Volume-regulated anion channels (VRACs) are crucial to the regulation of cell size by transporting chloride ions and various organic osmolytes, such as taurine or glutamate, across the plasma membrane, and that is not the only function these channels have been linked to. Some research has also suggested that VRACs may be water-permeable as well. The regulation of cell volume is necessary not only as a prevention against swelling or shrinkage caused by a change in the cell's environment, but also throughout all stages of a cell's life. The changing of a cell's volume, whether it be swelling or shrinkage, generally occurs without major changes, such as exocytic insertion or endocytic retrieval of the plasma membrane. Instead, volume regulation mostly occurs through the transport of potassium, sodium, chloride, and organic osmolytes across the membrane. The ramifications of cells not being able to regulate their volume size in relation to their environments are great as swelling leads to lysis, and shrinking eventually leads from dehydration to apoptosis. The specific role that VRACs play in the regulation of cell volume specifically is regulatory volume decrease (RVD) of cells. Research of VRACs has led some to conclude that they are widely expressed in mammalian cells and that they may even be ubiquitously expressed. VRACs have also been shown to participate in fundamental cellular processes other than basic volume regulation, such as cell proliferation, migration, and apoptosis.
Structure and mechanism Although the scientific community has known about VRACs for a long time, it was only recently discovered what the molecular composition of the channels is. They are composed of LRRC8 protein heteromers, of which there are five variations. However, the specific composition of LRRC8A, LRRC8B, LRRC8C, LRRC8D, and LRRC8E necessary for a properly functioning VRAC are unknown. LRRC8A alone can form a hexameric VRAC, for which the cyro-EM structure has been determined in its mice and human versions. Research has also shown that variations in the composition of the subunits leads to variations in the ability of VRACs to transport certain metabolites. For instance, the subunit LRRC8D being involved in the composition of VRAC has been highly associated with the transport of taurine along with specific anti-cancer drugs. Because of experiments like this, we know that it is likely that LRRC8 proteins create the VRAC pore as well. As for a mechanism for VRACs, recent research has suggested that they are activated when there is a reduction of intracellular ionic strength, which implies that VRACs may also act as sensors as well as affecters of cell volume regulation. However, researchers have not been able to find any intracellular signaling mechanisms that play a dominant role in VRAC activation. The transmembrane portion of LRRC8 proteins are similar to those in Pannexins.
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