Sensors and signal transduction pathways in vertebrate cell volume regulation

The ability to control cell volume is fundamental for proper cell function. This review highlights recent advances in the understanding of the complex sequences of events by which acute cell volume perturbation alters the activity of osmolyte transport proteins in cells from vertebrate organisms. After cell swelling, the main effectors in the process of regulatory volume decrease are swelling-activated K(+) and Cl(-) channels, a taurine efflux pathway, and KCl cotransport. After cell shrinkage, the main effectors in the process of regulatory volume increase are Na(+)/H(+) exchange, Na(+), K(+), 2Cl(-) cotransport, and in some cells, shrinkageactivated Na(+) channels. All of these proteins are regulated in a unique manner by cell volume perturbations. The molecular identity of most, although not all, of these transport pathways is now known. Among other important advances, this has lead to the identification of transporter binding partners such as protein kinases and phosphatases, cytoskeletal elements and lipids. Considerable progress has also been made recently in understanding the upstream elements in volume sensing and volume-sensitive signal transduction, and salient features of these systems will be discussed. In contrast to the simple pathway of osmosensing in yeast, cells from vertebrate organisms appear to exhibit multiple volume sensing systems, the specific mechanism(s) activated being cell type- and stimulus-dependent. Candidate sensors include integrins and growth factor receptors, while other early events include regulation of Rho family GTP binding proteins, Ste20-related protein kinases, and phospholipases, as well as cytoskeletal reorganization, Transient Receptor Potential channel-mediated Ca(2+) influx, and generation of reactive oxygen species.