Regulation of cell volume in response to osmotic stress is an essential function of every cell in the body. One well-characterized mechanism for maintaining osmotic balance is the release of Cl- via the Volume-Regulated Anion Channel (VRAC). VRAC is linked to many pathophysiological conditions, in particular, ischemic brain damage and edema during stroke. Normal VRAC activity includes the release of excitatory amino acids (EAAs) and taurine upon cell swelling. However, during a stroke, the release of these compounds contributes to ischemic-induced brain damage. A therapeutic approach that specifically targets neuronal VRAC could be extremely valuable. However, until recently, the identity of VRAC was unknown. Our lab has identified an essential component of VRAC, Swell1 (Leucine-rich-repeat-containing protein 8A, LRRC8A). Although Swell1 is necessary to form VRAC, it is not sufficient; at least one of the other four members of LRRC8 family must be present for normal channel activity. Given that the number and variety of subunits contributing to individual VRAC complexes is currently unknown, a large variety of VRAC compositions may yield functional channels. Tissue-specific differences in LRRC8 subunit expression levels suggest that knowledge of VRAC subunit composition might allow specific therapeutic modulation of VRAC in neuronal tissue. Using advanced membrane protein biochemistry, lipid bilayer electrophysiology to study VRAC function, and single-particle electron microscopy to determine high- resolution structural characteristics, we will investigate the hypothesis that a diverse set of VRAC complexes exist and there are the structural and functional consequences of these variations that could be targeted therapeutically.
The Volume-Regulated Anion Channel (VRAC) plays an essential role in the regulation of cell volume in response to osmotic stress; however, during a stroke, its normal function contributes to ischemic-induced brain damage. The recent identification of the LRRC8 family members as components of VRAC opens a novel avenue for studying structural and functional variations in VRAC composition that could be exploited for new therapeutic strategies against damage caused by stroke.
|Kefauver, Jennifer M; Saotome, Kei; Dubin, Adrienne E et al. (2018) Structure of the human volume regulated anion channel. Elife 7:|