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

• 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
• ISSN: 0888-8809; 1944-9917
• DOI: 10.1210/me.2004-0450

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.