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.

中文翻译：

---

PAC质子激活的氯离子通道有助于酸诱导的原代大鼠皮层神经元细胞死亡。

严重的局部酸中毒会导致组织损伤和疼痛，并伴有许多疾病，包括脑和心脏缺血，癌症，感染和炎症。但是，细胞对细胞外酸性环境的反应的分子机制尚未完全了解。我们最近发现了一种新型且进化上保守的膜蛋白PAC（也称为PACC1或TMEM206），其编码质子激活的氯离子（Cl-）通道，其活性在人细胞系中得到了广泛的观察。我们证明了Pac的基因缺失消除了小鼠神经元中质子激活的Cl-电流，也减弱了缺血性中风后酸诱导的神经元细胞死亡和脑损伤。在这里，我们显示质子激活的Cl-电流在原代大鼠皮层神经元中也保守，具有与人类和小鼠细胞相似的特征。Pac基因敲低几乎消除了大鼠神经元中质子激活的Cl-电流，并减少了酸处理触发的神经元细胞死亡。这些数据进一步支持了观念，即酸中毒期间PAC通道的激活和随后的Cl-进入神经元在酸中毒和脑损伤中起着致病作用。