Identification of LRRC8 Heteromers as an Essential Component of the Volume-Regulated Anion Channel VRAC

TLDR

When mammalian cells face osmotic challenges, they swell or shrink, yet the molecular identity of the volume‑regulated anion channel (VRAC) remains unknown despite many candidate proteins. The study aims to identify VRAC components to advance understanding of swelling‑activated ion channels and their physiological roles. A genome‑wide screen identified leucine‑rich repeat–containing (LRRC) proteins essential for VRAC formation. Suppressing LRRC8A almost abolished VRAC activity, and a heterooligomer of LRRC proteins was shown to constitute the channel. Voss et al.

Abstract

One Swell Ion Channel When mammalian cells are faced with osmotic challenges, they need to swell or shrink. The molecular characterization of the volume-regulated anion channel (VRAC) remains unknown, although many candidate proteins have been proposed. Voss et al. (p. 634 , published online 10 April; see the Perspective by Mindell ) used a genome-wide screen to identify a group of leucine-rich repeat–containing (LRRC) proteins necessary for forming VRAC. Suppression of LRRC8A nearly eliminated the presence of VRAC in mammalian cells. A heterooligomer of LRRC proteins appears to form VRAC. Identification of VRAC components is an essential step forward in the understanding of swelling-activated ion channels and provides opportunities for understanding both the mechanism of the channel and its role in physiology.