Volumeregulated

Volume-regulated describes cellular mechanisms that monitor and adjust to changes in cell volume, typically arising from shifts in extracellular osmolality. The term encompasses ion channels, transporters, and signaling pathways that sense swelling or shrinkage and trigger compensatory fluxes of ions and osmolytes to restore volume and maintain cell integrity.

A central outcome of volume-regulated responses is regulatory volume decrease (RVD), which occurs after cell swelling. Cells expel inorganic ions such as K+ and Cl− and organic osmolytes (taurine, glutamate, betaine), reducing intracellular osmolarity so water exits the cell. Conversely, regulatory volume increase (RVI) can occur during cell shrinkage by accumulating ions and osmolytes to attract water.

A key component of volume-regulated signaling is the volume-regulated anion channel (VRAC), also called VSOR. VRAC is activated by cell swelling and is formed by LRRC8 family subunits, with LRRC8A as essential. The channel conducts Cl− and a range of organic osmolytes, enabling the solute efflux that drives RVD. Activation is modulated by cytoskeletal status, phosphorylation, and cellular redox state.

In physiology and medicine, volume-regulated mechanisms help maintain cell and tissue osmolality in epithelia and neurons, influence edema formation, and affect responses to ischemia and chemotherapy, where VRAC can mediate uptake or release of drugs such as cisplatin. Defects or dysregulation of volume-regulated pathways can contribute to disease.