Scientists at the Scripps Research Institute (TSRI) have clarified the composition and working mechanism of cell regulator after in-depth study. The study, published in the journal Cell on 28 January, has solved a long-standing mystery in cell biology.
As early as a few decades ago, researchers have discovered the existence of a certain ion channels on the cell membrane, known as VRAC (volume-regulated anion channel), that prevent the cellular from uptake of too much water and over-expansion. When the cells swell, the VRAC will open, allowing chlorine ions and other negatively charged molecules outflow. Then will follow the outflow of water molecules, and ultimately reducing the swelling cells. Later, researchers gradually realized that the VRAC is also important on human health. Studies have shown that VRAC is tentatively linked to stroke-induced brain damage, diabetes, immune deficiency and even cancer treatment resistance
The new study has shown that VRAC is a complex structure consisting of five different protein subunits—the precise mix of which determines its relief-valve properties. The researchers also found that VRAC's relief-valve function is activated not by the physical swelling of a cell per se, but by a closely linked event: the low concentration of dissolved ions that results from a sudden flow of water into a cell.
"Knowing how VRAC is assembled and how it works is important not only because it is a fundamental regulatory mechanism in cells, but also because it seems to have relevance for a variety of diseases and conditions," said principal investigator Ardem Patapoutian, a professor at TSRI and a Howard Hughes Medical Institute (HHMI) Investigator.
But how exactly does VRAC sense the swelling of a cell? This issue has been a headache to scientists. Because it is difficult to imagine how cells directly determine their increased volume. This new study shows that they were not activated by membrane stretching; they were, however, readily activated when the usual concentration of dissolved ions was reduced. That made sense. "Local decrease in the ionic strength is an inevitable result when the water rushes in and the cell swells," Syeda said.
Further studies of VRAC will be aimed at determining its precise physical structure, how variations in that structure alter its ion-conducting properties, how VRAC varies in different cell types, and how VRAC variants or mutants contribute to disease.
LRRC8 Proteins Form Volume-Regulated Anion Channels that Sense Ionic Strength. Cell, 2016; 164 (3): 499 DOI