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Selective transport of neurotransmitters and modulators by distinct volume-regulated LRRC8 anion channels

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Item Type:Article
Title:Selective transport of neurotransmitters and modulators by distinct volume-regulated LRRC8 anion channels
Creators Name:Lutter, D. and Ullrich, F. and Lueck, J.C. and Kempa, S. and Jentsch, T.J.
Abstract:In response to swelling, mammalian cells release chloride and organic osmolytes through VRAC volume-regulated anion channels. VRACs are heteromers of LRRC8A and other LRRC8 isoforms (B-E) 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 and myo-inositol, LRRC8 channels transport the neurotransmitters glutamate, aspartate and 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 like myo-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 transport rates of all investigated substrates, but their inclusion into LRRC8 heteromers influenced VRAC's substrate preference. 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.
Keywords:VSOAC, VSOR, Swelling-Activated Chloride Channel, I(Cl,Vol), I(Cl,Swell), Gliotransmission
Source:Journal of Cell Science
ISSN:0021-9533
Publisher:Company of Biologists (U.K.)
Volume:130
Number:6
Page Range:1122-1133
Date:15 March 2017
Additional Information:Copyright © 2017 The Authors. Published by The Company of Biologists Ltd.
Official Publication:https://doi.org/10.1242/jcs.196253
PubMed:View item in PubMed

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