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      A 30-year journey from volume-regulated anion currents to molecular structure of the LRRC8 channel

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          Abstract

          Strange et al. review recent advances in our understanding of the molecular and structural basis of volume-regulated anion channel function within the framework of classical biophysical and physiological studies.

          Abstract

          The swelling-activated anion channel VRAC has fascinated and frustrated physiologists since it was first described in 1988. Multiple laboratories have defined VRAC’s biophysical properties and have shown that it plays a central role in cell volume regulation and possibly other fundamental physiological processes. However, confusion and intense controversy surrounding the channel’s molecular identity greatly hindered progress in the field for >15 yr. A major breakthrough came in 2014 with the demonstration that VRAC is a heteromeric channel encoded by five members of the Lrrc8 gene family, Lrrc8A–E. A mere 4 yr later, four laboratories described cryo-EM structures of LRRC8A homomeric channels. As the melee of structure/function and physiology studies begins, it is critical that this work be framed by a clear understanding of VRAC biophysics, regulation, and cellular physiology as well as by the field’s past confusion and controversies. That understanding is essential for the design and interpretation of structure/function studies, studies of VRAC physiology, and studies aimed at addressing the vexing problem of how the channel detects cell volume changes. In this review we discuss key aspects of VRAC biophysics, regulation, and function and integrate these into our emerging understanding of LRRC8 protein structure/function.

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          Physiology of cell volume regulation in vertebrates.

          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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            SWELL1, a plasma membrane protein, is an essential component of volume-regulated anion channel.

            Maintenance of a constant cell volume in response to extracellular or intracellular osmotic changes is critical for cellular homeostasis. Activation of a ubiquitous volume-regulated anion channel (VRAC) plays a key role in this process; however, its molecular identity in vertebrates remains unknown. Here, we used a cell-based fluorescence assay and performed a genome-wide RNAi screen to find components of VRAC. We identified SWELL1 (LRRC8A), a member of a four-transmembrane protein family with unknown function, as essential for hypotonicity-induced iodide influx. SWELL1 is localized to the plasma membrane, and its knockdown dramatically reduces endogenous VRAC currents and regulatory cell volume decrease in various cell types. Furthermore, point mutations in SWELL1 cause a significant change in VRAC anion selectivity, demonstrating that SWELL1 is an essential VRAC component. These findings enable further molecular characterization of the VRAC channel complex and genetic studies for understanding the function of VRAC in normal physiology and disease. Copyright © 2014 Elsevier Inc. All rights reserved.
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              Membrane-protein topology.

              In the world of membrane proteins, topology defines an important halfway house between the amino-acid sequence and the fully folded three-dimensional structure. Although the concept of membrane-protein topology dates back at least 30 years, recent advances in the field of translocon-mediated membrane-protein assembly, proteome-wide studies of membrane-protein topology and an exponentially growing number of high-resolution membrane-protein structures have given us a deeper understanding of how topology is determined and of how it evolves.
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                Author and article information

                Journal
                J Gen Physiol
                J. Gen. Physiol
                jgp
                jgp
                The Journal of General Physiology
                Rockefeller University Press
                0022-1295
                1540-7748
                04 February 2019
                : 151
                : 2
                : 100-117
                Affiliations
                [1 ]Department of Anesthesiology, Vanderbilt University Medical Center, Nashville, TN
                [2 ]Novo Biosciences, Inc., Bar Harbor, ME
                Author notes
                Correspondence to Kevin Strange: kevin.strange@novobiosciences.com
                Toshiki Yamada: toshiki.yamada@vumc.org
                Jerod S. Denton: jerod.s.denton@vumc.org
                Author information
                http://orcid.org/0000-0003-1435-0864
                http://orcid.org/0000-0001-5808-2625
                Article
                201812138
                10.1085/jgp.201812138
                6363415
                30651298
                4ca2497d-e7ad-469f-8288-36536abdf24b
                © 2019 Strange et al.

                This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).

                History
                : 29 November 2018
                : 03 January 2019
                Funding
                Funded by: National Institute of Diabetes and Digestive and Kidney Diseases, DOI https://doi.org/10.13039/100000062;
                Award ID: R01 DK51610
                Categories
                Reviews
                Review
                509
                511
                508

                Anatomy & Physiology
                Anatomy & Physiology

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