Key Osmotic Channel Protein Identified

So Qiu and his colleagues devised an assay to identify the proteins involved. They transfected cells with small interfering RNAs (siRNAs) and adapted a yellow fluorescent protein (YFP) to see which genes knocked were down by the siRNAs. Among the 51 genes the researchers homed in on, “there was only one gene that completely abolished the VRAC activity,” said Qiu. “Previously, very little was known of this gene.”

The researchers named the gene SWELL1. The same gene had been discovered a decade ago, and linked to B cell development. But little research had been done SWELL1 (once known as LRRC8A) since then. In 2012, it was found to be related to a class of proteins pannexins.

Using cells in which SWELL1 had been knocked down, Qiu and his colleagues found the SWELL1 is required for volume regulation. They also found that the protein was embedded in the cellular membrane in an unexpected way. “People have been thinking that the leucine-rich repeats were on the outside,” said Qiu, “However, the topology we found [indicated] they were on the inside.”

SWELL1 appears to form a pore-like structure, although it’s unlikely that the protein is responsible for channel function on its own. And overexpressing SWELL1 didn’t increase VRAC activity in the cell, the researchers found.

The identification of SWELL1 could impact biomedical research, said Geoffrey Abbott of the University of California, Irvine, who was not involved in the work. “Now that the gene is known, it opens the floodgate for geneticists and people interested in certain diseases to say ‘OK, let us start searching for human mutations in this gene that might be associated with disease states,’” he said.

Given the history of VRAC protein research, some ion channel researchers are cautious. “While very exciting, this excitement is tempered by the knowledge that several other protein candidates have been identified over the last 25 years,” Peter Brown of Manchester University in the U.K. told The Scientist in an e-mail. However, he added, “this study seems more robust than those supporting the claims of the previous pretenders.”

And questions remain as to the molecular mechanisms at play. “It’s not clear how this channel is able to sense osmotic stimuli and then react to them,” said Grandl. “This is very interesting, very novel, but it will still require a lot of work” to fully characterize SWELL1’s role, he added.

Qiu, Patapoutian, and their colleagues now plan to purify the protein and insert it into a lipid bilayer membrane to assess its activities on its own, and with the help of other proteins and activator molecules.

Z. Qiu et al., “SWELL1, a plasma membrane protein, is an essential component of volume-regulated anion channel,” Cell, 157:447–58, 2014.