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β-arrestin-biased agonism at the parathyroid hormone receptor uncouples bone formation from bone resorption.

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 IPTH/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 messenger-dependent pathways. In vitro, D-Trp(12),Tyr(34)-bPTH(7-34) (PTH-βarr), 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.
AuthorsBrittany N Bohinc, Diane Gesty-Palmer
JournalEndocrine, metabolic & immune disorders drug targets (Endocr Metab Immune Disord Drug Targets) Vol. 11 Issue 2 Pg. 112-9 (Jun 2011) ISSN: 2212-3873 [Electronic] United Arab Emirates
PMID21476967 (Publication Type: Journal Article, Review)
Chemical References
  • Arrestins
  • Receptor, Parathyroid Hormone, Type 1
  • beta-Arrestins
Topics
  • Animals
  • Arrestins (metabolism, pharmacology)
  • Bone Resorption (etiology, metabolism)
  • Drug Partial Agonism
  • Humans
  • Mice
  • Models, Biological
  • Osteogenesis (drug effects)
  • Receptor, Parathyroid Hormone, Type 1 (agonists, antagonists & inhibitors)
  • Signal Transduction (drug effects)
  • beta-Arrestins

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