cells. Pac gene knockdown nearly abolished the proton-activated Cl− currents in rat neurons and reduced the neuronal cell death triggered by acid treatment. These data further support the notion that activation of the PAC channel and subsequent Cl− entry into neurons during acidosis play a pathogenic role in acidotoxicity and brain injury.
KW - PACC1
KW - Proton-activated chloride channel
KW - TMEM206
KW - acid-induced neuronal death
KW - ischemic stroke
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U2 - 10.1080/19336950.2020.1730019
DO - 10.1080/19336950.2020.1730019
M3 - Article
C2 - 32093550
AN - SCOPUS:85087199853
SN - 1933-6950
VL - 14
SP - 53
EP - 58
JO - Channels
JF - Channels
IS - 1
ER -