title: Selective transport of neurotransmitters and modulators by distinct volume-regulated LRRC8 anion channels.
abstract: In response to swelling, mammalian cells release chloride and organic osmolytes through volume-regulated anion channels (VRACs). VRACs are heteromers of LRRC8A and other LRRC8 isoforms (LRRC8B to LRRC8E), which are co-expressed in HEK293 and most other cells. The spectrum of VRAC substrates and its dependence on particular LRRC8 isoforms remains largely unknown. We show that, besides the osmolytes taurine andmyo-inositol, LRRC8 channels transport the neurotransmitters glutamate, aspartate and γ-aminobutyric acid (GABA) and the co-activator D-serine. HEK293 cells engineered to express defined subsets of LRRC8 isoforms were used to elucidate the subunit-dependence of transport. Whereas LRRC8D was crucial for the translocation of overall neutral compounds likemyo-inositol, taurine and GABA, and sustained the transport of positively charged lysine, flux of negatively charged aspartate was equally well supported by LRRC8E. Disruption of LRRC8B or LRRC8C failed to decrease the transport rates of all investigated substrates, but their inclusion into LRRC8 heteromers influenced the substrate preference of VRAC. This suggested that individual VRACs can contain three or more different LRRC8 subunits, a conclusion confirmed by sequential co-immunoprecipitations. Our work suggests a composition-dependent role of VRACs in extracellular signal transduction.
authors.affiliation: Leibniz-Institut für Molekulare Pharmakologie (FMP), D-13125 Berlin, Germany.|Max-Delbrück-Centrum für Molekulare Medizin (MDC), D-13125 Berlin, Germany.|Graduate Program of the Freie Universität Berlin, D-14195 Berlin, Germany.
authors.forename: Darius
authors.initials: D
authors.lastname: Lutter
authors.affiliation: Leibniz-Institut für Molekulare Pharmakologie (FMP), D-13125 Berlin, Germany.|Max-Delbrück-Centrum für Molekulare Medizin (MDC), D-13125 Berlin, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Ullrich
authors.affiliation: Leibniz-Institut für Molekulare Pharmakologie (FMP), D-13125 Berlin, Germany.|Max-Delbrück-Centrum für Molekulare Medizin (MDC), D-13125 Berlin, Germany.|Graduate Program of the Freie Universität Berlin, D-14195 Berlin, Germany.
authors.forename: Jennifer C
authors.initials: JC
authors.lastname: Lueck
authors.affiliation: Max-Delbrück-Centrum für Molekulare Medizin (MDC), D-13125 Berlin, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Kempa
authors.affiliation: Leibniz-Institut für Molekulare Pharmakologie (FMP), D-13125 Berlin, Germany Jentsch@fmp-berlin.de.|Max-Delbrück-Centrum für Molekulare Medizin (MDC), D-13125 Berlin, Germany.|Neurocure, Charité Universitätsmedizin, D-10117 Berlin, Germany.
authors.forename: Thomas J
authors.identifier: 0000-0002-3509-2553
authors.initials: TJ
authors.lastname: Jentsch
mesh_terms: D000838:Anions / Q000378:metabolism; D001692:Biological Transport; D057809:HEK293 Cells; D006801:Humans; D047468:Immunoprecipitation; D015640:Ion Channel Gating; D007473:Ion Channels / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism*; D018377:Neurotransmitter Agents / Q000378:metabolism*; D020033:Protein Isoforms / Q000378:metabolism; D021122:Protein Subunits / Q000378:metabolism; D013379:Substrate Specificity
chemical_list: D000838:Anions; D007473:Ion Channels; C485976:LRRC8A protein, human; D008565:Membrane Proteins; D018377:Neurotransmitter Agents; D020033:Protein Isoforms; D021122:Protein Subunits
keywords: Gliotransmission; ICl,swell; ICl,vol; Swelling-activated chloride channel; VSOAC; VSOR