Evidence for functional selectivity in TUDC- and norUDCA-induced signal transduction via α5β1 integrin towards choleresis
Autor: | Dieter Häussinger, Natalia Qvartskhava, Michele Bonus, Horst Kessler, Beatrice Stefanie Ludwig, Boris Görg, Annika Sommerfeld, Holger Gohlke |
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Jazyk: | angličtina |
Rok vydání: | 2020 |
Předmět: |
0301 basic medicine
Multidisciplinary biology Chemistry p38 mitogen-activated protein kinases lcsh:R Integrin lcsh:Medicine Tauroursodeoxycholic acid Cell biology 03 medical and health sciences chemistry.chemical_compound 030104 developmental biology 0302 clinical medicine 030220 oncology & carcinogenesis biology.protein Functional selectivity lcsh:Q Epidermal growth factor receptor Signal transduction lcsh:Science Receptor Protein kinase A ddc:600 |
Zdroj: | Scientific reports 10(1), 5795 (2020). doi:10.1038/s41598-020-62326-y Scientific Reports, Vol 10, Iss 1, Pp 1-17 (2020) |
Popis: | Functional selectivity is the ligand-specific activation of certain signal transduction pathways at a receptor and has been described for G protein-coupled receptors. However, it has not yet been described for ligands interacting with integrins without αI domain. Here, we show by molecular dynamics simulations that four side chain-modified derivatives of tauroursodeoxycholic acid (TUDC), an agonist of α5β1 integrin, differentially shift the conformational equilibrium of α5β1 integrin towards the active state, in line with the extent of β1 integrin activation from immunostaining. Unlike TUDC, 24-nor-ursodeoxycholic acid (norUDCA)-induced β1 integrin activation triggered only transient activation of extracellular signal-regulated kinases and p38 mitogen-activated protein kinase and, consequently, only transient insertion of the bile acid transporter Bsep into the canalicular membrane, and did not involve activation of epidermal growth factor receptor. These results provide evidence that TUDC and norUDCA exert a functional selectivity at α5β1 integrin and may provide a rationale for differential therapeutic use of UDCA and norUDCA. |
Databáze: | OpenAIRE |
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