β-Arrestin- and G Protein Receptor Kinase-Mediated Calcium-Sensing Receptor Desensitization

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 β-arrestins are...

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Bibliographic Details
Published in:Molecular endocrinology (Baltimore, Md.) Md.), 2005-04, Vol.19 (4), p.1078-1087
Main Authors: Pi, Min, Oakley, Robert H, Gesty-Palmer, Diane, Cruickshank, Rachael D, Spurney, Robert F, Luttrell, Louis M, Quarles, L. Darryl
Format: Article
Language:English
Subjects:
Amino Acid Sequence
Animals
Arrestins - genetics
Arrestins - metabolism
beta-Arrestins
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
Parathyroid Glands - secretion
Phosphorylation
Protein Transport
Protein-Serine-Threonine Kinases - genetics
Protein-Serine-Threonine Kinases - metabolism
Receptors, Calcium-Sensing - agonists
Receptors, Calcium-Sensing - antagonists & inhibitors
Receptors, Calcium-Sensing - metabolism
RNA, Messenger - analysis
RNA, Messenger - metabolism
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Summary: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 β-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 β-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 Gαq signaling. In addition, we observed lower circulating PTH levels and an attenuated increase in serum PTH after hypocalcemic stimulation in β-arrestin2 null mice, suggesting a functional role of β-arrestin2-dependent desensitization pathways in regulating CASR function in vivo. We conclude that GRKs and β-arrestins play key roles in regulating CASR responsiveness in parathyroid glands.
ISSN:0888-8809
1944-9917
DOI:10.1210/me.2004-0450