1.A.114. The Proton-activated Chloride Channel (PACC) Family
Severe local acidosis causes tissue damage and pain, and is one of the hallmarks of many diseases including ischemia, cancer, and inflammation. Yang et al. 2019 performed an unbiased RNA interference screen and identified PAC (TMEM206) as being essential for the widely observed proton-activated Cl- (PAC) currents (I Cl,H). Overexpression of human PAC in PAC knockout cells generated I Cl,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,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 (Yang et al. 2019).
Ullrich et al. 2019 used a genome-wide siRNA screen to molecularly identify the widely expressed acid-sensitive outwardly-rectifying anion channel PAORAC/ASOR. ASOR is formed by TMEM206 proteins which display two TMSs and are expressed at the plasma membrane. Ion permeation-changing mutations along the length of TMS2 and at the end of TMS1 suggest that these segments line ASOR's pore. TMEM206 has orthologs in probably all vertebrates, but possibly not in other orgamism. Currents from evolutionarily distant orthologs share activation by protons, a feature essential for ASOR's role in acid-induced cell death (Ullrich et al. 2019).