PAC, an evolutionarily conserved membrane protein, is a proton-activated chloride channel

Abstract

Severe local acidosis causes tissue damage and pain, and is one of the hallmarks of many diseases including ischemia, cancer, and inflammation. However, the molecular mechanisms of the cellular response to acid are not fully understood. We performed an unbiased RNA interference screen and identified PAC (TMEM206) as being essential for the widely observed proton-activated Cl− (PAC) currents (ICl,H). Overexpression of human PAC in PAC knockout cells generated ICl,H with the same characteristics as the endogenous ones. Zebrafish PAC encodes a PAC channel with distinct properties. Knockout of mouse Pac abolished ICl,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.

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

“…Although their wide expression pattern across tissues and vertebrates suggests important physiological functions for all cells, these roles remain to be determined. The identification of TMEM206 as ASOR channel-forming protein in this work and in a recently published independent study by Qiu and coworkers [36] is an essential step forward towards the elucidation of these roles.…”

“…TMEM206/ASOR channels are involved in acid-induced cell death, but this role in pathology cannot explain its wide and possibly ubiquitous expression across tissues and vertebrate species. Its molecular identification in this work and in the parallel study of Yang et al [36] is an important step to identify its physiological roles and to mechanistically understand the diverse ways by which anion-selective channels can be formed.…”

“…Recently, while the present work was being completed, Yang et al reported on their independent identification and characterization of TMEM206 as integral component of the ASOR channel (which the authors renamed PAC for Proton-Activated Channel) [36]. They likewise reported protective effects of TMEM206 disruption on acid-induced cell death of HEK cells or cultured primary cortical neurons.…”

“…They likewise reported protective effects of TMEM206 disruption on acid-induced cell death of HEK cells or cultured primary cortical neurons. Intriguingly, these authors showed that Tmem206 −/− mice showed smaller stroke areas in a middle cerebral artery occlusion model [36], although the previously reported decrease of pH o in the stroke area (down to ~6.4) [26] is slightly above the value needed for ASOR activation. In a cysteine modification scan restricted to the extracellular half of TM2, they also found that reaction of I307C with MTSES reduces ASOR currents, and showed that the I307A mutant displayed moderately decreased iodide permeability.…”

“…5D). The current decrease at more acidic pH questions the reliability of determining Hill coefficients for the activation of ASOR by H + ions [12,13,36]. Differences between orthologs were also observed in depolarization-activated gating and current rectification (…”