β-arrestin-Biased Agonism at the Parathyroid Hormone Receptor Uncouples Bone Formation from Bone Resorption

Author(s): Brittany N. Bohinc , Diane Gesty-Palmer .

Journal Name: Endocrine, Metabolic & Immune Disorders - Drug Targets

Volume 11 , Issue 2 , 2011

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Abstract:

Parathyroid hormone (PTH) is a principle regulator of bone and calcium metabolism and PTH analogs hold great promise as a therapy for metabolic bone diseases such as osteoporosis. PTH acts principally through the type I PTH/PTH-related peptide receptor (PTH1R), a G protein-coupled receptor (GPCR). GPCRs are a family of seven transmembrane cell surface receptors that share conserved structural, functional, and regulatory properties. Recent studies demonstrate that the complex metabolic effects induced by PTH1R stimulation are not entirely a consequence of conventional GPCR signaling. β-arrestins, in addition to their GPCR desensitizing actions, also serve as multifunctional scaffolding proteins linking the PTH1R to signaling molecules independent of the classic G protein-coupled second messengerdependent pathways. In vitro, D-Trp12,Tyr34-bPTH(7-34) (PTH- arr), a β-arrestin selective biased agonist for the PTH1R, antagonizes receptor-G protein coupling but activates arrestin-dependent signaling. In vivo, intermittent administration of, PTH-βarr to mice, induces anabolic bone formation, completely independent of classic G protein-coupled signaling mechanisms. While both PTH-βarr and the conventional agonist PTH(1-34) stimulate anabolic bone formation in mice, unlike PTH(1-34), which activates G protein coupling, PTH-βarr does not induce hypercalcemia or increase markers of bone resorption. This newly recognized ability of β-arrestins to serve as signal transducers for the PTH1R represents an innovative paradigm of receptor signaling which can be targeted to induce a subset of physiologic responses in bone. Exploitation of β-arrestin biased agonism may offer therapeutic benefit for the treatment of metabolic bone diseases such as osteoporosis.

Keywords: β-arrestin, biased agonism, bone metabolism, G protein-coupled receptor, parathyroid hormone, parathyroid hormone receptor type 1, osteoporosis, bone-resorption, prostaglandins, anabolic therapies, amino acid peptide, parathyroid, hypercalcemia, heterotrimeric

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Article Details

VOLUME: 11
ISSUE: 2
Year: 2011
Page: [112 - 119]
Pages: 8
DOI: 10.2174/187153011795564151
Price: $58

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