To survive, cells have to avoid excessive alterations of cell volume that jeopardize structural integrity and constancy of intracellular milieu. The function of cellular proteins seems specifically sensitive to dilution and concentration, determining the extent of macromolecular crowding. Even at constant extracellular osmolarity, volume constancy of any mammalian cell is permanently challenged by transport of osmotically active substances across the cell membrane and formation or disappearance of cellular osmolarity by metabolism. Thus cell volume constancy requires the continued operation of cell volume regulatory mechanisms, including ion transport across the cell membrane as well as accumulation or disposal of organic osmolytes and metabolites. The various cell volume regulatory mechanisms are triggered by a multitude of intracellular signaling events including alterations of cell membrane potential and of intracellular ion composition, various second messenger cascades, phosphorylation of diverse target proteins, and altered gene expression. Hormones and mediators have been shown to exploit the volume regulatory machinery to exert their effects. Thus cell volume may be considered a second message in the transmission of hormonal signals. Accordingly, alterations of cell volume and volume regulatory mechanisms participate in a wide variety of cellular functions including epithelial transport, metabolism, excitation, hormone release, migration, cell proliferation, and cell death.
Mammalian cells utilize a wide variety of cell volume regulatory mechanisms. For rapid adjustment of cell volume cells release or accumulate ions through respective channels and transport systems across the cell membrane. The most widely used mechanisms of cell volume regulatory ion release include ion channels and KCl symport. Ion uptake is most frequently mediated by Na+ channels, Na+, K+, 2Cl– cotransport, and Na+/H+ exchange. Chronic adjustment of cell osmolarity is accomplished by the formation or accumulation of organic osmolytes, molecules specifically designed to create intracellular osmolarity without interfering with cellular function. The most widely occurring osmolytes are sorbitol, inositol, glycerophosphorylcholine, betaine, taurine, and amino acids. The osmolytes are either synthesized by or transported into shrunken cells. During cell swelling osmolytes can be rapidly degraded or released. Any given cell may utilize several volume-regulatory mechanisms. Moreover, different mechanisms are utilized in different tissues. The diversity of cell volume regulatory mechanisms allows the cells to defend the constancy of cell volume against a myriad of challenges with relatively little impairment of cellular function.
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