Biased regulation of glucocorticoid receptors signaling

Ginsenoside compound K plays an anti-inflammatory effect without inducing glucose metabolism disorder in adjuvant-induced arthritis rats

“…15,16 Such differences as described above may be related to the differential regulation of signaling in different disease states. 17…”

“…15,16 Such differences as described above may be related to the differential regulation of signaling in different disease states. 17 Why this anti-inflammatory advantage, without hyperglycemic adverse effects, of GCK occurs, the group has previously summarized the factors of biased regulation exerted by GR ligands, according to the perspective of GR exerting genomic effects. 17 The binding of ligands to GR is a crucial step in translocating it into the nucleus and subsequently exerting genomic effects.…”

“…17 Why this anti-inflammatory advantage, without hyperglycemic adverse effects, of GCK occurs, the group has previously summarized the factors of biased regulation exerted by GR ligands, according to the perspective of GR exerting genomic effects. 17 The binding of ligands to GR is a crucial step in translocating it into the nucleus and subsequently exerting genomic effects. Different ligands, when bound to specific sites of the GR, induce distinct conformational changes, resulting in varying degrees of phosphorylation at different sites of the GR.…”

Bias translation: The final frontier?

“…In general, these ideas centre on the emphasis of beneficial signalling pathways—for example, β‐arrestin for PTH receptor in bone building in osteoporosis (Ferrari et al, 2005), β‐arrestin‐mediated glucagon‐like peptide‐1 (GLP1) for insulin secretion in diabetes (Sonoda et al, 2008), or the elimination of negative signalling (opioid‐mediated respiratory depression and/or negative behavioural effects mediated by β‐arrestin; Raehal & Bohn, 2011; Raehal et al, 2005; Bohn et al, 2003; Urs & Caron, 2014). There are many more recent proposals for improved drug candidates based on the biased concept including agonists for muscarinic acetylcholine receptors (McDonald et al, 2022; Randakova & Jakubic, 2021), opioid receptors (Che et al, 2021; Conibear et al, 2020), ghrelin receptors (Mende et al, 2018), neurotensin receptors (Krumm et al, 2023), glucocorticoid receptors (Mao et al, 2023), and 5‐HT 2A receptors (Allen et al, 2011; Pottie et al, 2023). Interestingly, efforts to achieve selectivity through allosteric modulation in studies for Alzheimer's disease and schizophrenia fall short of yielding the selectivity needed without added biased signalling (in this case, induced bias through allosteric modulation) (van der Westhuizen et al, 2021).…”