The Potential Role of Leucine-rich Repeat-containing Protein 8A in Central Nervous System: Current Situation and Prospect

Abstract

Cell swelling usually initiates the regulatory volume decrease (RVD) process mediated mainly by volume-regulated anion channels (VRACs), which are formed by multiple different leucine-rich repeat-containing protein 8 (LRRC8) family members. VRAC currents have been widely recorded in astrocytes, neurons and microglia in the brain, and VRACs have been suggested to be involved in the important pathogenesis of cell swelling-related central nervous system (CNS) diseases, such as ischemic stroke, epilepsy and epileptogenesis, glioblastoma (GBM), and so on. Recently, the increasing studies started to focus on LRRC8A (SWELL1), an obligatory subunit of VRAC indentified in 2014, which may be the key target to regulate the VRAC functions. After cerebral ischemia, the swollen astrocytes, neurons and microglia can activate LRRC8A-dependent VRACs, which may respectively promote the release of excitatory amino acids (EAA), interaction with ionotropic glutamate receptors, and regulating inflammation, suggesting the pleiotropic roles of LRRC8A in swollen brain cells. For the treatment of cell swelling-related CNS diseases, specific targeting LRRC8A may be a superior strategy to inhibit swollen-induced VRAC hyperactivity without blocking the normal VRAC function.

Keywords: cellular volume regulation; central nervous system; leucine-rich repeat-containing protein 8A; stroke; volume-regulated anion channels.