The proton-activated Cl^- (PAC) channel, which opens by extracellular acidic pH, has been well characterized in several cells and tissues by electrophysiology recordings, although its molecular identity was unknown.

Recently, two independent groups, identified a two-transmembrane protein named PACC1 (or TMEM206) as the molecular underlie of the proton-activated Cl^- channel ^1,2.

PACC1 has no discernible sequence homology with previously characterized Cl^- channels, although its structure of two transmembrane domains with cytoplasmic N- and C-termini and a large extracellular loop, resembles that of the Na⁺ -selective channels ASICs and ENaCs. In fact, recent work suggests that the functional unit of the proton-activated Cl^- channel is a trimeric form of PACC1 subunits^3,4.

PAC activity that is stimulated by the lowering of extracellular pH and has been recorded in a wide range of mammalian cells and tissues. Acidic pH is crucial for the function of intracellular organelles in the secretory and endocytic pathways and is also one of the pathological hallmarks of many diseases, including cerebral and cardiac ischemia, cancer, infection and inflammation.  Therefore, it is no surprise that the involvement of PACC1 in several physiological processes of the endocytic pathway^5,6 and pathological conditions such as acid-induced cell death and brain damage after ischemic stroke⁷ or that upregulation of PACC1 is associated with poor prognosis in patients with hepatocellular carcinoma⁸.