PACC1 encodes the proton-activated chloride (PAC) channel, a pH-gated ion channel that facilitates chloride entry into cells upon exposure to extracellular acidic conditions 1. The channel exists as a trimeric structure with each subunit containing two transmembrane helices and an extracellular domain that undergoes conformational changes during pH-dependent activation 2. PAC channels are broadly expressed across tissues, with particularly high expression in the brain where they localize to both neurons and astrocytes 3. The channel plays a critical role in acidosis-induced cell death by mediating chloride influx and subsequent cell swelling 14. Alternative splicing produces distinct isoforms with different cellular localizations: PACC1-V1 accumulates at the plasma membrane and enhances acid-induced cell death, while PACC1-V2 localizes to endosomes and prevents endosomal hyperacidification 3. Beyond neuronal function, PAC channels contribute to osteoclast-mediated bone resorption and associated pain in spine degeneration 5. The channel is inhibited by phosphatidylinositol (4,5)-bisphosphate (PIP2), which stabilizes it in a desensitized conformation 6. Clinically, PACC1 expression correlates with poor prognosis in triple-negative breast cancer and influences type 2 diabetes susceptibility 78.