Osmotransduction Through Volume-Sensitive Cl- Channels

Abstract

To sense environmental changes and various stresses is crucial for cells to survive by adjusting themselves to new environments. For this purpose, cells should have a mechanism to sense the environmental changes including osmotic stress and to respond immediately to them. Osmotic stress has been recognized to produce mechanical stress by membrane stretch and/or deformation through alteration of cell volume. A drastic cell volume change is observed by hypo-osmotic stress, namely an initial cell swelling followed by a regulatory volume decrease (RVD). Membrane stretch/deformation caused by the initial cell swelling might be the first step to transduce the stress into intracellular signaling cascades by modulating functions of membrane proteins including volume-sensitive ion channels and transporters. The conversion of physical forces produced by membrane stretch/deformation into biochemical signals has been discussed to clarify the regulatory mechanism of osmo-transduction and to identify the osmosensitive signal molecules. Recent studies have indicated that stretch-activated ion channels, integrins, growth factor receptors, cytoskelton, extracellular matrix and other various molecules contribute to the osmotransduction. However, a little is known how these molecules sense the osmotic- and mechanical-stresses and function to transduce the stress. So far, RVD is considered to be required for recovering the original cell volume after the initial cell swelling through activation of volume-sensitive Cl-/K+ channels. Recently, we have indicated that a part of hypo-osmotic stress might be converted into the RVD-induced decrease in intracellular Cl- concentration ([Cl-]i), which plays a key role in response to hypo-osmotic stress. In a renal epithelium, plasma hypo-osmolality stimulates Na+ reabsorption to maintain normal plasma osmolality by inducing epithelial Na+ channel (ENaC) gene expression through the RVD-induced decrease in [Cl-]i. This is a newly recognized physiological role of RVD in response to hypo-osmotic stress. In this review, we focus our discussion on understanding of regulatory mechanism of volume-sensitive Cl- channel by hypo-osmotic stress and the cytosolic Cl--dependent cellular responses through volume-sensitive Cl- channels.