title: SWELL1, a plasma membrane protein, is an essential component of volume-regulated anion channel.
abstract: 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.
authors.affiliation: Genomics Institute of the Novartis Research Foundation, San Diego, CA 92121, USA; Department of Molecular and Cellular Neuroscience, Howard Hughes Medical Institute, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: Zhaozhu
authors.initials: Z
authors.lastname: Qiu
authors.affiliation: Department of Molecular and Cellular Neuroscience, Howard Hughes Medical Institute, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: Adrienne E
authors.initials: AE
authors.lastname: Dubin
authors.affiliation: Genomics Institute of the Novartis Research Foundation, San Diego, CA 92121, USA.
authors.forename: Jayanti
authors.initials: J
authors.lastname: Mathur
authors.affiliation: Genomics Institute of the Novartis Research Foundation, San Diego, CA 92121, USA.
authors.forename: Buu
authors.initials: B
authors.lastname: Tu
authors.affiliation: Genomics Institute of the Novartis Research Foundation, San Diego, CA 92121, USA.
authors.forename: Kritika
authors.initials: K
authors.lastname: Reddy
authors.affiliation: Genomics Institute of the Novartis Research Foundation, San Diego, CA 92121, USA.
authors.forename: Loren J
authors.initials: LJ
authors.lastname: Miraglia
authors.affiliation: Novartis Institutes for Biomedical Research, Basel 4056, Switzerland.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Reinhardt
authors.affiliation: Genomics Institute of the Novartis Research Foundation, San Diego, CA 92121, USA.
authors.forename: Anthony P
authors.initials: AP
authors.lastname: Orth
authors.affiliation: Department of Molecular and Cellular Neuroscience, Howard Hughes Medical Institute, The Scripps Research Institute, La Jolla, CA 92037, USA. Electronic address: ardem@scripps.edu.
authors.forename: Ardem
authors.initials: A
authors.lastname: Patapoutian
mesh_terms: D000818:Animals; D002462:Cell Membrane / Q000737:chemistry / Q000378:metabolism; D048429:Cell Size; D020869:Gene Expression Profiling; D055785:Gene Knockdown Techniques; D055106:Genome-Wide Association Study; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D007454:Iodides / Q000378:metabolism; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D034622:RNA Interference
chemical_list: D007454:Iodides; C485976:LRRC8A protein, human; D008565:Membrane Proteins
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