Pacc1, also known as TMEM206, encodes the proton-activated chloride (PAC) channel, an evolutionarily conserved membrane protein. The PAC channel is involved in processes related to extracellular acidosis, regulating endosomal acidification and macropinosome shrinkage by releasing chloride from organelle lumens. It also contributes to acid-induced cell death under pathological acidosis conditions. Understanding its function is crucial for uncovering cellular responses to acidic environments [1,3,4].

Genetic knockout of the Pacc1 gene significantly reduced endplate porosity and spinal pain in a mouse chronic low-back-pain (LBP) model. This indicates that Pacc1 plays a role in osteoclast-mediated processes, as its expression was induced during osteoclast differentiation in porous endplates via a RANKL/NFATc1 signaling pathway. Also, genetic deletion of Pac (the mouse ortholog) abolished proton-activated Cl-currents in mouse neurons and attenuated acid-induced neuronal cell death and brain damage after ischemic stroke, suggesting its role in acidotoxicity and brain injury [2,4].

In conclusion, Pacc1, through encoding the PAC channel, is involved in cellular responses to acidosis. The gene knockout mouse models have revealed its significance in pain-related conditions such as LBP and in acid-induced neuronal cell death, highlighting its potential as a therapeutic target for these disease areas.

References:

1. Yang, Junhua, Chen, Jianan, Del Carmen Vitery, Maria, Sun, Shuying, Qiu, Zhaozhu. 2019. PAC, an evolutionarily conserved membrane protein, is a proton-activated chloride channel. In Science (New York, N.Y.), 364, 395-399. doi:10.1126/science.aav9739. https://pubmed.ncbi.nlm.nih.gov/31023925/

2. Xue, Peng, Zhang, Weixin, Shen, Mengxi, Qiu, Zhaozhu, Cao, Xu. 2024. Proton-activated chloride channel increases endplate porosity and pain in a mouse spine degeneration model. In The Journal of clinical investigation, 134, . doi:10.1172/JCI168155. https://pubmed.ncbi.nlm.nih.gov/39196784/

3. Mihaljević, Ljubica, Ruan, Zheng, Osei-Owusu, James, Lü, Wei, Qiu, Zhaozhu. 2023. Inhibition of the proton-activated chloride channel PAC by PIP2. In eLife, 12, . doi:10.7554/eLife.83935. https://pubmed.ncbi.nlm.nih.gov/36633397/

4. Osei-Owusu, James, Yang, Junhua, Del Carmen Vitery, Maria, Tian, Mengnan, Qiu, Zhaozhu. . PAC proton-activated chloride channel contributes to acid-induced cell death in primary rat cortical neurons. In Channels (Austin, Tex.), 14, 53-58. doi:10.1080/19336950.2020.1730019. https://pubmed.ncbi.nlm.nih.gov/32093550/