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.
journal_name
Sci Repjournal_title
Scientific reportsauthors
Koch A,Bonus M,Gohlke H,Klöcker Ndoi
10.1038/s41598-019-46496-ysubject
Has Abstractpub_date
2019-07-11 00:00:00pages
10068issue
1issn
2045-2322pii
10.1038/s41598-019-46496-yjournal_volume
9pub_type
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