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

Mol Endocrinol. 2005 Apr;19(4):1078-87. doi: 10.1210/me.2004-0450. Epub 2005 Jan 6.

Abstract

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.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Arrestins / genetics
  • Arrestins / metabolism*
  • Calcium / metabolism
  • Calcium / pharmacology
  • Cells, Cultured
  • Down-Regulation
  • G-Protein-Coupled Receptor Kinase 4
  • Humans
  • Mice
  • Mice, Mutant Strains
  • Molecular Sequence Data
  • Mutation
  • Parathyroid Glands / metabolism*
  • Phosphorylation
  • Protein Transport
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism*
  • RNA, Messenger / analysis
  • RNA, Messenger / metabolism
  • Receptors, Calcium-Sensing / agonists*
  • Receptors, Calcium-Sensing / antagonists & inhibitors
  • Receptors, Calcium-Sensing / metabolism*
  • beta-Arrestins

Substances

  • Arrestins
  • RNA, Messenger
  • Receptors, Calcium-Sensing
  • beta-Arrestins
  • Protein-Serine-Threonine Kinases
  • G-Protein-Coupled Receptor Kinase 4
  • GRK4 protein, human
  • GRK4 protein, mouse
  • Calcium