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@ARTICLE{Koch:863891,
      author       = {Koch, Angela and Bonus, Michele and Gohlke, Holger and
                      Klöcker, Nikolaj},
      title        = {{I}soform-specific {I}nhibition of {N}-methyl-{D}-aspartate
                      {R}eceptors by {B}ile {S}alts},
      journal      = {Scientific reports},
      volume       = {9},
      number       = {1},
      issn         = {2045-2322},
      address      = {[London]},
      publisher    = {Macmillan Publishers Limited, part of Springer Nature},
      reportid     = {FZJ-2019-03862},
      pages        = {10068},
      year         = {2019},
      abstract     = {The N-methyl-D-aspartate subfamily of ionotropic glutamate
                      receptors (NMDARs) is well known for its important roles in
                      the central nervous system (CNS), e.g. learning and memory
                      formation. Besides the CNS, NMDARs are also expressed in
                      numerous peripheral tissues including the pancreas, kidney,
                      stomach, and blood cells, where an understanding of their
                      physiological and pathophysiological roles is only evolving.
                      Whereas subunit composition increases functional diversity
                      of NMDARs, a great number of endogenous cues tune receptor
                      signaling. Here, we characterized the effects of the steroid
                      bile salts cholate and chenodeoxycholate (CDC) on
                      recombinantly expressed NMDARs of defined molecular
                      composition. CDC inhibited NMDARs in an isoform-dependent
                      manner, preferring GluN2D and GluN3B over GluN2A and GluN2B
                      receptors. Determined IC50 values were in the range of bile
                      salt serum concentrations in severe cholestatic disease
                      states, pointing at a putative pathophysiological
                      significance of the identified receptor modulation. Both
                      pharmacological and molecular simulation analyses indicate
                      that CDC acts allosterically on GluN2D, whereas it competes
                      with agonist binding on GluN3B receptors. Such differential
                      modes of inhibition may allow isoform-specific targeted
                      interference with the NMDAR/bile salt interaction. In
                      summary, our study provides further molecular insight into
                      the modulation of NMDARs by endogenous steroids and points
                      at a putative pathophysiological role of the receptors in
                      cholestatic disease.},
      cin          = {NIC / JSC / ICS-6},
      ddc          = {600},
      cid          = {I:(DE-Juel1)NIC-20090406 / I:(DE-Juel1)JSC-20090406 /
                      I:(DE-Juel1)ICS-6-20110106},
      pnm          = {511 - Computational Science and Mathematical Methods
                      (POF3-511) / Forschergruppe Gohlke $(hkf7_20170501)$ /
                      Energetic and structural characterization of the activation
                      processes of the human HCN2 ion channel $(hdd17_20180501)$ /
                      Disinhibition and inhibition of HCN2 channel function by
                      ligand binding to the cyclic nucleotide bin
                      $(hdd17_20170501)$},
      pid          = {G:(DE-HGF)POF3-511 / $G:(DE-Juel1)hkf7_20170501$ /
                      $G:(DE-Juel1)hdd17_20180501$ / $G:(DE-Juel1)hdd17_20170501$},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:31296930},
      UT           = {WOS:000474821000014},
      doi          = {10.1038/s41598-019-46496-y},
      url          = {https://juser.fz-juelich.de/record/863891},
}