Journal Article

FZJ-2019-03862

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Isoform-specific Inhibition of N-methyl-D-aspartate Receptors by Bile Salts

Koch, A. ; Bonus, M. ; Gohlke, H.FZJ* ; Klöcker, N. (Corresponding author)

2019
Macmillan Publishers Limited, part of Springer Nature [London]

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Please use a persistent id in citations: http://hdl.handle.net/2128/22503  doi:10.1038/s41598-019-46496-y

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.

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Contributing Institute(s):

1. John von Neumann - Institut für Computing (NIC)
2. Jülich Supercomputing Center (JSC)
3. Strukturbiochemie (ICS-6)

Research Program(s):

1. 511 - Computational Science and Mathematical Methods (POF3-511) (POF3-511)
2. Forschergruppe Gohlke (hkf7_20170501) (hkf7_20170501)
3. Energetic and structural characterization of the activation processes of the human HCN2 ion channel (hdd17_20180501) (hdd17_20180501)
4. Disinhibition and inhibition of HCN2 channel function by ligand binding to the cyclic nucleotide bin (hdd17_20170501) (hdd17_20170501)

Appears in the scientific report 2019

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