PAC, an evolutionarily conserved membrane protein, is a proton-activated chloride channel
PAC, an evolutionarily conserved membrane protein, is a proton-activated chloride channel
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DOI：
10.1126/science.aav9739
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发表时间：
2019-04-26
期刊：
影响因子：
56.9
通讯作者：
Qiu, Zhaozhu
中科院分区：
文献类型：
--
作者：
Yang, Junhua;Chen, Jianan;Qiu, Zhaozhu
严重的局部酸中毒导致组织损伤和疼痛，是包括缺血、癌症和炎症在内的许多疾病的特征之一。然而，细胞对酸的反应的分子机制还不完全清楚。我们进行了无偏的RNA干扰筛选，发现PAC(TMEM206)对于广泛观察到的质子激活的Cl-(PAC)电流(I-Cl，I-H)是必不可少的。在PAC基因敲除细胞中过表达人PAC产生了与内源性相同的特征的I-Cl，I-H。斑马鱼PAC编码具有不同属性的PAC频道。小鼠Pac基因敲除可消除神经元的I-Cl、I-H，减轻缺血性卒中后的脑损伤。PAC的广泛表达表明，这个保守的氯通道家族在与酸性pH相关的生理和病理过程中发挥着广泛的作用。
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,I-H). Overexpression of human PAC in PAC knockout cells generated I-Cl,I-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,I-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.