LRRC8/VRAC chloride and metabolite channels in signaling and volume regulation

Volume-regulated anion channels (VRACs) are almost ubiquitously expressed plasma membrane (PM) channels of vertebrate cells with roles in cell volume regulation and signaling. Besides conducting anions such as chloride, VRACs transport metabolites, neurotransmitters, immunomodulators, and drugs irrespective of their electrical charge. VRAC-mediated transport of these molecules has profound (patho)physiological significance. The recent identification of VRACs as heteromers of up to five different LRRC8 proteins allowed the roles of VRACs to be addressed with genetic and molecular tools. Cryogenic electron microscopy (cryo-EM) and mutagenesis yielded insights into the structure and function of VRACs, yet their activation mechanisms remain enigmatic. Here we focus on new developments and suggest that the ability of VRAC to transport metabolites and signaling molecules may be physiologically more important than its role in cell volume regulation.