Identification of TMEM206 proteins as pore of PAORAC/ASOR acid-sensitive chloride channels

• Published in: eLife Vol. 8
• Main Authors: Ullrich, Florian, Blin, Sandy, Lazarow, Katina, Daubitz, Tony, von Kries, Jens Peter, Jentsch, Thomas J
• Format: Journal Article
• Language: English
• Published: England eLife Science Publications, Ltd 18.07.2019; eLife Sciences Publications Ltd; eLife Sciences Publications, Ltd
• Subjects: Acidification; Acidity; acidotoxicity; Acids; Acids - metabolism; Animals; Anions - metabolism; Apoptosis; Cell Biology; Cell death; Cell Death - genetics; Cell Membrane - genetics; Cell Membrane - metabolism; Cell membranes; Channel pores; Chloride; Chloride channels; Chloride Channels - chemistry; Chloride Channels - genetics; Chloride Channels - metabolism; Chlorides - metabolism; Cl- channel; Genetic screening; Genome, Human - genetics; Genomes; Genomics; HeLa Cells; Humans; Hydrogen-Ion Concentration; ICl,H; Identification and classification; Ion channels; Membrane proteins; naked mole rat; Novels; PAC; Physiological aspects; Proteins; proton-activated; Protons; RNA; siRNA; Sodium channels; Structural Biology and Molecular Biophysics; Transmembrane domains; United States; Berlin Germany; acidotoxicity; naked mole rat; PAC; cell biology; Cl- channel; proton-activated; ICl,H; structural biology; molecular biophysics; human
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/eLife.49187

Acid-sensing ion channels have important functions in physiology and pathology, but the molecular composition of acid-activated chloride channels had remained unclear. We now 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 transmembrane domains (TMs) and are expressed at the plasma membrane. Ion permeation-changing mutations along the length of TM2 and at the end of TM1 suggest that these segments line ASOR’s pore. While not belonging to a gene family, TMEM206 has orthologs in probably all vertebrates. Currents from evolutionarily distant orthologs share activation by protons, a feature essential for ASOR’s role in acid-induced cell death. TMEM206 defines a novel class of ion channels. Its identification will help to understand its physiological roles and the diverse ways by which anion-selective pores can be formed.