Present publication of Ravshan Z. Sibirov et al. reveals an intriguing new role for Volume-Regulated Anion Channels (VRAC) – the ubiquitously expressed chloride/anion permeability pathway. In spite of more than two decades of research, the molecular identity of VRAC remains a mystery. However, indirect evidence points to numerous important roles for this molecule (or molecules); and the present paper adds an exciting new dimension.

VRAC are also known in the literature as Volume-Sensitive Outwardly Rectifying (VSOR) anion channels or Volume-Sensitive Organic osmolyte/Anion Channels (VSOAC). They can be easily detected in majority of cell types using an electrophysiological approach as transmembrane chloride currents that are activated in response to cellular swelling. Loss of chloride and other osmotically active molecules via VRAC is coupled to passive loss of water, and determines cells’ ability to maintain their volume at a relatively constant level.

In addition to biologically “inert” chloride, bicarbonate, and several other small osmolytes, VRAC can pass through their relatively large and unselective pore several signaling molecules, contributing to autocrine and paracrine stimulation of cell surface receptors. ATP, the excitatory amino acid neurotransmitter glutamate, the inhibitory neurotransmitter GABA, and the aminosulfonic acid taurine are just few examples. In the present superb work, the Authors provide extensive electrophysiological and pharmacological evidence that VRAC/VSOR is permeable to tripeptide glutathione. VRAC/VSOR serves as quantitatively important route for export of glutathione from rat thymocytes, particularly when these cells are subjected to hypoosmotic swelling.

As eloquently narrated by the Authors, glutathione plays numerous roles and is engaged in so-called gamma-glutamyl cycle. When release to the extracellular space, glutathione is degraded to the precursor dipeptide and single amino acid constituents. These can be used as building blocks for glutathione synthesis in neighboring cells, but are also critical for intercellular accumulation of other amino acids via gamma-glutamyl transpeptidase. Coincidently, activity of gamma-glutamyl transpeptidase is quintessential in gastrointestinal tract and renal tissue, i.e. in two tissues, where cells are subjected to dramatic variations of osmolarity and cellular volume. The present findings bring into light new, cell-volume coupled mechanism for glutathione release. They are likely to set in motion further exciting work addressing novel roles for VRAC in intestinal and renal epithelia, as well as in other tissues.

Alexander A. Mongin, Ph.D.
Academic Editor, PLOS ONE