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    SUR1-TRPM4 and AQP4 form a heteromultimeric complex that amplifies ion/water osmotic coupling and drives astrocyte swelling

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    Author
    Stokum, J.A.
    Kwon, M.S.
    Woo, S.K.
    Date
    2018
    Journal
    GLIA
    Publisher
    John Wiley and Sons Inc.
    Type
    Article
    
    Metadata
    Show full item record
    See at
    https://dx.doi.org/10.1002/glia.23231
    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5759053/
    Abstract
    Astrocyte swelling occurs after CNS injury and contributes to brain swelling, which can increase mortality. Mechanisms proffered to explain astrocyte swelling emphasize the importance of either aquaporin-4 (AQP4), an astrocyte water channel, or of Na+-permeable channels, which mediate cellular osmolyte influx. However, the spatio-temporal functional interactions between AQP4 and Na+-permeable channels that drive swelling are poorly understood. We hypothesized that astrocyte swelling after injury is linked to an interaction between AQP4 and Na+-permeable channels that are newly upregulated. Here, using co-immunoprecipitation and Förster resonance energy transfer, we report that AQP4 physically co-assembles with the sulfonylurea receptor 1 – transient receptor potential melastatin 4 (SUR1-TRPM4) monovalent cation channel to form a novel heteromultimeric water/ion channel complex. In vitro cell-swelling studies using calcein fluorescence imaging of COS-7 cells expressing various combinations of AQP4, SUR1 and TRPM4 showed that the full tripartite complex, comprised of SUR1-TRPM4-AQP4, was required for fast, high-capacity transmembrane water transport that drives cell swelling, with these findings corroborated in cultured primary astrocytes. In a murine model of brain edema involving cold-injury to the cerebellum, we found that astrocytes newly upregulate SUR1-TRPM4, that AQP4 co-associates with SUR1-TRPM4, and that genetic inactivation of the solute pore of the SUR1-TRPM4-AQP4 complex blocked in vivo astrocyte swelling measured by diolistic labeling, thereby corroborating our in vitro functional studies. Together, these findings demonstrate a novel molecular mechanism involving the SUR1-TRPM4-AQP4 complex to account for bulk water influx during astrocyte swelling. These findings have broad implications for the understanding and treatment of AQP4-mediated pathological conditions. Copyright 2017 Wiley Periodicals, Inc.
    Sponsors
    The authors thank Dr. Joseph Maubin for support with confocal microscopy, Dr. Scott Thompson for the use of the Helios Gene Gun System, and Dr. Joseph Kao for careful review of the manuscript. This work was supported by grants to J.M.S. from NHLBI (R01 HL082517) and NINDS (R01 NS060801, R01 NS102589) and to V.G. from NINDS (R01 NS061934).
    Keyword
    astrocyte
    ion channels
    ions
    osmosis
    water
    Identifier to cite or link to this item
    https://www.scopus.com/inward/record.uri?eid=2-s2.0-85029449362&doi=10.1002%2fglia.23231&partnerID=40&md5=ce6b32b8ca65a4ae8eca6ea790841bfb; http://hdl.handle.net/10713/10151
    ae974a485f413a2113503eed53cd6c53
    10.1002/glia.23231
    Scopus Count
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    UMB Open Access Articles 2018

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