Mediation of cell volume regulation by Ca²⁺ influx through stretch-activated channels

Abstract

Animal cells initially swell in hypotonic media by osmotic water equilibration, but their volume is subsequently regulated by a net loss of KCl and amino acids with concomitant loss of cell water^1,2. Mechanisms for regulating cell volume are important in allowing cells to adapt to variations in external tonicity and metabolic load³. In red cells the KCl loss is mediated by electroneutral ion transport mechanisms⁴. In contrast, conductive K⁺ and Cl^– transport pathways are activated during regulatory volume decrease in several cell types^5,6 including epithelia^7,8. The activation seems to be mediated⁹ by internal Ca²⁺, but the detailed mechanism is not known. In a leaky epithelium, the choroid plexus epithelium, we have found a cation-selective, Ca²⁺-permeable channel which opens with membrane stretch^10–12. The epithelium also contains a high density of the large (∼200 pS) type of Ca²⁺- and voltage-activated K⁺ channel¹³. Both channels are normally closed. I propose that in hypotonic media, the stretching of the cell membrane produced by the initial swelling causes influx of Ca²⁺ through the stretch-activated channels, which activates the neighbouring large K⁺ channels to produce increased K⁺ outflux with associated loss of cell water.