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      Identification of LRRC8 Heteromers as an Essential Component of the Volume-Regulated Anion Channel VRAC

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          Abstract

          Regulation of cell volume is critical for many cellular and organismal functions, yet the molecular identity of a key player, the volume-regulated anion channel VRAC, has remained unknown. A genome-wide small interfering RNA screen in mammalian cells identified LRRC8A as a VRAC component. LRRC8A formed heteromers with other LRRC8 multispan membrane proteins. Genomic disruption of LRRC8A ablated VRAC currents. Cells with disruption of all five LRRC8 genes required LRRC8A cotransfection with other LRRC8 isoforms to reconstitute VRAC currents. The isoform combination determined VRAC inactivation kinetics. Taurine flux and regulatory volume decrease also depended on LRRC8 proteins. Our work shows that VRAC defines a class of anion channels, suggests that VRAC is identical to the volume-sensitive organic osmolyte/anion channel VSOAC, and explains the heterogeneity of native VRAC currents.

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          Physiology of cell volume regulation in vertebrates.

          Else K. Hoffmann, Ian H. Lambert, Stine F. Pedersen (2009)
          The ability to control cell volume is pivotal for cell function. Cell volume perturbation elicits a wide array of signaling events, leading to protective (e.g., cytoskeletal rearrangement) and adaptive (e.g., altered expression of osmolyte transporters and heat shock proteins) measures and, in most cases, activation of volume regulatory osmolyte transport. After acute swelling, cell volume is regulated by the process of regulatory volume decrease (RVD), which involves the activation of KCl cotransport and of channels mediating K(+), Cl(-), and taurine efflux. Conversely, after acute shrinkage, cell volume is regulated by the process of regulatory volume increase (RVI), which is mediated primarily by Na(+)/H(+) exchange, Na(+)-K(+)-2Cl(-) cotransport, and Na(+) channels. Here, we review in detail the current knowledge regarding the molecular identity of these transport pathways and their regulation by, e.g., membrane deformation, ionic strength, Ca(2+), protein kinases and phosphatases, cytoskeletal elements, GTP binding proteins, lipid mediators, and reactive oxygen species, upon changes in cell volume. We also discuss the nature of the upstream elements in volume sensing in vertebrate organisms. Importantly, cell volume impacts on a wide array of physiological processes, including transepithelial transport; cell migration, proliferation, and death; and changes in cell volume function as specific signals regulating these processes. A discussion of this issue concludes the review.
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            Structure of the connexin 26 gap junction channel at 3.5 A resolution.

            Shoji Maeda, So Nakagawa, Michihiro Suga … (2009)
            Gap junctions consist of arrays of intercellular channels between adjacent cells that permit the exchange of ions and small molecules. Here we report the crystal structure of the gap junction channel formed by human connexin 26 (Cx26, also known as GJB2) at 3.5 A resolution, and discuss structural determinants of solute transport through the channel. The density map showed the two membrane-spanning hemichannels and the arrangement of the four transmembrane helices of the six protomers forming each hemichannel. The hemichannels feature a positively charged cytoplasmic entrance, a funnel, a negatively charged transmembrane pathway, and an extracellular cavity. The pore is narrowed at the funnel, which is formed by the six amino-terminal helices lining the wall of the channel, which thus determines the molecular size restriction at the channel entrance. The structure of the Cx26 gap junction channel also has implications for the gating of the channel by the transjunctional voltage.
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              LRRC8 proteins share a common ancestor with pannexins, and may form hexameric channels involved in cell-cell communication.

              Rafael Zardoya, Federico Abascal (2012)
              Leucine-rich repeat-containing 8 (LRRC8) proteins are composed of four transmembrane helices and 17 leucine-rich repeats (LRR). Although LRRC8 proteins have been associated with important processes, like maturation of B cells or adipocyte differentiation, their biology and molecular function are largely unknown. We found that LRRC8 proteins originated from the combination of a pannexin and an LRR domain (most likely related to the SHOC2, LAP, RSU1 and LRRIQ4 protein families) before the diversification of chordates. We propose that, like pannexins, LRRC8 proteins form hexameric channels, which participate in cell-cell communication processes. According to the inferred topological model, and contrary to what was previously assumed, the six LRR domains are located in the cytoplasm, and could participate in the organisation of signalling cascades. By compiling available proteomics and gene expression data, and on the basis of the LRRC8 proposed hexameric channel structure, we present clues to the function of this family. Copyright © 2012 WILEY Periodicals, Inc.
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                Author and article information

                Journal
                Title: Science
                Abbreviated Title: Science
                Publisher: American Association for the Advancement of Science (AAAS)
                ISSN (Print): 0036-8075
                ISSN (Electronic): 1095-9203
                Publication date Created: May 08 2014
                Publication date Created: May 09 2014
                Publication date (Electronic): April 10 2014
                Publication date (Print): May 09 2014
                Volume: 344
                Issue: 6184
                Pages: 634-638
                Article
                DOI: 10.1126/science.1252826
                PubMed ID: 24790029
                SO-VID: 7657c887-2e4c-4636-ad0f-a5a8c5c8f692
                Copyright © © 2014
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