Volume-regulated anion channels (VRACs) regulate the cell volume in mammalian cells and, in response to swelling, release chloride and organic osmolytes, such as myo-inositol and taurine, to reduce intracellular osmolarity. VRACs are heteromeric complexes consisting of the obligatory subunit LRRC8A and at least one of the other five LRRC8 isoforms (LRRC8B to LRRC8E). However, the full spectrum of VRAC substrates and their dependence on specific subunits remains unknown. In this issue (p. 1122), Thomas Jentsch and co-workers use HEK293 cell lines carrying genomic disruptions of individual LRRC8 genes to test whether previously proposed neurotransmitters are VRAC substrates and to evaluate a dependence of their transport on specific LRRC8 subunits. They now find that, unexpectedly, GABA, the main inhibitory neurotransmitter in the brain, is transported through VRACs, as are the previous candidate substrates aspartate and glutamate. Interestingly, LRRC8D is important for the transport of all tested organic substrates, but can be replaced by LRRC8E for those that are negatively charged. Further systematic analysis of different LRRC8 combinations reveals for the first time that VRACs can contain at least three different LRRC8 subunits in the same complex. This could affect VRAC substrate specificity, as LRRC8 isoform expression varies between different cells and tissues, and so provide a means to control the efflux of subsets of neuroactive compounds with relevance for physiological and disease conditions.
- © 2017. Published by The Company of Biologists Ltd