Translating in vitro ligand bias into in vivo efficacy

Cellular Signalling
Louis M LuttrellDiane Gesty-Palmer

Abstract

It is increasingly apparent that ligand structure influences both the efficiency with which G protein-coupled receptors (GPCRs) engage their downstream effectors and the manner in which they are activated. Thus, 'biased' agonists, synthetic ligands whose intrinsic efficacy differs from the native ligand, afford a strategy for manipulating GPCR signaling in ways that promote beneficial signals while blocking potentially deleterious ones. Still, there are significant challenges in relating in vitro ligand efficacy, which is typically measured in heterologous expression systems, to the biological response in vivo, where the ligand is acting on natively expressed receptors and in the presence of the endogenous ligand. This is particularly true of arrestin pathway-selective 'biased' agonists. The type 1 parathyroid hormone receptor (PTH1R) is a case in point. Parathyroid hormone (PTH) is the principal physiological regulator of calcium homeostasis, and PTH1R expressed on cells of the osteoblast lineage are an established therapeutic target in osteoporosis. In vitro, PTH1R signaling is highly sensitive to ligand structure, and PTH analogs that affect the selectivity/kinetics of G protein coupling or that engage arrestin-dependent sig...Continue Reading

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Citations

Jun 28, 2017·Trends in Cell Biology·Ravi RanjanArun K Shukla
Mar 28, 2019·Pharmacological Reviews·Terry Kenakin
Dec 18, 2019·Pharmacological Reviews·Jhana O HendrickxStuart Maudsley
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Jul 6, 2021·Biochemical Pharmacology·Tianhong ChenJingfeng Li
Jul 31, 2021·Pharmacological Research : the Official Journal of the Italian Pharmacological Society·Alexander Kalinkovich, Gregory Livshits

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