Properties, Structures, and Physiological Roles of Three Types of Anion Channels Molecularly Identified in the 2010’s

Abstract

Molecular identification was, at last, successfully accomplished for three types of anion channels that are all implicated in cell volume regulation/dysregulation. LRRC8A plus LRRC8C/D/E, SLCO2A1, and TMEM206 were shown to be the core or pore-forming molecules of the volume-sensitive outwardly rectifying anion channel (VSOR) also called the volume-regulated anion channel (VRAC), the large-conductance maxi-anion channel (Maxi-Cl), and the acid-sensitive outwardly rectifying anion channel (ASOR) also called the proton-activated anion channel (PAC) in 2014, 2017, and 2019, respectively. More recently in 2020 and 2021, we have identified the S100A10-annexin A2 complex and TRPM7 as the regulatory proteins for Maxi-Cl and VSOR/VRAC, respectively. In this review article, we summarize their biophysical and structural properties as well as their physiological roles by comparing with each other on the basis of their molecular insights. We also point out unsolved important issues to be elucidated soon in the future.

Effect of pinocembrin on thymocyte proliferation and death

“…Apoptotic volume decrease (AVD) is one of the earliest events during apoptosis; the RVD machinery and the underlying ion channels (especially, VSOR) are activated by pro-apoptotic signaling pathways even under normotonic conditions (18,21,(41)(42)(43). Therefore, the blocking effects of pinocembrin on RVD and VSOR channels are expected to suppress apoptosis as we have actually observed in our experiments for the combined effects of DX and the flavonoid.…”

“…Patch-clamp studies have revealed the presence of two volume-regulated anion channels important for the CVR response to the hypoosmotic stress: the volume-sensitive outwardly rectifying Clchannel (VSOR) and the maxi-anion channel of Maxi-Cl phenotype (14). In addition to its involvement in the CVR, the VSOR serves as a pathway for releasing glutathione from thymocytes into the extracellular matrix (15), whereas the Maxi-Cl channel is known as a pathway for adenosine triphosphate (ATP) and other signaling molecules (16)(17)(18).…”

“…Previously, pinocembrin was demonstrated to effectively suppress the CVR under hypoosmotic conditions by blocking the VSOR (34). Given the key roles of the CVR and VSOR in cell proliferation and death (18,20,21), we have set on the identification of the effects pinocembrin produces on the proliferation and death of thymocytes. As the immune cells have never been considered as a target for pinocembrin, our findings may have implications on the immunity protection in inflammation and therapy with glucocorticoids.…”

Effect of glycyrrhizin and its derivatives on integrity of human red blood cells

“…Based on this hypothesis, we may assume that recently identified VSOR-inhibitors of plant origin, such as flavonoids (41) and tannins (42), could also be able to modulate the osmoresistivity of the RBC. In addition, GL and its derivatives are expected to have an impact on the cell death induction and protection in other cell types, in which VSOR plays a critical role (43)(44)(45)(46)(47).…”

Physiology of the volume-sensitive/regulatory anion channel VSOR/VRAC. Part 1: from its discovery and phenotype characterization to the molecular entity identification

“…Subsequently, a prerequisite role of LRRC8A in VSOR/VRAC activity was confirmed in mouse cells [ 40 , 75 , 121 , 122 ], in rat cells [ 123 , 124 ], in chicken cells [ 10 ], and in zebrafish cells [ 125 ]. Recent cryo-EM studies demonstrated that not only LRRC8A [ 126 – 130 ] but also another LRRC8 member, LRRC8D [ 131 ], form homo-hexameric structures consisting of the transmembrane pore domain, as depicted in Fig. 2 for LRRC8A.…”