VRACs and other ion channels and transporters in the regulation of cell volume and beyond

Key Points Cells need to adjust their volume in response to external osmotic stress, but also during the execution of cellular functions. These adjustments include changes in metabolism, transepithelial transport, cell division, growth, migration and programmed cell death. Cell volume regulation uses the generation of osmotic gradients across the plasma membrane. These gradients drive water through the membrane, which is facilitated by specialized water channels. Short-term volume regulation depends on plasma membrane channels or transporters that accumulate or release cellular osmolytes — mainly potassium, sodium and chloride, and organic osmolytes such as taurine, glutamate and inositol — in response to cell shrinkage and swelling, respectively. The underlying volume sensors and signalling cascades are complex and generally remain poorly understood. Most volume-regulatory plasma membrane transporters have additional important cellular and organismal functions, linking cell volume to processes such as regulation of cytoplasmic pH, transepithelial transport and the release of signalling molecules. Key players in cell volume regulation are the volume-regulated anion channels (VRACs), which have only recently been discovered to be composed of LRRC8 heteromers. Depending on the particular subunit composition, VRACs not only transport chloride, but also organic osmolytes and even clinically important anticancer drugs, and they have a role in apoptosis. VRAC-mediated release of taurine, glutamate and other metabolites may activate neurotransmitter receptors in the nervous system, suggesting a role for VRACs in astrocyte–neuron communication, systemic volume regulation and pathologies such as stroke. Vertebrate cell volume is controlled to maintain homeostasis. Volume adjustment is achieved by regulating transmembrane transport of ions and small organic osmolytes through diverse transporters and channels (including volume regulated anion channels (VRACs)), which are also implicated in other physiological processes such as metabolite transport and apoptosis, as well as in pathology. Cells need to regulate their volume to counteract osmotic swelling or shrinkage, as well as during cell division, growth, migration and cell death. Mammalian cells adjust their volume by transporting potassium, sodium, chloride and small organic osmolytes using plasma membrane channels and transporters. This generates osmotic gradients, which drive water in and out of cells. Key playe