Identification of novel, potent and selective inhibitor of VRAC

Abstract

Tight regulation of cell volume is essential for normal cell function. Sudden changes in the osmolarity of the extracellular fluid (ECF) cause cell swelling or shrinkage, and leads to regulatory volume decrease (RVD) and regulatory volume increase (RVI). In the cell volume regulation, RVD involves activation of ion transport which mediates the efflux of K+ and Clfrom the cells. The volume‐regulated anion channel (VRAC) is involved in Cl− efflux and plays a pivotal role in the regulation of cell volume. In addition, it is known that various processes such as cell division, migration, necrotic and apoptotic cell death are directly related to VRAC. Short circuit current measurement in FRT cells expressing ANO1 chloride channel revealed that the most potent and selective VRAC inhibitor, DCPIB, strongly inhibited ANO1 chloride current. Several cell lines express both ANO1 and VRAC, and there is cross talk between these chloride channels. Thus, the lack of selective inhibitors of VRAC limits VRAC and ANO1 research. In this study, we performed a cell‐based high‐throughput screening to identify potent and selective VRAC inhibitors. Screening of 55,000 compounds and electrophysiological studies revealed a novel, potent and selective VRAC inhibitor, VRACi‐A01 (IC50 = 2.7 μM). It did not affect the ANO1 chloride channel activity at the concentration showing complete inhibition of VRAC. To the best of our knowledge, VRACi‐A01 is the most potent and selective VRAC inhibitor reported to date and a useful research tool for pharmacological dissection of VRAC in the cells expressing VRAC and ANO1.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.