LRRC8/VRAC Channels Beyond Volume Regulation: Molecular Mechanisms, Physiological Functions, and Therapeutic Perspectives

Volume-regulated anion channels (VRACs) drive regulatory volume decrease and maintain cellular homeostasis in nearly all vertebrate cells. The identification of leucine-rich repeat-containing 8 (LRRC8) proteins as the molecular components of VRAC transformed the field by showing that these channels are heteromers composed of the essential LRRC8A subunit together with one or more LRRC8B-E subunits. Advances in structural biology, electrophysiology, and molecular studies have since improved our understanding of LRRC8 channel assembly, regulation, and function. LRRC8 complexes operate through two distinct functional modalities. The first is substrate permeation through the channel pore: beyond chloride transport, LRRC8 channels mediate the movement of organic osmolytes, amino acids, ATP, glutamate, cyclic dinucleotides, and platinum-based anticancer drugs, with permeability determined by subunit composition. The second is pore-independent signal transduction, in which LRRC8A also acts as a signaling scaffold through its cytoplasmic leucine-rich repeat domain (LRRD), which binds partners such as GRB2 and caveolin-1. Because deleting the protein removes both modalities at once and many reported phenotypes cannot yet be attributed to either alone. Altered LRRC8 channel activity has been linked to cancer, ischemic brain injury, epilepsy, diabetes, inflammatory diseases, and inherited disorders caused by both loss and gain of LRRC8 function. This review discusses recent advances in the molecular architecture, regulatory mechanisms, transport properties, and pore-independent signaling functions of LRRC8 channels. It also examines their physiological and pathophysiological roles across the nervous, cardiovascular, immune, metabolic, renal, epidermal, and reproductive systems, highlighting the strength of the supporting evidence. Finally, the review addresses recent progress in pharmacological targeting, with particular emphasis on the off-target effects of current inhibitors and the lack of subunit-selective modulators. Understanding how LRRC8 channels sense cell volume, assemble into native channel complexes, act through the pore or through the LRRD, and can be selectively targeted will be critical for translating recent discoveries into future therapeutic strategies.