A SWELL time to develop the molecular pharmacology of the volume-regulated anion channel (VRAC)

Newly emerging roles of LRRC8 volume-regulated anion channels (VRAC) raise important questions about the therapeutic potential of VRAC in the treatment of epilepsy, type 2 diabetes, and other human diseases. A critical barrier to evaluating whether VRAC represents a viable drug target is the lack of potent and specific small-molecule inhibitors and activators of the channel. Here we review recent progress in developing the molecular pharmacology of VRAC made by screening a library of FDA-approved drugs for novel channel modulators. We discuss the discovery and characterization of cysteinyl leukotriene receptor antagonists Pranlukast and Zafirlukast as novel VRAC inhibitors, and zinc pyrithione (ZPT), which apparently activates VRAC through a reactive oxygen species (ROS)-dependent mechanism. These ongoing efforts set the stage for developing a pharmacological toolkit for probing the integrative physiology, molecular pharmacology, and therapeutic potential of VRAC.

Automated summary

The newly emerging roles of LRRC8 volume-regulated anion channels (VRAC) in the treatment of epilepsy, type 2 diabetes, and other human diseases raise important questions about their therapeutic potential. However, the lack of potent and specific small-molecule inhibitors and activators of VRAC hinders the evaluation of VRAC as a viable drug target. Recent progress has been made in developing the molecular pharmacology of VRAC through screening FDA-approved drugs, leading to the discovery of novel VRAC inhibitors and activators. This sets the stage for further research on the molecular pharmacology and therapeutic potential of VRAC.