TY  - JOUR
AU  - Koch, Angela
AU  - Bonus, Michele
AU  - Gohlke, Holger
AU  - Klöcker, Nikolaj
TI  - Isoform-specific Inhibition of N-methyl-D-aspartate Receptors by Bile Salts
JO  - Scientific reports
VL  - 9
IS  - 1
SN  - 2045-2322
CY  - [London]
PB  - Macmillan Publishers Limited, part of Springer Nature
M1  - FZJ-2019-03862
SP  - 10068
PY  - 2019
AB  - 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.
LB  - PUB:(DE-HGF)16
C6  - pmid:31296930
UR  - <Go to ISI:>//WOS:000474821000014
DO  - DOI:10.1038/s41598-019-46496-y
UR  - https://juser.fz-juelich.de/record/863891
ER  -