Isoform-specific Inhibition of N-methyl-D-aspartate Receptors by Bile Salts
| Autor: | Michele Bonus, Nikolaj Klöcker, Holger Gohlke, Angela Koch |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Agonist Models Molecular medicine.drug_class Physiology Protein Conformation Allosteric regulation lcsh:Medicine Chenodeoxycholic Acid Receptors N-Methyl-D-Aspartate Article Bile Acids and Salts 03 medical and health sciences Structure-Activity Relationship Xenopus laevis 0302 clinical medicine Allosteric Regulation medicine Animals Protein Isoforms Computer Simulation Cloning Molecular Chenodeoxycholate Receptor lcsh:Science Multidisciplinary Chemistry lcsh:R Glutamate receptor Gastroenterology Hydrogen Bonding Cell biology 030104 developmental biology nervous system Mutation Mutagenesis Site-Directed NMDA receptor lcsh:Q Signal transduction ddc:600 030217 neurology & neurosurgery Ionotropic effect Protein Binding Signal Transduction |
| Zdroj: | Scientific Reports Scientific reports 9(1), 10068 (2019). doi:10.1038/s41598-019-46496-y Scientific Reports, Vol 9, Iss 1, Pp 1-17 (2019) |
| ISSN: | 2045-2322 |
| DOI: | 10.1038/s41598-019-46496-y |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|