Beta-arrestin- and G protein receptor kinase-mediated calcium-sensing receptor desensitization.

Published

Journal Article

Extracellular calcium rapidly controls PTH secretion through binding to the G protein-coupled calcium-sensing receptor (CASR) expressed in parathyroid glands. Very little is known about the regulatory proteins involved in desensitization of CASR. G protein receptor kinases (GRK) and beta-arrestins are important regulators of agonist-dependent desensitization of G protein-coupled receptors. In the present study, we investigated their role in mediating agonist-dependent desensitization of CASR. In heterologous cell culture models, we found that the transfection of GRK4 inhibits CASR signaling by enhancing receptor phosphorylation and beta-arrestin translocation to the CASR. In contrast, we found that overexpression of GRK2 desensitizes CASR by classical mechanisms as well as through phosphorylation-independent mechanisms involving disruption of Galphaq signaling. In addition, we observed lower circulating PTH levels and an attenuated increase in serum PTH after hypocalcemic stimulation in beta-arrestin2 null mice, suggesting a functional role of beta-arrestin2-dependent desensitization pathways in regulating CASR function in vivo. We conclude that GRKs and beta-arrestins play key roles in regulating CASR responsiveness in parathyroid glands.

Full Text

Duke Authors

Cited Authors

  • Pi, M; Oakley, RH; Gesty-Palmer, D; Cruickshank, RD; Spurney, RF; Luttrell, LM; Quarles, LD

Published Date

  • April 2005

Published In

Volume / Issue

  • 19 / 4

Start / End Page

  • 1078 - 1087

PubMed ID

  • 15637145

Pubmed Central ID

  • 15637145

Electronic International Standard Serial Number (EISSN)

  • 1944-9917

International Standard Serial Number (ISSN)

  • 0888-8809

Digital Object Identifier (DOI)

  • 10.1210/me.2004-0450

Language

  • eng