Abstract
Molecular identification was, at last, successfully accomplished for three types of anion channels that are all implicated in cell volume regulation/dysregulation. LRRC8A plus LRRC8C/D/E, SLCO2A1, and TMEM206 were shown to be the core or pore-forming molecules of the volume-sensitive outwardly rectifying anion channel (VSOR) also called the volume-regulated anion channel (VRAC), the large-conductance maxi-anion channel (Maxi-Cl), and the acid-sensitive outwardly rectifying anion channel (ASOR) also called the proton-activated anion channel (PAC) in 2014, 2017, and 2019, respectively. More recently in 2020 and 2021, we have identified the S100A10-annexin A2 complex and TRPM7 as the regulatory proteins for Maxi-Cl and VSOR/VRAC, respectively. In this review article, we summarize their biophysical and structural properties as well as their physiological roles by comparing with each other on the basis of their molecular insights. We also point out unsolved important issues to be elucidated soon in the future.
Highlights
According to the activation mechanisms, mammalian anion channels have been classified into six major groups: voltage-gated, ligand-gated receptor-coupled, Ca2+-activated, cAMP-activated, volume-activated, and acid-activated ones
The firmest evidence for pore-forming roles in maxi-anion channel (Maxi-Cl) and ASOR/proton-activated anion channel (PAC) was provided by the observations that a charge-neutralizing K613G mutant of SLCO2A1 (Sabirov et al, 2017) and a chargereversing K319E mutant of TMEM206 (Ruan et al, 2020) converted their activities from anion-selective to cation-selective channels, respectively
FUNCTIONAL PROPERTIES OF VOLUME-SENSITIVE OUTWARDLY RECTIFYING ANION CHANNEL/VOLUME-REGULATED ANION CHANNEL, MAXI-ANION CHANNEL, AND ACID-SENSITIVE OUTWARDLY RECTIFYING/PROTON-ACTIVATED ANION CHANNEL. Electrophysiological properties of these three types of volumerelated anion channels were directly studied by observing their channel currents using patch-clamp techniques, and those were described in detail so far in the review articles for volume-sensitive outwardly rectifying anion channel (VSOR)/volumeregulated anion channel (VRAC) (Strange et al, 1996; Nilius et al, 1997; Okada, 1997), Maxi-Cl (Sabirov et al, 2016, 2021), and ASOR/PAC (Okada et al, 2021b)
Summary
According to the activation mechanisms, mammalian anion channels have been classified into six major groups: voltage-gated, ligand-gated receptor-coupled, Ca2+-activated, cAMP-activated, volume-activated, and acid-activated ones. The core molecules for VSOR/VRAC, Maxi-Cl, and ASOR/PAC were identified at last in 2014–2019 (see below) all by unbiased genome-wide approaches, whereas molecular entities of other types of anion channels were elucidated much earlier.
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