Scientists Discover Protein Essential For Cell Volume Regulation
All living cells absorb water to carry out essential biochemical processes. Now, scientists from The Scripps Research Institute (TSRI) have identified the protein that regulates the intake of water by cells and prevents them from bursting. Their research has been reported in detail in the April 10, 2014 issue of the journal Cell.
This protein called SWELL1, which scientists have been trying to find for decades, is the missing link in the study of cell biology. Scientists are now attempting to understand its role in important biological functions and why its deficiency leads to a serious immune disorder. "Knowing the identity of this protein and its gene opens up a broad new avenue of research," said the study's principal investigator Ardem Patapoutian, according to a press release Thursday. Water passes through the cell membranes with relative ease and flows in a direction that evens out the concentration of dissolved molecules or "solutes". "Water in effect follows the solutes," explained Zhaozhu Qiu, a member of the Patapoutian laboratory who was first author of the study. "Any decrease in the solute concentration outside a cell or an increase within the cell will make the cell swell with water."
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For many years scientist have known that there are channels that control the cell volume regulation. This ion channel is called volume-regulated anion channels (VRAC). VRAC opens when the cell starts to swell and permits an outflow of chloride ions and some other negatively charged molecules. Water molecules also flow out, thus reducing the swelling.
"For the past 30 years, scientists have known that there is this VRAC channel, and yet they haven't known its molecular identity," said Patapoutian.
The main aim for the scientists was to find the protein that regulates VRAC. This was never attempted before due to the technical difficulties involved. But in this research the scientists were able to set up a rapid, "high-throughput" screening test based on fluorescence. Human cells were engineered to produce a fluorescent protein, which would eventually lose its glow when VRAC channels would be opened, in response to cell swelling.
With the help of automated screening specialists at the La Jolla-based Genomics Institute of the Novartis Research Foundation (GNF), which recently began a broad new collaboration agreement with TSRI, the team cultured large arrays of the cells and used the RNA interference technique to inhibit gene expression for each clump of cells. This gene inhibition caused the disruption of the VRAC. The scientists could then identify the groups of cells that continued to glow due to failure of the VRAC mechanism.
The team conducted the test on several human genes until that one gene whose disruption reliably terminated VRAC activity, was found. This gene, named "LRRC8" had already been discovered in 2003 and is known to encode the Leucine-rich repeat-containing protein 8A protein. Not much was known about this gene and the Qiu's team renamed it as SWELL1. Further research showed that SWELL1 does indeed localize to the cell membrane as an ion channel protein would and certain mutations in this gene effects the ion-passing properties of VRAC, indicating its significance. "It is at least a major part of the VRAC channel for which cell biologists have been searching all this time," said Patapoutian.
The team now plans to further study this gene and its potential role in a very rare type of disease called agammaglobulinemia, where the body is unable to produce normal B-cells, which in turn are needed for producing antibodies.
"There also have been suggestions from prior studies that this volume-sensitive ion channel is involved in stroke because of the brain-tissue swelling associated with stroke and that it may be involved as well in the secretion of insulin by pancreatic cells," said Patapoutian. "So there are lots of hints out there about its relevance to disease-we just have to go and figure it all out now."
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