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A beta-arrestin-biased agonist of the parathyroid hormone receptor (PTH1R) promotes bone formation independent of G protein activation.

Publication ,  Journal Article
Gesty-Palmer, D; Flannery, P; Yuan, L; Corsino, L; Spurney, R; Lefkowitz, RJ; Luttrell, LM
Published in: Sci Transl Med
October 7, 2009

About 40% of the therapeutic agents in use today exert their effects through seven-transmembrane receptors (7TMRs). When activated by ligands, these receptors trigger two pathways that independently transduce signals to the cell: one through heterotrimeric GTP-binding proteins (G proteins) and one through beta-arrestins; so-called biased agonists can selectively activate these distinct pathways. Here, we investigate selective activation of these pathways through the use of a biased agonist for the type 1 parathyroid hormone (PTH)-PTH-related protein receptor (PTH1R), (D-Trp(12),Tyr(34))-PTH(7-34) (PTH-betaarr), which activates beta-arrestin but not classic G protein signaling. In mice, PTH-betaarr induces anabolic bone formation, as does the nonselective agonist PTH(1-34), which activates both mechanisms. In beta-arrestin2-null mice, the increase in bone mineral density evoked by PTH(1-34) is attenuated and that stimulated by PTH-betaarr is ablated. The beta-arrestin2-dependent pathway contributes primarily to trabecular bone formation and does not stimulate bone resorption. These results show that a biased agonist selective for the beta-arrestin pathway can elicit a response in vivo distinct from that elicited by nonselective agonists. Ligands with these properties may form the basis for improved 7TMR-directed pharmacologic agents with enhanced therapeutic specificity.

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Published In

Sci Transl Med

DOI

EISSN

1946-6242

Publication Date

October 7, 2009

Volume

1

Issue

1

Start / End Page

1ra1

Location

United States

Related Subject Headings

  • beta-Arrestins
  • Signal Transduction
  • Receptor, Parathyroid Hormone, Type 1
  • Mice, Knockout
  • Mice
  • Male
  • GTP-Binding Proteins
  • Bone Development
  • Bone Density
  • Arrestins
 

Citation

APA
Chicago
ICMJE
MLA
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Gesty-Palmer, D., Flannery, P., Yuan, L., Corsino, L., Spurney, R., Lefkowitz, R. J., & Luttrell, L. M. (2009). A beta-arrestin-biased agonist of the parathyroid hormone receptor (PTH1R) promotes bone formation independent of G protein activation. Sci Transl Med, 1(1), 1ra1. https://doi.org/10.1126/scitranslmed.3000071
Gesty-Palmer, Diane, Pat Flannery, Ling Yuan, Leonor Corsino, Robert Spurney, Robert J. Lefkowitz, and Louis M. Luttrell. “A beta-arrestin-biased agonist of the parathyroid hormone receptor (PTH1R) promotes bone formation independent of G protein activation.Sci Transl Med 1, no. 1 (October 7, 2009): 1ra1. https://doi.org/10.1126/scitranslmed.3000071.
Gesty-Palmer D, Flannery P, Yuan L, Corsino L, Spurney R, Lefkowitz RJ, et al. A beta-arrestin-biased agonist of the parathyroid hormone receptor (PTH1R) promotes bone formation independent of G protein activation. Sci Transl Med. 2009 Oct 7;1(1):1ra1.
Gesty-Palmer, Diane, et al. “A beta-arrestin-biased agonist of the parathyroid hormone receptor (PTH1R) promotes bone formation independent of G protein activation.Sci Transl Med, vol. 1, no. 1, Oct. 2009, p. 1ra1. Pubmed, doi:10.1126/scitranslmed.3000071.
Gesty-Palmer D, Flannery P, Yuan L, Corsino L, Spurney R, Lefkowitz RJ, Luttrell LM. A beta-arrestin-biased agonist of the parathyroid hormone receptor (PTH1R) promotes bone formation independent of G protein activation. Sci Transl Med. 2009 Oct 7;1(1):1ra1.

Published In

Sci Transl Med

DOI

EISSN

1946-6242

Publication Date

October 7, 2009

Volume

1

Issue

1

Start / End Page

1ra1

Location

United States

Related Subject Headings

  • beta-Arrestins
  • Signal Transduction
  • Receptor, Parathyroid Hormone, Type 1
  • Mice, Knockout
  • Mice
  • Male
  • GTP-Binding Proteins
  • Bone Development
  • Bone Density
  • Arrestins