Evidence for functional selectivity in TUDC- and norUDCA-induced signal transduction via α5β1 integrin towards choleresis

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 alpha I domain. Here, we show by molecular dynamics simulations that four side chain-modified derivatives of tauroursodeoxycholic acid (TUDC), an agonist of alpha (5)beta (1) integrin, differentially shift the conformational equilibrium of alpha (5)beta (1) integrin towards the active state, in line with the extent of beta (1) integrin activation from immunostaining. Unlike TUDC, 24-nor-ursodeoxycholic acid (norUDCA)-induced beta (1) 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 alpha (5)beta (1) integrin and may provide a rationale for differential therapeutic use of UDCA and norUDCA.