Channels and Volume Changes in the Life and Death of the Cell

Volume changes deviating from original cell volume represent a major challenge for cellular homeostasis. Cell volume may be altered either by variations in the external osmolarity or by disturbances in the transmembrane ion gradients that generate an osmotic imbalance. Cells respond to anisotonicity-induced volume changes by active regulatory mechanisms that modify the intracellular/extracellular concentrations of K+, Cl-, Na+, and organic osmolytes in the direction necessary to reestablish the osmotic equilibrium. Corrective osmolyte fluxes permeate across channels that have a relevant role in cell volume regulation. Channels also participate as causal actors in necrotic swelling and apoptotic volume decrease. This is an overview of the types of channels involved in either corrective or pathologic changes in cell volume. The review also underlines the contribution of transient receptor potential (TRP) channels, notably TRPV4, in volume regulation after swelling and describes the role of other TRPs in volume changes linked to apoptosis and necrosis. Lastly we discuss findings showing that multimers derived from LRRC8A (leucine-rich repeat containing 8A) gene are structural components of the volume-regulated Cl-channel (VRAC), and we underline the intriguing possibility that different heteromer combinations comprise channels with different intrinsic properties that allow permeation of the heterogenous group of molecules acting as organic osmolytes.