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

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
  • 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

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.
Realize the full power of the drug-disease research graph!

Choose Username:
Verify Password:
Enter Code Shown: