Biased agonism at the parathyroid hormone receptor: a demonstration of functional selectivity in bone metabolism.
'Biased agonism' refers to the ability of a ligand to selectively recruit different intracellular signaling proteins to elicit distinct phenotypic effects in cells. While conventional G protein-coupled receptor (GPCR) agonism and antagonism can be regarded as modulating the quantity of efficacy, functionally selective or 'biased' ligands qualitatively change the trafficking of information flowing across the plasma membrane. The concept of ligand directed signaling fundamentally raises the potential of pharmacologic agents with novel therapeutic profiles possessing improved therapeutic efficacy or reduced side effects. Currently, there is little experimental evidence that biased ligands offer advantages over conventional agonists/antagonists in vivo. Recent work examining biased agonism at the type I parathyroid hormone receptor (PTH1R) demonstrates that selective activation of G protein-independent arrestin-mediated signaling pathways elicits a physiologic response in bone distinct from that induced by the conventional PTH1R agonist PTH(1-34). While intermittent (daily) administration of PTH(1-34) (teriparitide) is effective in increasing bone formation, PTH(1-34) administration is also associated with increases in bone resorption and a propensity to promote hypercalcemia/hypercalcuria. In contrast, D-Trp12,Tyr34-bPTH(7-34) (PTH-βarr), an arrestin pathway-selective agonist for the PTH1R, induces anabolic bone formation independent of classic G protein-coupled signaling mechanisms. Unlike PTH(1-34), PTH-βarr appears to 'uncouple' the anabolic effects of PTH1R activation from its catabolic and calcitropic effects. Such findings offer evidence that arrestin pathway-selective GPCR agonists can elicit potentially beneficial effects in vivo that cannot be achieved using conventional agonist or antagonist ligands.
Department of Medicine, Division of Endocrinology and Metabolism, Duke University Medical Center, Durham, NC 27710, USA.
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D000818:Animals; D019390:Arrestins / Q000819:agonists* / Q000378:metabolism; D001862:Bone Resorption / Q000517:prevention & control; D001842:Bone and Bones / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D006934:Hypercalcemia / Q000139:chemically induced / Q000517:prevention & control; D053565:Hypercalciuria / Q000139:chemically induced / Q000517:prevention & control; D008024:Ligands; D051379:Mice; D010012:Osteogenesis / Q000187:drug effects* / Q000502:physiology; D010281:Parathyroid Hormone / Q000008:administration & dosage / Q000378:metabolism; D044162:Parathyroid Hormone-Related Protein / Q000008:administration & dosage* / Q000378:metabolism; D044168:Receptor, Parathyroid Hormone, Type 1 / Q000819:agonists* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
D019390:Arrestins; D008024:Ligands; D010281:Parathyroid Hormone; D044162:Parathyroid Hormone-Related Protein; D044168:Receptor, Parathyroid Hormone, Type 1