ß-arrestin-biased agonism at the parathyroid hormone receptor uncouples bone formation from bone resorption.
Endocr Metab Immune Disord Drug Targets
; 11(2): 112-9, 2011 Jun.
Article
em En
| MEDLINE
| ID: mdl-21476967
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. ß-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-ßarr), a ß-arrestin selective biased agonist for the PTH1R, antagonizes receptor-G protein coupling but activates arrestin-dependent signaling. In vivo, intermittent administration of, PTH-ßarr to mice, induces anabolic bone formation, completely independent of classic G protein-coupled signaling mechanisms. While both PTH-ßarr and the conventional agonist PTH(1-34) stimulate anabolic bone formation in mice, unlike PTH(1-34), which activates G protein coupling, PTH-ßarr does not induce hypercalcemia or increase markers of bone resorption. This newly recognized ability of ß-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 ß-arrestin biased agonism may offer therapeutic benefit for the treatment of metabolic bone diseases such as osteoporosis.
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Base de dados:
MEDLINE
Assunto principal:
Osteogênese
/
Reabsorção Óssea
/
Arrestinas
/
Receptor Tipo 1 de Hormônio Paratireóideo
Idioma:
En
Ano de publicação:
2011
Tipo de documento:
Article