title: VRAC: molecular identification as LRRC8 heteromers with differential functions.
abstract: A major player of vertebrate cell volume regulation is the volume-regulated anion channel (VRAC), which conducts halide ions and organic osmolytes to counteract osmotic imbalances. The molecular entity of this channel was unknown until very recently, although its biophysical characteristics and diverse physiological roles have been extensively studied over the last 30 years. On the road to the molecular identification of VRAC, experimental difficulties led to the proposal of a variety of false candidates. In 2014, in a final breakthrough, two groups independently identified LRRC8A as indispensable component of VRAC. LRRC8A is part of the leucine-rich repeat containing 8 family, which is comprised of five members (LRRC8A-E). Of those, LRRC8A is an obligatory subunit of VRAC but it needs at least one of the other family members to mediate the swelling-induced Cl(-) current ICl,vol. This review discusses the remarkable journey which led to the molecular identification of VRAC, evidence for LRRC8 proteins forming the VRAC pore and their heteromeric assembly. Furthermore, first major insights on the role of LRRC8 proteins in cancer drug resistance and apoptosis and the role of LRRC8D in cisplatin and taurine transport will be summarized.
authors.affiliation: Leibniz-Institut für Molekulare Pharmakologie (FMP) and Max-Delbrück-Centrum für Molekulare Medizin (MDC), Robert-Rössle-Strasse 10, 13125, Berlin, Germany. Jentsch@fmp-berlin.de.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Jentsch
authors.affiliation: Leibniz-Institut für Molekulare Pharmakologie (FMP) and Max-Delbrück-Centrum für Molekulare Medizin (MDC), Robert-Rössle-Strasse 10, 13125, Berlin, Germany.
authors.forename: Darius
authors.initials: D
authors.lastname: Lutter
authors.affiliation: Leibniz-Institut für Molekulare Pharmakologie (FMP) and Max-Delbrück-Centrum für Molekulare Medizin (MDC), Robert-Rössle-Strasse 10, 13125, Berlin, Germany.
authors.forename: Rosa
authors.initials: R
authors.lastname: Planells-Cases
authors.affiliation: Leibniz-Institut für Molekulare Pharmakologie (FMP) and Max-Delbrück-Centrum für Molekulare Medizin (MDC), Robert-Rössle-Strasse 10, 13125, Berlin, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Ullrich
authors.affiliation: Leibniz-Institut für Molekulare Pharmakologie (FMP) and Max-Delbrück-Centrum für Molekulare Medizin (MDC), Robert-Rössle-Strasse 10, 13125, Berlin, Germany.
authors.forename: Felizia K
authors.initials: FK
authors.lastname: Voss
mesh_terms: D000818:Animals; D017209:Apoptosis; D048429:Cell Size; D002712:Chlorides / Q000378:metabolism*; D006801:Humans; D007473:Ion Channels / Q000737:chemistry / Q000378:metabolism*; D017136:Ion Transport; D008565:Membrane Proteins / Q000737:chemistry / Q000378:metabolism*; D055503:Protein Multimerization
chemical_list: D002712:Chlorides; D007473:Ion Channels; C485976:LRRC8A protein, human; D008565:Membrane Proteins
keywords: Chloride channel; Swelling-activated; VSOAC; VSOR