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

Abstract

Acid-sensing ion channels have important functions in physiology and pathology, but the molecular composition of acid-activated anion channels had remained unclear. We now used a genome-wide siRNA screen to molecularly identify the widely expressed acid-sensitive outwardly-rectifying ASOR chloride channel. 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.

Acid- and Volume-Sensitive Chloride Currents in Microglial Cells

“…Accordingly, the knock-down of a specific channel protein candidate might not necessarily mean a significant impact on the absolute current magnitude or phenotype, but rather cause changes, e.g., in the pH sensitivity, ion selectivity, or pharmacological profile. Just recently, by performing RNA interference screening, a significant step towards the identification of the molecular basis of ASOR currents has been made with the identification of TMEM206 as a core component of the ASOR channel pore [49,50], which will push the understanding of ASOR channel function in future studies.…”

Proton-Activated Chloride Channel: Physiology and Disease

“…It was proposed that cell swelling induced by extracellular acidity is caused by the osmotic gradient generated by PAC-mediated Cl − influx. Knockout of TMEM206 partially protects cells from cell death caused by extracellular acidity [27]. When exposed to extracellular pH 4.5, the cell volume gradually recovered their volume and even shrank after reaching the peak swelling.…”

“…PAC belongs to a unique and highly conserved family of ion channels that are probably highly conserved in all vertebrate species and shares no significant sequence with any other families of membrane proteins, such as cystic fibrosis transmembrane regulator (CFTR), CLCs and NHE [2,27]. PAC has been identified in 27 kinds of tissues in human including brain, kidney, testis, lymph node and bone marrow [12].…”